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Sample records for human colon tumor

  1. Negligible colon cancer risk from food-borne acrylamide exposure in male F344 rats and nude (nu/nu mice-bearing human colon tumor xenografts.

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    Jayadev Raju

    Full Text Available Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a "complete carcinogen", but acts as a "co-carcinogen" by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters.

  2. Study on therapy of 188Re labelled stannic sulfur suspension in nude mice bearing human colon tumor

    International Nuclear Information System (INIS)

    Li Huiyuan; Wu Yuanfang; Dong Mo

    2003-01-01

    The effect of therapy, tissue distribution and stability are studied in nude mice bearing human colon tumor after injections of 188 Re labelled stannic sulfur suspension. The tissues are observed with electric microscope. The results show that 188 Re labelled stannic sulfur suspension is stabilized in the tumor and its inhibitive effects on human colon tumor cells are obvious. 188 Re labelled stannic sulfur suspension is a potential radiopharmaceuticals for therapy of human tumor

  3. Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors.

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    Mei, Wenhan; Wang, Kemin; Huang, Jian; Zheng, Xinmin

    2016-01-01

    Expression of wild-type protein tyrosine phosphatase (PTP) 1B may act either as a tumor suppressor by dysregulation of protein tyrosine kinases or a tumor promoter through Src dephosphorylation at Y527 in human breast cancer cells. To explore whether mutated PTP1B is involved in human carcinogenesis, we have sequenced PTP1B cDNAs from human tumors and found splice mutations in ~20% of colon and thyroid tumors. The PTP1BΔE6 mutant expressed in these two tumor types and another PTP1BΔE5 mutant expressed in colon tumor were studied in more detail. Although PTP1BΔE6 revealed no phosphatase activity compared with wild-type PTP1B and the PTP1BΔE5 mutant, its expression induced oncogenic transformation of rat fibroblasts without Src activation, indicating that it involved signaling pathways independent of Src. The transformed cells were tumourigenic in nude mice, suggesting that the PTP1BΔE6 affected other molecule(s) in the human tumors. These observations may provide a novel therapeutic target for colon and thyroid cancer.

  4. Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice.

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    Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet F; Zepp, Jarod A; Karagkounis, Georgio; Martin, Bradley N; Zhou, Hao; Yu, Minjia; Liu, Xiuli; Huang, Emina; Fox, Paul L; Kalady, Matthew F; Markowitz, Sanford D; Li, Xiaoxia

    2015-12-01

    Single immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL-1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer. We performed RNA sequence analyses of pairs of colon tumor and nontumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRR(N86/102S), which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane (AOM) and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses. RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRR(ΔE8), in colorectal cancer tissues compared to paired nontumor tissues. SIGIRR(ΔE8) is not modified by complex glycans and is therefore retained in the cytoplasm-it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRR(ΔE8) interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in nontumor tissues it was found at the cell membrane. Mice that expressed SIGIRR(N86/102S) developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant mice expressed

  5. Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature.

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    Herrera, Mercedes; Islam, Abul B M M K; Herrera, Alberto; Martín, Paloma; García, Vanesa; Silva, Javier; Garcia, Jose M; Salas, Clara; Casal, Ignacio; de Herreros, Antonio García; Bonilla, Félix; Peña, Cristina

    2013-11-01

    Cancer-associated fibroblasts (CAF) actively participate in reciprocal communication with tumor cells and with other cell types in the microenvironment, contributing to a tumor-permissive neighborhood and promoting tumor progression. The aim of this study is the characterization of how CAFs from primary human colon tumors promote migration of colon cancer cells. Primary CAF cultures from 15 primary human colon tumors were established. Their enrichment in CAFs was evaluated by the expression of various epithelial and myofibroblast specific markers. Coculture assays of primary CAFs with different colon tumor cells were performed to evaluate promigratory CAF-derived effects on cancer cells. Gene expression profiles were developed to further investigate CAF characteristics. Coculture assays showed significant differences in fibroblast-derived paracrine promigratory effects on cancer cells. Moreover, the association between CAFs' promigratory effects on cancer cells and classic fibroblast activation or stemness markers was observed. CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different promigratory CAFs. The gene expression signature, derived from the most protumorogenic CAFs, was identified. Interestingly, this "CAF signature" showed a remarkable prognostic value for the clinical outcome of patients with colon cancer. Moreover, this prognostic value was validated in an independent series of 142 patients with colon cancer, by quantitative real-time PCR (qRT-PCR), with a set of four genes included in the "CAF signature." In summary, these studies show for the first time the heterogeneity of primary CAFs' effect on colon cancer cell migration. A CAF gene expression signature able to classify patients with colon cancer into high- and low-risk groups was identified.

  6. Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.

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    Selmin, Ornella I; Fang, Changming; Lyon, Adam M; Doetschman, Tom C; Thompson, Patricia A; Martinez, Jesse D; Smith, Jeffrey W; Lance, Peter M; Romagnolo, Donato F

    2016-02-01

    The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. Normal proximal colonic mucosa and normal-appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxrα3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (∼50%) FXR expression, which was further reduced (∼80%) by DCA. In human HCT-116 but not HT-29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells

  7. Imaging analysis of colonic villous tumors

    International Nuclear Information System (INIS)

    Lee, Choon Hyeong; Lim, Joo Won; Lee, Dong Ho; Ko, Yung Tae; Yang, Ik

    1996-01-01

    To evaluate the CT and US features of the colonic villous tumors. We retrospectively reviewed the CT findings of 11 cases with histologically proved colonic villous tumor. CT parameters evaluated were morphological appearances and enhancing pattern (size, shape, margin, presence or absence of fronds, bowel wall thickening). CT features of six cases with malignant change were compared with five tumors without malignant change. US features available in 10 patients were also analyzed. On CT, the tumors showed irregular margin(n=9), presence of fronds(n=6), lobulated shape(n=11), with pericolonic invasion(n=1). Six cases with malignant change were larger(mean, 6.8 cm in diameter) than those without malignant change(mean, 3.3cm). US features in 10 cases were intraluminal mass(n=5), colonic wall thickening(n=5), with variable echogenicity. Colonic villous tumor appeared as a nonspecific mass on CT and US with a difficulty in distinguishing from colon carcinoma

  8. Diet-induced obesity promotes colon tumor development in azoxymethane-treated mice.

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    Iina Tuominen

    Full Text Available Obesity is an important risk factor for colon cancer in humans, and numerous studies have shown that a high fat diet enhances colon cancer development. As both increased adiposity and high fat diet can promote tumorigenesis, we examined the effect of diet-induced obesity, without ongoing high fat diet, on colon tumor development. C57BL/6J male mice were fed regular chow or high fat diet for 8 weeks. Diets were either maintained or switched resulting in four experimental groups: regular chow (R, high fat diet (H, regular chow switched to high fat diet (RH, and high fat diet switched to regular chow (HR. Mice were then administered azoxymethane to induce colon tumors. Tumor incidence and multiplicity were dramatically smaller in the R group relative to all groups that received high fat diet at any point. The effect of obesity on colon tumors could not be explained by differences in aberrant crypt foci number. Moreover, diet did not alter colonic expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, interleukin-1β, and interferon-γ, which were measured immediately after azoxymethane treatment. Crypt apoptosis and proliferation, which were measured at the same time, were increased in the HR relative to all other groups. Our results suggest that factors associated with obesity - independently of ongoing high fat diet and obesity - promote tumor development because HR group animals had significantly more tumors than R group, and these mice were fed the same regular chow throughout the entire carcinogenic period. Moreover, there was no difference in the number of aberrant crypt foci between these groups, and thus the effect of obesity appears to be on subsequent stages of tumor development when early preneoplastic lesions transition into adenomas.

  9. 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.

    LENUS (Irish Health Repository)

    Yan, Min

    2009-06-09

    Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib\\'s anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.

  10. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells.

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    Lugini, Luana; Valtieri, Mauro; Federici, Cristina; Cecchetti, Serena; Meschini, Stefania; Condello, Maria; Signore, Michele; Fais, Stefano

    2016-08-02

    Cancer cells, including colorectal cancer ones (CRC), release high amounts of nanovesicles (exosomes), delivering biochemical messages for paracrine or systemic crosstalk. Mesenchymal stromal cells (MSCs) have been shown to play contradicting roles in tumor progression. CRC exosomes induce in cMSCs: i) atypical morphology, higher proliferation, migration and invasion; ii) formation of spheroids; iii) an acidic extracellular environment associated with iv) a plasma membrane redistribution of vacuolar H+-ATPase and increased expression of CEA. Colon cancer derived MSCs, which were isolated from tumor masses, produce umbilicated spheroids, a future frequently observed in the inner core of rapidly growing tumors and recapitulate the changes observed in normal colonic MSCs exposed to CRC exosomes. Tissue specific colonic (c)MSCs were exposed to primary or metastatic CRC exosomes and analysed by light and electron microscopy, proliferation in 2D and 3D cultures, migration and invasion assays, Western blot and confocal microscopy for vacuolar H+-ATPase expression. CRC exosomes are able to induce morphological and functional changes in colonic MSCs, which may favour tumor growth and its malignant progression. Our results suggest that exosomes are actively involved in cancer progression and that inhibiting tumor exosome release may represent a way to interfere with cancer.

  11. A simple, quantitative method using alginate gel to determine rat colonic tumor volume in vivo.

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    Irving, Amy A; Young, Lindsay B; Pleiman, Jennifer K; Konrath, Michael J; Marzella, Blake; Nonte, Michael; Cacciatore, Justin; Ford, Madeline R; Clipson, Linda; Amos-Landgraf, James M; Dove, William F

    2014-04-01

    Many studies of the response of colonic tumors to therapeutics use tumor multiplicity as the endpoint to determine the effectiveness of the agent. These studies can be greatly enhanced by accurate measurements of tumor volume. Here we present a quantitative method to easily and accurately determine colonic tumor volume. This approach uses a biocompatible alginate to create a negative mold of a tumor-bearing colon; this mold is then used to make positive casts of dental stone that replicate the shape of each original tumor. The weight of the dental stone cast correlates highly with the weight of the dissected tumors. After refinement of the technique, overall error in tumor volume was 16.9% ± 7.9% and includes error from both the alginate and dental stone procedures. Because this technique is limited to molding of tumors in the colon, we utilized the Apc(Pirc/+) rat, which has a propensity for developing colonic tumors that reflect the location of the majority of human intestinal tumors. We have successfully used the described method to determine tumor volumes ranging from 4 to 196 mm³. Alginate molding combined with dental stone casting is a facile method for determining tumor volume in vivo without costly equipment or knowledge of analytic software. This broadly accessible method creates the opportunity to objectively study colonic tumors over time in living animals in conjunction with other experiments and without transferring animals from the facility where they are maintained.

  12. The intraportal injection model: A practical animal model for hepatic metastases and tumor cell dissemination in human colon cancer

    International Nuclear Information System (INIS)

    Thalheimer, Andreas; Waaga-Gasser, Ana M; Otto, Christoph; Bueter, Marco; Illert, Bertram; Gattenlohner, Stefan; Gasser, Martin; Meyer, Detlef; Fein, Martin; Germer, Christoph T

    2009-01-01

    The development of new therapeutic strategies for treatment of metastasized colorectal carcinoma requires biologically relevant and adequate animal models that generate both reproducible metastasis and the dissemination of tumor cells in the form of so-called minimal residual disease (MRD), an expression of the systemic character of neoplastic disease. We injected immunoincompetent nude mice intraportally with different numbers (1 × 10 5 , 1 × 10 6 and 5 × 10 6 cells) of the human colon carcinoma cell lines HT-29 and SW-620 and investigated by histological studies and CK-20 RT-PCR the occurrence of hematogenous metastases and the dissemination of human tumor cells in bone marrow. Only the injection of 1 × 10 6 cells of each colon carcinoma cell line produced acceptable perioperative mortality with reproducible induction of hepatic metastases in up to 89% of all animals. The injection of 1 × 10 6 cells also generated tumor cell dissemination in the bone marrow in up to 63% of animals with hepatic metastases. The present intraportal injection model in immunoincompetent nude mice represents a biologically relevant and adequate animal model for the induction of both reproducible hepatic metastasis and tumor cell dissemination in the bone marrow as a sign of MRD

  13. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4.

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    Todaro, Matilde; Alea, Mileidys Perez; Di Stefano, Anna B; Cammareri, Patrizia; Vermeulen, Louis; Iovino, Flora; Tripodo, Claudio; Russo, Antonio; Gulotta, Gaspare; Medema, Jan Paul; Stassi, Giorgio

    2007-10-11

    A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD133(+) cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immunodeficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133(+) cells. Further analysis revealed that the CD133(+) cells produce and utilize IL-4 to protect themselves from apoptosis. Consistently, treatment with IL-4Ralpha antagonist or anti-IL-4 neutralizing antibody strongly enhances the antitumor efficacy of standard chemotherapeutic drugs through selective sensitization of CD133(+) cells. Our data suggest that colon tumor growth is dictated by stem-like cells that are treatment resistant due to the autocrine production of IL-4.

  14. PREOPERATIVE ENDOSCOPIC MARKING OF UNPALPABLE COLONIC TUMORS

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    A. L. Goncharov

    2013-01-01

    Full Text Available The identification of small colon lesions is one of the major problems in laparoscopic colonic resection.Research objective: to develop a technique of visualization of small tumors of a colon by preoperative endoscopic marking of a tumor.Materials and methods. In one day prior to operation to the patient after bowel preparation the colonoscopy is carried out. In the planned point near tumor on antimesentery edge the submucous infiltration of marking solution (Micky Sharpz blue tattoo pigment, UK is made. The volume of entered solution of 1–3 ml. In only 5 months of use of a technique preoperative marking to 14 patients with small (the size of 1–3 cm malignant tumors of the left colon is performed.Results. The tattoo mark was well visualized by during operation at 13 of 14 patients. In all cases we recorded no complications. Time of operation with preoperative marking averaged 108 min, that is significantly less in comparison with average time of operation with an intra-operative colonoscopy – 155 min (р < 0.001.Conclusions. The first experience of preoperative endoscopic marking of non palpable small tumors of a colon is encouraging. Performance of a technique wasn't accompanied by complications and allowed to reduce significantly time of operation and to simplify conditions of performance of operation.

  15. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4

    NARCIS (Netherlands)

    Todaro, Matilde; Alea, Mileidys Perez; Di Stefano, Anna B.; Cammareri, Patrizia; Vermeulen, Louis; Iovino, Flora; Tripodo, Claudio; Russo, Antonio; Gulotta, Gaspare; Medema, Jan Paul; Stassi, Giorgio

    2007-01-01

    A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The

  16. Transverse colon cancer with Krukenberg tumor : A case report

    OpenAIRE

    東門, 敦子; 松原, 洋孝; 下地, 英明; 伊佐, 勉; 濱安, 俊吾; 仲地, 厚; 宮里, 浩; 白石, 祐之; 武藤, 良弘; Tomon, Atsuko; Matsubara, Hirotaka; Shimoji, Hideaki; Isa, Tsutomu; Nakachi, Atsushi; Miyazato, Hiroshi

    1999-01-01

    A case of Krukenberg tumor in a 30-year-old woman with transverse colon cancer is reported herein. The patient was found to have bilateral ovarian tumors and abnormal elevation of serum CEA at a community hospital. Subsequently, she was referred to the University Hospital for further work. Diagnostic examinations including US, CT and colonoscopy demonstrated transverse colon cancer and bilateral ovarian tumors. Exploratory laparotomy showed the growth of transverse colon cancer over the perit...

  17. Complement 5a stimulates macrophage polarization and contributes to tumor metastases of colon cancer.

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    Piao, Chunmei; Zhang, Wen-Mei; Li, Tao-Tao; Zhang, Cong-Cong; Qiu, Shulan; Liu, Yan; Liu, Sa; Jin, Ming; Jia, Li-Xin; Song, Wen-Chao; Du, Jie

    2018-05-15

    Inflammatory cells such as macrophages can play a pro-tumorigenic role in the tumor stroma. Tumor-associated macrophages (TAMs) generally display an M2 phenotype with tumor-promoting activity; however, the mechanisms regulating the TAM phenotype remain unclear. Complement 5a (C5a) is a cytokine-like polypeptide that is generated during complement system activation and is known to promote tumor growth. Herein, we investigated the role of C5a on macrophage polarization in colon cancer metastasis in mice. We found that deficiency of the C5a receptor (C5aR) severely impairs the metastatic ability of implanted colon cancer cells. C5aR was expressed on TAMs, which exhibited an M2-like functional profile in colon cancer liver metastatic lesions. Furthermore, C5a mediated macrophage polarization and this process relied substantially on activation of the nuclear factor-kappa B (NF-κB) pathway. Finally, analysis of human colon carcinoma indicated that C5aR expression is negatively associated with tumor differentiation grade. Our results demonstrate that C5aR has a central role in regulating the M2 phenotype of TAMs, which in turn, contributes to hepatic metastasis of colon cancer through NF-κB signaling. C5a is a potential novel marker for cancer prognosis and drugs targeting complement system activation, specifically the C5aR pathway, may offer new therapeutic opportunities for colon cancer management. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals

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    A. Alicia Koblansky

    2016-03-01

    Full Text Available NOD-like receptor (NLR proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1−/− mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB, mitogen-activated protein kinase (MAPK, signal transducer and activator of transcription 3 (STAT3, and interleukin 6 (IL-6. The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apcmin/+ genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apcmin/+ colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1−/−Apcmin/+ mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.

  19. Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation on Tumor-Associated Endothelial Cells Leads to Treatment of Orthotopic Human Colon Cancer in Nude Mice

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    Takamitsu Sasaki

    2007-12-01

    Full Text Available The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR and vascular endothelial growth factor receptor (VEGFR signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-α and vascular endothelial growth factor (VEGF but were negative for EGFR, human epidermal growth factor receptor 2 (HER2, VEGFR. Double immunofluorescence staining revealed that tumorassociated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR, phosphorylated VEGFR (pVEGFR. Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01; this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001. AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, increased the level of apoptosis in both tumorassociated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer.

  20. FXR silencing in human colon cancer by DNA methylation and KRAS signaling.

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    Bailey, Ann M; Zhan, Le; Maru, Dipen; Shureiqi, Imad; Pickering, Curtis R; Kiriakova, Galina; Izzo, Julie; He, Nan; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Liang, Han; Kopetz, Scott; Powis, Garth; Guo, Grace L

    2014-01-01

    Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

  1. Characterization and significance of ACE2 and Mas receptor in human colon adenocarcinoma.

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    Bernardi, Stella; Zennaro, Cristina; Palmisano, Silvia; Velkoska, Elena; Sabato, Nicoletta; Toffoli, Barbara; Giacomel, Greta; Buri, Luigi; Zanconati, Fabrizio; Bellini, Giuseppe; Burrell, Louise M; De Manzini, Nicolò; Fabris, Bruno

    2012-03-01

    A new arm of the renin-angiotensin system (RAS) has been recently characterized; this includes angiotensin converting enzyme (ACE)2 and angiotensin (Ang)1-7, a heptapeptide acting through the Mas receptor (MasR). Recent studies show that Ang1-7 has an antiproliferative action on lung adenocarcinoma cells. The aim of this study was to characterize RAS expression in human colon adenocarcinoma and to investigate whether Ang1-7 exerts an antiproliferative effect on human colon adenocarcinoma cells. Gene, protein expression and enzymatic activity of the main components of the RAS were determined on non-neoplastic colon mucosa as well as on the tumor mass and the mucosa taken 5 cm distant from it, both collected from patients with colon adenocarcinoma. Two different human colon cancer cell lines were treated with AngII and Ang1-7. The novel finding of this study was that MasR was significantly upregulated in colon adenocarcinoma compared with non-neoplastic colon mucosa, which showed little or no expression of it. ACE gene expression and enzymatic activity were also increased in the tumors. However, AngII and Ang1-7 did not have any pro-/antiproliferative effects in the cell lines studied. The data suggest that upregulation of the MasR could be used as a diagnostic marker of colon adenocarcinoma.

  2. Colon and rectal cancer survival by tumor location and microsatellite instability: the Colon Cancer Family Registry.

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    Phipps, Amanda I; Lindor, Noralane M; Jenkins, Mark A; Baron, John A; Win, Aung Ko; Gallinger, Steven; Gryfe, Robert; Newcomb, Polly A

    2013-08-01

    Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability. We assessed the differences in survival by colon or rectal cancer site, considering the contribution of microsatellite instability to such differences. This is a population-based prospective cohort study for cancer survival. This study was conducted within the Colon Cancer Family Registry, an international consortium. Participants were identified from population-based cancer registries in the United States, Canada, and Australia. Information on tumor site, microsatellite instability, and survival after diagnosis was available for 3284 men and women diagnosed with incident invasive colon or rectal cancer between 1997 and 2002, with ages at diagnosis ranging from 18 to 74. Cox regression was used to calculate hazard ratios for the association between all-cause mortality and tumor location, overall and by microsatellite instability status. Distal colon (HR, 0.59; 95% CI, 0.49-0.71) and rectal cancers (HR, 0.68; 95% CI, 0.57-0.81) were associated with lower mortality than proximal colon cancer overall. Compared specifically with patients with proximal colon cancer exhibiting no/low microsatellite instability, patients with distal colon and rectal cancers experienced lower mortality, regardless of microsatellite instability status; patients with proximal colon cancer exhibiting high microsatellite instability had the lowest mortality. Study limitations include the absence of stage at diagnosis and cause-of-death information for all but a subset of study participants. Some patient groups defined jointly by tumor site and microsatellite instability status are subject to small numbers. Proximal colon cancer survival differs from survival for distal colon and rectal cancer in a manner apparently dependent on microsatellite instability status. These

  3. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    Science.gov (United States)

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (Pcolon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  4. Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

    Science.gov (United States)

    Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

    2017-09-18

    Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

  5. Identifying colon cancer risk modules with better classification performance based on human signaling network.

    Science.gov (United States)

    Qu, Xiaoli; Xie, Ruiqiang; Chen, Lina; Feng, Chenchen; Zhou, Yanyan; Li, Wan; Huang, Hao; Jia, Xu; Lv, Junjie; He, Yuehan; Du, Youwen; Li, Weiguo; Shi, Yuchen; He, Weiming

    2014-10-01

    Identifying differences between normal and tumor samples from a modular perspective may help to improve our understanding of the mechanisms responsible for colon cancer. Many cancer studies have shown that signaling transduction and biological pathways are disturbed in disease states, and expression profiles can distinguish variations in diseases. In this study, we integrated a weighted human signaling network and gene expression profiles to select risk modules associated with tumor conditions. Risk modules as classification features by our method had a better classification performance than other methods, and one risk module for colon cancer had a good classification performance for distinguishing between normal/tumor samples and between tumor stages. All genes in the module were annotated to the biological process of positive regulation of cell proliferation, and were highly associated with colon cancer. These results suggested that these genes might be the potential risk genes for colon cancer. Copyright © 2013. Published by Elsevier Inc.

  6. CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors

    Science.gov (United States)

    Shmelkov, Sergey V.; Butler, Jason M.; Hooper, Andrea T.; Hormigo, Adilia; Kushner, Jared; Milde, Till; St. Clair, Ryan; Baljevic, Muhamed; White, Ian; Jin, David K.; Chadburn, Amy; Murphy, Andrew J.; Valenzuela, David M.; Gale, Nicholas W.; Thurston, Gavin; Yancopoulos, George D.; D’Angelica, Michael; Kemeny, Nancy; Lyden, David; Rafii, Shahin

    2008-01-01

    Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10–/–CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133– population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133– metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133– cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24–), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic

  7. Absceso de pared abdominal por tumor maligno de colon transverso.

    OpenAIRE

    Morales Polanco, Sergio; Díaz Rosales, Juan de Dios; Arenas Valles, Jorge

    2017-01-01

    Introduction: Colon cancer is one of the most frequent and mortal digestive tumors. Complications of this disease could be several and in a few cases, could be rare and infrequent. This article present a case of patient with an abdominal wall abscess due to a malignant transverse colonic tumor. Clinic presentation: Male 56 years-old patient with sepsis and a mass in left superior quadrant on abdomen. The patient was underwent to exploratory laparotomy and findings were a large tumor in transv...

  8. Polar solvent modification of x ray induced potentially lethal damage in heterogeneous human colon tumor cells in vitro

    International Nuclear Information System (INIS)

    Arundel, C.M.; Leith, J.T.; Dexter, D.L.; Glicksman, A.S.

    1984-01-01

    Two subpopulations of tumor cells (clones A and D) obtained from a human colon adenocarcinoma were examined for their sensitivities to x-irradiation as unfed, early plateau phase cultures. Both the single dose survival curves and the kinetics of potentially lethal damage recovery (PLDR) were determined for the two tumor lines. Also, possible modification of PLDR by N,N-dimethylformamide (DMF), which has previously been shown to enhance the radiosensitivity of exponentially growing tumor cells, was investigated by adding DMF (0.8% v/v) to plateau phase cultures immediately after irradiation, and determining effects on the extent of PLDR. For non-DMF treated cells, the survival curve parameters of the diploid (clone D) and aneuploid (clone A) lines were very similar. Using initial survival levels of 3.5% (clone D) or 5.5% (clone A) to investigate PLDR, it was found that the increase in survival for clone D was 2.2, while the SFR for clone A was 1.6. DMF did not change either the kinetics or extent of PLDR in these two tumor lines when added to cultures immediately after irradiation. These results indicate that significant heterogeneity in PLDR exists between these closely related tumor subpopulations

  9. Rhein induces apoptosis of HCT-116 human colon cancer cells via ...

    African Journals Online (AJOL)

    Rhein, a major compound in rhubarb, has been found to have anti-tumor properties in many human cancer cells. However, the details about rhein suppressing the growth of human colon cancer cells remained elusive. In this paper, we explored the potential of rhein as a chemotherapeutic agent on HCT- 116 cells and ...

  10. Promoter hypermethylation mediated downregulation of FBP1 in human hepatocellular carcinoma and colon cancer.

    Directory of Open Access Journals (Sweden)

    Mingquan Chen

    Full Text Available FBP1, fructose-1,6-bisphosphatase-1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. The mechanism that it functions to antagonize glycolysis and was epigenetically inactivated through NF-kappaB pathway in gastric cancer has been reported. However, its role in the liver carcinogenesis still remains unknown. Here, we investigated the expression and DNA methylation of FBP1 in primary HCC and colon tumor. FBP1 was lowly expressed in 80% (8/10 human hepatocellular carcinoma, 66.7% (6/9 liver cancer cell lines and 100% (6/6 colon cancer cell lines, but was higher in paired adjacent non-tumor tissues and immortalized normal cell lines, which was well correlated with its promoter methylation status. Methylation was further detected in primary HCCs, gastric and colon tumor tissues, but none or occasionally in paired adjacent non-tumor tissues. Detailed methylation analysis of 29 CpG sites at a 327-bp promoter region by bisulfite genomic sequencing confirmed its methylation. FBP1 silencing could be reversed by chemical demethylation treatment with 5-aza-2'-deoxycytidine (Aza, indicating direct epigenetic silencing. Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest. Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS generation. In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer. FBP1 appears to be a functional tumor suppressor involved in the liver and colon carcinogenesis.

  11. Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation.

    Science.gov (United States)

    Le Rolle, Anne-France; Chiu, Thang K; Zeng, Zhaoshi; Shia, Jinru; Weiser, Martin R; Paty, Philip B; Chiu, Vi K

    2016-01-19

    Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer.

  12. Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

    Directory of Open Access Journals (Sweden)

    Cheng M

    2014-12-01

    Full Text Available Michelle Cheng,1,* Samantha Ho,1,* Jun Hwan Yoo,1,2,* Deanna Hoang-Yen Tran,1,* Kyriaki Bakirtzi,1 Bowei Su,1 Diana Hoang-Ngoc Tran,1 Yuzu Kubota,1 Ryan Ichikawa,1 Hon Wai Koon1 1Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Republic of Korea *These authors share co-first authorship Background: Cathelicidin (LL-37 in humans and mCRAMP in mice represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-ß1-induced EMT of colon cancer cells. Media conditioned by the

  13. CRH promotes human colon cancer cell proliferation via IL-6/JAK2/STAT3 signaling pathway and VEGF-induced tumor angiogenesis.

    Science.gov (United States)

    Fang, Xianjun; Hong, Yali; Dai, Li; Qian, Yuanyuan; Zhu, Chao; Wu, Biao; Li, Shengnan

    2017-11-01

    Corticotrophin-releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis-associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH-treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin-6 (IL-6) and vascular endothelial growth factor (VEGF) through activating nuclear factor-kappa B (NF-κB). The CRH-induced IL-6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH-induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF-κB/IL-6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF-κB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer. © 2017 Wiley Periodicals, Inc.

  14. Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors.

    Science.gov (United States)

    Sweeney, Carol; Boucher, Kenneth M; Samowitz, Wade S; Wolff, Roger K; Albertsen, Hans; Curtin, Karen; Caan, Bette J; Slattery, Martha L

    2009-01-01

    Our understanding of somatic alterations in colon cancer has evolved from a concept of a series of events taking place in a single sequence to a recognition of multiple pathways. An oncogenetic tree is a model intended to describe the pathways and sequence of somatic alterations in carcinogenesis without assuming that tumors will fall in mutually exclusive categories. We applied this model to data on colon tumor somatic alterations. An oncogenetic tree model was built using data on mutations of TP53, KRAS2, APC, and BRAF genes, methylation at CpG sites of MLH1 and TP16 genes, methylation in tumor (MINT) markers, and microsatellite instability (MSI) for 971 colon tumors from a population-based series. Oncogenetic tree analysis resulted in a reproducible tree with three branches. The model represents methylation of MINT markers as initiating a branch and predisposing to MSI, methylation of MHL1 and TP16, and BRAF mutation. APC mutation is the first alteration in an independent branch and is followed by TP53 mutation. KRAS2 mutation was placed a third independent branch, implying that it neither depends on, nor predisposes to, the other alterations. Individual tumors were observed to have alteration patterns representing every combination of one, two, or all three branches. The oncogenetic tree model assumptions are appropriate for the observed heterogeneity of colon tumors, and the model produces a useful visual schematic of the sequence of events in pathways of colon carcinogenesis.

  15. Circumvention and reactivation of the p53 oncogene checkpoint in mouse colon tumors.

    Science.gov (United States)

    Aizu, Wataru; Belinsky, Glenn S; Flynn, Christopher; Noonan, Emily J; Boes, Colleen C; Godman, Cassandra A; Doshi, Bindi; Nambiar, Prashant R; Rosenberg, Daniel W; Giardina, Charles

    2006-10-16

    The p53 tumor suppressor protein is sequence-normal in azoxymethane (AOM)-induced mouse colon tumors, making them a good model for human colon cancers that retain a wild type p53 gene. Cellular localization and co-immunoprecipitation experiments using a cell line derived from an AOM-induced colon tumor (AJ02-NM(0) cells) pointed to constitutively expressed Mdm2 as being an important negative regulator of p53 in these cells. Although the Mdm2 inhibitory protein p19/ARF was expressed in AJ02-NM(0) cells, its level of expression was not sufficient for p53 activation. We tested the response of AJ02-NM(0) cells to the recently developed Mdm2 inhibitor, Nutlin-3. Nutlin-3 was found to activate p53 DNA binding in AJ02-NM(0) cells, to a level comparable to doxorubicin and 5-fluorouracil (5-FU). In addition, Nutlin-3 increased expression of the p53 target genes Bax and PERP to a greater extent than doxorubicin or 5-FU, and triggered a G2/M phase arrest in these cells, compared to a G1 arrest triggered by doxorubicin and 5-FU. The differences in the cellular response may be related to differences in the kinetics of p53 activation and/or its post-translational modification status. In an ex vivo experiment, Nutlin-3 was found to activate p53 target gene expression and apoptosis in AOM-induced tumor tissue, but not in normal adjacent mucosa. Our data indicate that Mdm2 inhibitors may be an effective means of selectively targeting colon cancers that retain a sequence-normal p53 gene while sparing normal tissue and that the AOM model is an appropriate model for the preclinical development of these drugs.

  16. The G-protein coupled chemoattractant receptor FPR2 promotes malignant phenotype of human colon cancer cells

    Science.gov (United States)

    Xiang, Yi; Yao, Xiaohong; Chen, Keqiang; Wang, Xiafei; Zhou, Jiamin; Gong, Wanghua; Yoshimura, Teizo; Huang, Jiaqiang; Wang, Rongquan; Wu, Yuzhang; Shi, Guochao; Bian, Xiuwu; Wang, Jiming

    2016-01-01

    The G-protein coupled chemoattractant receptor formylpeptide receptor-2 (FPR2 in human, Fpr2 in mice) is expressed by mouse colon epithelial cells and plays a critical role in mediating mucosal homeostasis and inflammatory responses. However, the biological role of FPR2 in human colon is unclear. Our investigation revealed that a considerable number of human colon cancer cell lines expressed FPR2 and its ligands promoted cell migration and proliferation. Human colon cancer cell lines expressing high levels of FPR2 also formed more rapidly growing tumors in immunocompromised mice as compared with cell lines expressing lower levels of FPR2. Knocking down of FPR2 from colon cancer cell lines highly expressing FPR2 reduced their tumorigenicity. Clinically, FPR2 is more highly expressed in progressive colon cancer, associated with poorer patient prognosis. These results suggest that FPR2 can be high-jacked by colon cancer cells for their growth advantage, thus becoming a potential target for therapeutic development. PMID:27904774

  17. Regional and systemic distribution of anti-tumor x anti-CD3 heteroaggregate antibodies and cultured human peripheral blood lymphocytes in a human colon cancer xenograft

    International Nuclear Information System (INIS)

    Nelson, H.; Ramsey, P.S.; Kerr, L.A.; McKean, D.J.; Donohue, J.H.

    1990-01-01

    Anti-tumor antibody (317G5) covalently coupled to an anti-CD3 antibody (OKT3) produces a heteroaggregate (HA) antibody that can target PBL to lyse tumor cells expressing the appropriate tumor Ag. The i.v. and i.p. distribution of radiolabeled HA antibody 317G5 x OKT3 and of radiolabeled cultured human PBL were studied in athymic nude mice bearing solid intraperitoneal tumor established from the human colon tumor line, LS174T. Mice were injected with 125I-labeled HA antibody, 125I-labeled anti-tumor mAb, or 111In-labeled PBL, and at designated timepoints tissues were harvested and measured for radioactivity. 125I-317G5 x OKT3 localized specifically to tumor sites. Tumor radioactivity levels (percent injected dose/gram) were lower with 125I-317G5 x OKT3 HA antibody than with 125I-317G5 anti-tumor mAb, but were similar to levels reported for other anti-tumor mAb. The major difference in radioactivity levels observed between i.v. and i.p. administration of 125I-317G5 x OKT3 was an increase in hepatic radioactivity after i.v. HA antibody administration. HA antibodies produced from F(ab')2 fragments, which exhibit decreased m. w. and decreased Fc receptor-mediated binding, demonstrated improved tumor:tissue ratios as compared to intact antibody HA. 125I-317G5 F(ab')2 x OKT3 F(ab')2 antibody levels were equivalent to intact HA antibody levels in tumor, but were lower than intact HA antibody levels in the blood, bowel, and liver. Tumor:bowel ratios (20:1 at 48 h) were highest when 317G5 F(ab')2 x OKT3 F(ab')2 was injected i.p. Autoradiography confirmed that anti-tumor x anti-CD3 HA antibodies localized specifically to intraperitoneal tumor; that i.p. administered HA antibodies penetrated tumor directly; and that i.v. administered HA antibodies distributed along tumor vasculature

  18. shRNA-Mediated XRCC2 Gene Knockdown Efficiently Sensitizes Colon Tumor Cells to X-ray Irradiation in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Qin Wang

    2014-01-01

    Full Text Available Colon cancer is one of the most common tumors of the digestive tract. Resistance to ionizing radiation (IR decreased therapeutic efficiency in these patients’ radiotherapy. XRCC2 is the key protein of DNA homologous recombination repair, and its high expression is associated with enhanced resistance to DNA damage induced by IR. Here, we investigated the effect of XRCC2 silencing on colon tumor cells’ growth and sensitivity to X-radiation in vitro and in vivo. Colon tumor cells (T84 cell line were cultivated in vitro and tumors originated from the cell line were propagated as xenografts in nude mice. The suppression of XRCC2 expression was achieved by using vector-based short hairpin RNA (shRNA in T84 cells. We found that the knockdown of XRCC2 expression effectively decreased T84 cellular proliferation and colony formation, and led to cell apoptosis and cell cycle arrested in G2/M phase induced by X-radiation in vitro. In addition, tumor xenograft studies suggested that XRCC2 silencing inhibited tumorigenicity after radiation treatment in vivo. Our data suggest that the suppression of XRCC2 expression rendered colon tumor cells more sensitive to radiation therapy in vitro and in vivo, implying XRCC2 as a promising therapeutic target for the treatment of radioresistant human colon cancer.

  19. Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition

    International Nuclear Information System (INIS)

    Hackl, Christina; Stoeltzing, Oliver; Lang, Sven A; Moser, Christian; Mori, Akira; Fichtner-Feigl, Stefan; Hellerbrand, Claus; Dietmeier, Wolfgang; Schlitt, Hans J; Geissler, Edward K

    2010-01-01

    Activating transcription factor-3 (ATF3) is involved in the complex process of cellular stress response. However, its exact role in cancer is discussed controversially because both tumor suppressive and oncogenic effects have been described. Here we followed-up on our previous observation that inhibition of Hsp90 may increase ATF3 expression and sought to determine the role of ATF3 in colon cancer. Regulation of ATF3 was determined in cancer cells using signaling inhibitors and a heat-shock protein-90 (Hsp90) antagonist. Human HCT116 cancer cells were stably transfected with an ATF3-shRNA or a luciferase-shRNA expression plasmid and alterations in cell motility were assessed in migration assays. The impact of ATF3 down-regulation on cancer growth and metastasis were investigated in a subcutaneous tumor model, a model of hepatic tumor growth and in a model of peritoneal carcinomatosis. Human colon cancer tissues were analyzed for ATF3 expression. The results show that therapeutic Hsp90 inhibition substantially up-regulates the expression of ATF3 in various cancer cells, including colon, gastric and pancreatic cancer. This effect was evident both in vitro and in vivo. RNAi mediated knock-down of ATF3 in HCT116 colon cancer cells significantly increased cancer cell migration in vitro. Moreover, in xenogenic mouse models, ATF3 knock-down promoted subcutaneous tumor growth and hepatic metastasis, as well as peritoneal carcinomatosis. Importantly, ATF3 expression was lower in human colon cancer specimens, as compared to corresponding normal surrounding tissues, suggesting that ATF3 may represent a down-regulated tumor suppressor in colon cancer. In conclusion, ATF3 down-regulation in colon cancer promotes tumor growth and metastasis. Considering that blocking Hsp90 induces ATF3 expression, Hsp90 inhibition may represent a valid strategy to treat metastatic colon cancer by up-regulating this anti-metastatic transcription factor

  20. Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research.

    Science.gov (United States)

    Tetteh, Paul W; Kretzschmar, Kai; Begthel, Harry; van den Born, Maaike; Korving, Jeroen; Morsink, Folkert; Farin, Henner; van Es, Johan H; Offerhaus, G Johan A; Clevers, Hans

    2016-10-18

    Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1 CreER knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1 CreER KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4 Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1 CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.

  1. Intraoperative Tumor Perforation is Associated with Decreased 5-Year Survival in Colon Cancer

    DEFF Research Database (Denmark)

    Bundgaard, N S; Bendtsen, V O; Ingeholm, P

    2017-01-01

    BACKGROUND: It is a widely held belief that intraoperative tumor perforation in colon cancer impairs survival and causes local recurrence, although the prognostic importance remains unclear. AIM: The aim of this study was to assess the effect of unintended intraoperative tumor perforation...... on postoperative mortality and long-term survival. MATERIAL AND METHODS: This national cohort study was based on data from a prospectively maintained nationwide colorectal cancer database. We included 16,517 colon cancer patients who were resected with curative intent from 2001 to 2012. RESULTS: Intraoperative...... tumor perforation produced a significantly impaired 5-year survival of 40% compared to 64% in non-perforated colon cancer. Intraoperative tumor perforation was an independent risk factor for death, hazard ratio 1.63 (95% confidence interval: 1.4-1.94), with a significantly increased 90-day postoperative...

  2. Decorin in Human Colon Cancer: Localization In Vivo and Effect on Cancer Cell Behavior In Vitro.

    Science.gov (United States)

    Nyman, Marie C; Sainio, Annele O; Pennanen, Mirka M; Lund, Riikka J; Vuorikoski, Sanna; Sundström, Jari T T; Järveläinen, Hannu T

    2015-09-01

    Decorin is generally recognized as a tumor suppressing molecule. Nevertheless, although decorin has been shown to be differentially expressed in malignant tissues, it has often remained unclear whether, in addition to non-malignant stromal cells, cancer cells also express it. Here, we first used two publicly available databases to analyze the current information about decorin expression and immunoreactivity in normal and malignant human colorectal tissue samples. The analyses demonstrated that decorin expression and immunoreactivity may vary in cancer cells of human colorectal tissues. Therefore, we next examined decorin expression in normal, premalignant and malignant human colorectal tissues in more detail using both in situ hybridization and immunohistochemistry for decorin. Our results invariably demonstrate that malignant cells within human colorectal cancer tissues are devoid of both decorin mRNA and immunoreactivity. Identical results were obtained for cells of neuroendocrine tumors of human colon. Using RT-qPCR, we showed that human colon cancer cell lines are also decorin negative, in accordance with the above in vivo results. Finally, we demonstrate that decorin transduction of human colon cancer cell lines causes a significant reduction in their colony forming capability. Thus, strategies to develop decorin-based adjuvant therapies for human colorectal malignancies are highly rational. © The Author(s) 2015.

  3. Surgical resection of locally advanced primary transverse colon cancer--not a worse outcome in stage II tumor.

    Science.gov (United States)

    Hung, Hsin-Yuan; Yeh, Chien-Yuh; Changchien, Chung-Rong; Chen, Jinn-Shiun; Fan, Chung-Wei; Tang, Reiping; Hsieh, Pao-Shiu; Tasi, Wen-Sy; You, Yau-Tong; You, Jeng-Fu; Wang, Jeng-Yi; Chiang, Jy-Ming

    2011-07-01

    In locally advanced primary transverse colon cancer, a tumor may cause perforation or invade adjacent organs. Extensive resection is the best choice of treatment, but such procedures must be weighed against the potential survival benefits. This study was performed to identify the clinicopathological features and treatment outcomes of such tumors. We retrospectively reviewed the database of the Colorectal Cancer Registry of Chang Gung Memorial Hospital between February 1995 and December 2005. Patients with colon cancer sited between the hepatic and splenic flexure that involved an adjacent organ without distant metastasis were defined as having locally advanced transverse colon cancer. A total of 827 patients who underwent surgery for transverse primary colon cancer were enrolled in the study. Stage II and stage III colon cancer were diagnosed in 548 patients. Thirty-two (5.8%) patients were diagnosed with locally advanced tumors. Multivariate analysis revealed that stage III, preoperative carcinoembryonic antigen ≥5 ng/mL, a tumor with perforation or obstruction, and the presence of a locally advanced tumor were significant prognostic factors for both overall and cancer-specific survival. Postoperative morbidity rates differed significantly between the locally advanced and non-locally advanced tumor groups (22.7% vs. 12.3%, P transverse colon tumors (P = 0.21). Surgical resection of locally advanced transverse colon tumors resulted in a higher morbidity and mortality than that of non-locally advanced tumors, but the benefit of extensive surgery in the case of locally advanced tumors cannot be underestimated. Furthermore, this benefit is more pronounced in the case of stage II tumors.

  4. The evaluation of interstitial Cajal cells distribution in non-tumoral colon disorders.

    Science.gov (United States)

    Becheanu, G; Manuc, M; Dumbravă, Mona; Herlea, V; Hortopan, Monica; Costache, Mariana

    2008-01-01

    Interstitial cells of Cajal (ICC) are pacemakers that generate electric waves recorded from the gut and are important for intestinal motility. The aim of the study was to evaluate the distribution of interstitial cells of Cajal in colon specimens from patients with idiopathic chronic pseudo-obstruction and other non-tumoral colon disorders as compared with samples from normal colon. The distribution pattern of ICC in the normal and pathological human colon was evaluated by immunohistochemistry using antibodies for CD117, CD34, and S-100. In two cases with intestinal chronic idiopathic pseudo-obstruction we found a diffuse or focal reducing number of Cajal cells, the loss of immunoreactivity for CD117 being correlated with loss of immunoreactivity for CD34 marker. Our study revealed that the number of interstitial cells of Cajal also decrease in colonic diverticular disease and Crohn disease (p<0.05), whereas the number of enteric neurones appears to be normal. These findings might explain some of the large bowel motor abnormalities known to occur in these disorders. Interstitial Cajal cells may play an important role in pathogenesis and staining for CD117 on transmural intestinal surgical biopsies could allow a more extensive diagnosis in evaluation of chronic intestinal pseudo-obstruction.

  5. Continued colonization of the human genome by mitochondrial DNA.

    Directory of Open Access Journals (Sweden)

    Miria Ricchetti

    2004-09-01

    Full Text Available Integration of mitochondrial DNA fragments into nuclear chromosomes (giving rise to nuclear DNA sequences of mitochondrial origin, or NUMTs is an ongoing process that shapes nuclear genomes. In yeast this process depends on double-strand-break repair. Since NUMTs lack amplification and specific integration mechanisms, they represent the prototype of exogenous insertions in the nucleus. From sequence analysis of the genome of Homo sapiens, followed by sampling humans from different ethnic backgrounds, and chimpanzees, we have identified 27 NUMTs that are specific to humans and must have colonized human chromosomes in the last 4-6 million years. Thus, we measured the fixation rate of NUMTs in the human genome. Six such NUMTs show insertion polymorphism and provide a useful set of DNA markers for human population genetics. We also found that during recent human evolution, Chromosomes 18 and Y have been more susceptible to colonization by NUMTs. Surprisingly, 23 out of 27 human-specific NUMTs are inserted in known or predicted genes, mainly in introns. Some individuals carry a NUMT insertion in a tumor-suppressor gene and in a putative angiogenesis inhibitor. Therefore in humans, but not in yeast, NUMT integrations preferentially target coding or regulatory sequences. This is indeed the case for novel insertions associated with human diseases and those driven by environmental insults. We thus propose a mutagenic phenomenon that may be responsible for a variety of genetic diseases in humans and suggest that genetic or environmental factors that increase the frequency of chromosome breaks provide the impetus for the continued colonization of the human genome by mitochondrial DNA.

  6. 2-Dodecylcyclobutanone, a radiolytic product of palmitic acid, is genotoxic in primary human colon cells and in cells from preneoplastic lesions

    International Nuclear Information System (INIS)

    Knoll, Nadine; Weise, Anja; Claussen, Uwe; Sendt, Wolfgang; Marian, Brigitte; Glei, Michael; Pool-Zobel, Beatrice L.

    2006-01-01

    The irradiation of fat results in the formation of 2-alkylcyclobutanones, a new class of food contaminants. Results of previous in vitro studies with primary human colon cells and in vivo experiments with rats fed with 2-alkylcyclobutanones indicated that these radiolytic derivatives may be genotoxic and enhance the progression of colon tumors. The underlying mechanisms of these effects, however, are not clearly understood. Therefore we performed additional investigations to elucidate the genotoxic potential of 2-dodecylcyclobutanone (2dDCB) that is generated from palmitic acid. In particular, we explored the relative sensitivities of human colon cells, representing different stages of tumor development and healthy colon tissues, respectively. HT29clone19A cells, LT97 adenoma cells and primary human epithelial cells were exposed to 2dDCB (150-2097 μM). We determined cytotoxic effects using trypan blue exclusion. Genotoxicity, reflected as strand breaks, was assessed using the alkaline version of the comet assay and chromosomal abnormalities were investigated by 24-color fluorescence-in-situ-hybridization. 2dDCB was cytotoxic in a time- and dose-dependent manner in LT97 adenoma cells and in freshly isolated primary cells but not in the human colon tumor cell line. Associated with this was a marked induction of DNA damage by 2dDCB in LT97 adenoma cells and in freshly isolated colonocytes, whereas in the HT29clone19A cells no strand breaks were detectable. A long-term incubation of LT97 adenoma cells with lower concentrations of 2dDCB revealed cytogenetic effects. In summary, 2dDCB was clearly genotoxic in healthy human colon epithelial cells and in cells representing preneoplastic colon adenoma. These findings provide additional evidence that this compound may be regarded as a possible risk factor for processes in colon carcinogenesis related to initiation and progression

  7. Tumor-stroma ratio predicts recurrence in patients with colon cancer treated with neoadjuvant chemotherapy

    DEFF Research Database (Denmark)

    Hansen, Torben Frøstrup; Kjær-Frifeldt, Sanne; Lindebjerg, Jan

    2017-01-01

    BACKGROUND: Neoadjuvant chemotherapy represents a new treatment approach to locally advanced colon cancer. The aim of this study was to analyze the ability of tumor-stroma ratio (TSR) to predict disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy....... MATERIAL AND METHODS: This study included 65 patients with colon cancer treated with neoadjuvant chemotherapy in a phase II trial. All patients were planned for three cycles of capecitabine and oxaliplatin before surgery. Hematoxylin and eosin stained tissue sections from surgically resected primary tumors...... was 55%, compared to 94% in the group of patients with a high TSR. CONCLUSIONS: TSR assessed in the surgically resected primary tumor from patients with locally advanced colon cancer treated with neoadjuvant chemotherapy provides prognostic value and may serve as a relevant parameter in selecting...

  8. Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/β-catenin in SW480 human colon cancer cells

    Directory of Open Access Journals (Sweden)

    Park Hae-Duck

    2011-07-01

    Full Text Available Abstract Background Polysaccharides extracted from the Phellinus linteus (PL mushroom are known to possess anti-tumor effects. However, the molecular mechanisms responsible for the anti-tumor properties of PL remain to be explored. Experiments were carried out to unravel the anticancer effects of PL. Methods The anti-cancer effects of PL were examined in SW480 colon cancer cells by evaluating cell proliferation, invasion and matrix metallo-proteinase (MMP activity. The anti-angiogenic effects of PL were examined by assessing human umbilical vein endothelial cell (HUVEC proliferation and capillary tube formation. The in vivo effect of PL was evaluated in an athymic nude mouse SW480 tumor engraft model. Results PL (125-1000 μg/mL significantly inhibited cell proliferation and decreased β-catenin expression in SW480 cells. Expression of cyclin D1, one of the downstream-regulated genes of β-catenin, and T-cell factor/lymphocyte enhancer binding factor (TCF/LEF transcription activity were also significantly reduced by PL treatment. PL inhibited in vitro invasion and motility as well as the activity of MMP-9. In addition, PL treatment inhibited HUVEC proliferation and capillary tube formation. Tumor growth of SW480 cells implanted into nude mice was significantly decreased as a consequence of PL treatment, and tumor tissues from treated animals showed an increase in the apoptotic index and a decrease in β-catenin expression. Moreover, the proliferation index and microvessel density were significantly decreased. Conclusions These data suggest that PL suppresses tumor growth, invasion, and angiogenesis through the inhibition of Wnt/β-catenin signaling in certain colon cancer cells.

  9. Prehistoric human colonization of India

    Indian Academy of Sciences (India)

    Unknown

    2. Earliest human colonization of south Asia. The early human colonization of south Asia is represented largely by an abundance of stone tool assemblages. The oldest known tools ..... component among finished tools is conspicuous in the hinterland riverine ...... sativum), green gram (Vigna radiata), gram/chicken pea.

  10. Expression and clinical significance of tyrosine phosphatase SHP-2 in colon cancer.

    Science.gov (United States)

    Cai, Peifen; Guo, Wenjie; Yuan, Huaqin; Li, Qian; Wang, Weicheng; Sun, Yang; Li, Xiaomin; Gu, Yanhong

    2014-04-01

    Protein-tyrosine phosphatase SHP-2, encoded by gene PTPN11, has been identified as a tumor-promoting factor in several types of leukemia and is hyper-activated by other mechanisms in some solid tumors including gastric cancer, breast cancer, non-small cell lung cancer (NSCLC), etc. But few were reported on the expression and significances of SHP-2 in colon cancer. Here, we detect SHP-2 expression in colon cancer cells, colon cancer-induced by AOM+DSS in mice and 232 human colon cancer specimens, including 58 groups of self-matched adjacent peritumor tissues and normal tissues. We found that compared to the normal colon tissues, SHP-2 significantly decreased in tumor tissues (Pcolon tumor cells as well as mice colon tumors. And in humans samples, low SHP-2 expression showed a significantly correlation with poor tumor differentiation (P<0.05), late TNM stage (P=0.1666) and lymph node metastasis (P<0.05). Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  11. Fluorescence-guided surgery of human colon cancer increases complete resection resulting in cures in an orthotopic nude mouse model.

    Science.gov (United States)

    Metildi, Cristina A; Kaushal, Sharmeela; Snyder, Cynthia S; Hoffman, Robert M; Bouvet, Michael

    2013-01-01

    We inquired if fluorescence-guided surgery (FGS) could improve surgical outcomes in fluorescent orthotopic nude mouse models of human colon cancer. We established fluorescent orthotopic mouse models of human colon cancer expressing a fluorescent protein. Tumors were resected under bright light surgery (BLS) or FGS. Pre- and post-operative images with the OV-100 Small Animal Imaging System (Olympus Corp, Tokyo Japan) were obtained to assess the extent of surgical resection. All mice with primary tumor that had undergone FGS had complete resection compared with 58% of mice in the BLS group (P = 0.001). FGS resulted in decreased recurrence compared with BLS (33% versus 62%, P = 0.049) and lengthened disease-free median survival from 9 to >36 wk. The median overall survival increased from 16 wk in the BLS group to 31 weeks in the FGS group. FGS resulted in a cure in 67% of mice (alive without evidence of tumor at >6 mo after surgery) compared with only 37% of mice that underwent BLS (P = 0.049). Surgical outcomes in orthotopic nude mouse models of human colon cancer were significantly improved with FGS. The present study can be translated to the clinic by various effective methods of fluorescently labeling tumors. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Dying and regeneration of human tumor cells after heterotransplantation to athymic mice

    OpenAIRE

    Köpf-Maler, P.

    1986-01-01

    The histologic phenomena occurring immediately after heterotransplantation of two human colon adenocarcinomas to athymic mice have been studied. The tumors differed with respect to velocity of growth and passage age. Three phases were discernible in both cases. (1) During the first phase, most inoculated tumor cells died. (2) The second phase was characterized by removal of the necrotic tumor cells by immigrated inflammatory cells and by penetration of the conn...

  13. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis.

    Science.gov (United States)

    Huang, Emina H; Hynes, Mark J; Zhang, Tao; Ginestier, Christophe; Dontu, Gabriela; Appelman, Henry; Fields, Jeremy Z; Wicha, Max S; Boman, Bruce M

    2009-04-15

    Although the concept that cancers originate from stem cells (SC) is becoming scientifically accepted, mechanisms by which SC contribute to tumor initiation and progression are largely unknown. For colorectal cancer (CRC), investigation of this problem has been hindered by a paucity of specific markers for identification and isolation of SC from normal and malignant colon. Accordingly, aldehyde dehydrogenase 1 (ALDH1) was investigated as a possible marker for identifying colonic SC and for tracking them during cancer progression. Immunostaining showed that ALDH1(+) cells are sparse and limited to the normal crypt bottom, where SCs reside. During progression from normal epithelium to mutant (APC) epithelium to adenoma, ALDH1(+) cells increased in number and became distributed farther up the crypt. CD133(+) and CD44(+) cells, which are more numerous and broadly distributed in normal crypts, showed similar changes during tumorigenesis. Flow cytometric isolation of cancer cells based on enzymatic activity of ALDH (Aldefluor assay) and implantation of these cells in nonobese diabetic-severe combined immunodeficient mice (a) generated xenograft tumors (Aldefluor(-) cells did not), (b) generated them after implanting as few as 25 cells, and (c) generated them dose dependently. Further isolation of cancer cells using a second marker (CD44(+) or CD133(+) serially) only modestly increased enrichment based on tumor-initiating ability. Thus, ALDH1 seems to be a specific marker for identifying, isolating, and tracking human colonic SC during CRC development. These findings also support our original hypothesis, derived previously from mathematical modeling of crypt dynamics, that progressive colonic SC overpopulation occurs during colon tumorigenesis and drives CRC development.

  14. The influence of arachidonic acid metabolites on cell division in the intestinal epithelium and in colonic tumors.

    Science.gov (United States)

    Petry, F M; Tutton, P J; Barkla, D H

    1984-09-01

    Various metabolites of arachidonic acid are now known to influence cell division. In this paper the effects on cell proliferation of arachidonic acid, some inhibitors of arachidonic acid metabolism and some analogs of arachidonic acid metabolites is described. The epithelial cell proliferation rate in the jejunum, in the descending colon and in dimethylhydrazine-induced tumors of rat colon was measured using a stathmokinetic technique. Administration of arachidonic acid resulted in retardation of cell proliferation in each of the tissues examined. A cyclooxygenase inhibitor (Flurbiprofen) prevented this effect of arachidonic acid in the jejunal crypts and in colonic tumors, but not in colonic crypts. In contrast, inhibitors of both cyclooxygenase and lipoxygenase (Benoxaprofen and BW755c) prevented the effect of arachidonic acid in the colonic crypts and reduced its effect on colonic tumours but did not alter its effect on the jejunum. An inhibitor of thromoboxane A2 synthetase (U51,605) was also able to prevent the inhibitory effect of arachidonic acid on colonic tumors. Treatment with 16,16-dimethyl PGE2 inhibited cell proliferation in jejunal crypts and in colonic tumors, as did a thromboxane A2 mimicking agent, U46619. Nafazatrom, an agent that stimulates prostacyclin synthesis and inhibits lypoxygenase, promoted cell proliferation in the jejunal crypts and colonic crypts, but inhibited cell proliferation in colonic tumours.

  15. Synchronous Gastric Gastrointestinal Stromal Tumor and Colon Adenocarcinoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Thivi Vasilakaki

    2014-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs represent the majority of primary mesenchymal tumors of the gastrointestinal tract. They are generally considered to be solitary tumors and therefore the synchronous occurrence with other primary malignancies of gastrointestinal track is considered a rare event. Here we present the case of a 75-year-old man admitted to our hospital with a 10-day history of gastrointestinal bleeding. Colonoscopy revealed an ulcerative mass of 4 cm in diameter in the ascending colon. Gastroscopy revealed a bulge in the gastric body measuring 1 cm in diameter with normal overlying mucosa. Surgical intervention was suggested and ileohemicolectomy with regional lymph node resection along with gastric wedge resection was performed. Pathologic examination of the ascending colon mass showed an invasive moderately differentiated adenocarcinoma stage III B (T3N1M0. Grossly resected wedge of stomach showed a well circumscribed intramural tumor which microscopically was consistent with essentially benign gastrointestinal stromal tumor (according to Miettinen criteria. The patient did not receive additional treatment. Two years later the patient showed no evidence of recurrence or metastasis.

  16. Comparative Study of Carcinoembryonic Antigen Tumor Marker in Stomach and Colon Cancer Patients in Khyber Pakhtunkhwa.

    Science.gov (United States)

    Ahmad, Bashir; Gul, Bushra; Ali, Sajid; Bashir, Shumaila; Mahmood, Nourin; Ahmad, Jamshed; Nawaz, Seema

    2015-01-01

    Due to the increase in morbidity and mortality rate, cancer has become an alarming threat to the human population worldwide. Since cancer is a progressive disorder, timely diagnosis would be helpful to prevent/stop cancer from progressing to severe stage. In Khyber Pakhtunkhwa, Pakistan, most of the time, tumors are diagnosed with endoscopy and biopsy; therefore rare studies exist regarding the diagnosis of gastrointestinal (GIT) carcinomas based on tumor markers, especially CEA. This study made a comparative analysis of CEA in admitted hospitalized stomach and colon cancer patients diagnosed as GIT with biopsy. In this study, a total of 66 cases were included. The level of CEA was determined in the blood of these patients using ELISA technique. Out of 66 patients, the level of CEA was high in 59.1% of the total, 60.7% in colon cancer patients and 57.9 % in stomach cancer patients. Moreover, the incidence of colorectal and stomach cancer was greater in males as compared to females. Patients were more of the age group of 40- 60 and the level of CEA was comparatively higher in patients (51.5%) with histology which was moderately differentiated, than patients with well differentiated and poorly differentiated tumor histology. CEA level was high in more than 50% of the total patients. Moreover, CEA exhibited higher sensitivity for colon than stomach cancer.

  17. Expression of radiation damage in two tumor subpopulations obtained from a heterogeneous human colon carcinoma as a function of growth state

    International Nuclear Information System (INIS)

    Arundel, C.M.; Leith, J.T.

    1984-01-01

    The authors have defined changes in intrinsic x-ray (100 kVp) radiation sensitivity that occur when human tumor cells are grown either exponentially, or as plateau (both fed and unfed) phase cultures in vitro. Two subpopulations of a human colon carcinoma were studied (clones A and D), and values for single hit, multitarget inactivation were obtained. For clone A the n, D/sub o/ (Gy), and D/sub q/ (Gy) values for exponential cells were 8.2, 1.06, and 2.23. For clone D, these values were 5.8, 1.08, and 2.23. For fed plateau phase cultures the clone A values were 18.4, 0.86, and 2.52, while for fed clone D cells these values were 16.1, 0.80, and 2.24. For unfed plateau phase cultures the clone A values were 28.5, 0.71, and 2.40, while for unfed clone D cells these values were 15.5, 0.76, and 2.10. These data indicate that the major change in intrinsic radiation sensitivity of these heterogeneous tumor subpopulations is the increase in the number of lesions per unit dose produced in plateau phase cells. Complete studies of repair of potentially lethal damage in these 2 tumor lines are being done to fully define radiation responses in plateau phase cultures

  18. Cell surface fucosylation does not affect development of colon tumors in mice with germline Smad3 mutation

    Science.gov (United States)

    Domino, Steven E.; Karnak, David M.; Hurd, Elizabeth A.

    2006-01-01

    Background/Aims: Neoplasia-related alterations in cell surface α(1,2)fucosylated glycans have been reported in multiple tumors including colon, pancreas, endometrium, cervix, bladder, lung, and choriocarcinoma. Spontaneous colorectal tumors from mice with a germline null mutation of transforming growth factor-β signaling gene Smad3 (Madh3) were tested for α(1,2)fucosylated glycan expression. Methods: Ulex Europaeus Agglutinin-I lectin staining, fucosyltransferase gene northern blot analysis, and a cross of mutant mice with Fut2 and Smad3 germline mutations were performed. Results: Spontaneous colorectal tumors from Smad3 (-/-) homozygous null mice were found to express α(1,2)fucosylated glycans in an abnormal pattern compared to adjacent nonneoplastic colon. Northern blot analysis of α(1,2)fucosyltransferase genes Fut1 and Fut2 revealed that Fut2, but not Fut1, steady-state mRNA levels were significantly increased in tumors relative to adjacent normal colonic mucosa. Mutant mice with a Fut2-inactivating germline mutation were crossed with Smad3 targeted mice. In Smad3 (-/-)/Fut2 (-/-) double knock-out mice, UEA-I lectin staining was eliminated from colon and colon tumors, however, the number and size of tumors present by 24 weeks of age did not vary regardless of the Fut2 genotype. Conclusions: In this model of colorectal cancer, cell surface α(1,2)fucosylation does not affect development of colon tumors. PMID:17264540

  19. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

    Science.gov (United States)

    Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

    2003-01-01

    Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.

  20. Differential expression of carbohydrate antigen 19-9 in human colorectal cancer: A comparison with colon and rectal cancers

    Science.gov (United States)

    ZHANG, SHUAI; CHEN, YIJUN; ZHU, ZHANMENG; DING, YUNLONG; REN, SHUANGYI; ZUO, YUNFEI

    2013-01-01

    Colorectal cancer is one of the leading causes of cancer-related mortality, being the third most commonly diagnosed cancer among men and the second among women. Accumulating evidence regarding carbohydrate antigen (CA) demonstrated that tumor-associated antigens are clinically useful for the diagnosis, staging and monitoring of human gastrointestinal cancers, particularly colorectal cancer. There has been an extensive investigation for sensitive and specific markers of this disease. Currently, the gastrointestinal cancer-associated carbohydrate antigen 19-9 (CA19-9) is the most widely applied tumor marker in cancer diagnosis. Despite a similar etiology and cancer incidence rates, there are anatomical and clinical differences between colon and rectal cancer, as well as differences regarding tumor progression and adjuvant treatments. To investigate whether CA19-9 is differentially expressed between colon and rectal cancer, we conducted a differential analysis of serum CA19-9 levels among 227 cases of colorectal cancer, analyzing gender, age, Dukes’ stage and distant metastasis for human colon and rectal cancer as a single entity, separately and as matched pairs. We demonstrated that the serum CA19-9 levels in colorectal cancer were upregulated in advanced stages with distant metastasis. By contrast, the serum CA19-9 levels in colon cancer displayed a differential and upregulated behavior in advanced stages with distant metastasis. By analyzing as matched pairs, the upregulated serum CA19-9 levels in rectal cancer during the early stages without distant metastasis further supported our hypothesis that the expression of CA19-9 displays a site-specific differential behavior. The integrative analysis suggested a significant difference between human colon and rectal cancer, justifying individualized therapy for these two types of cancer. PMID:24649295

  1. Tryptophan autofluorescence imaging of neoplasms of the human colon

    Science.gov (United States)

    Banerjee, Bhaskar; Renkoski, Timothy; Graves, Logan R.; Rial, Nathaniel S.; Tsikitis, Vassiliki Liana; Nfonsom, Valentine; Pugh, Judith; Tiwari, Piyush; Gavini, Hemanth; Utzinger, Urs

    2012-01-01

    Detection of flat neoplasia is a major challenge in colorectal cancer screening, as missed lesions can lead to the development of an unexpected `incident' cancer prior to the subsequent endoscopy. The use of a tryptophan-related autofluorescence has been reported to be increased in murine intestinal dysplasia. The emission spectra of cells isolated from human adenocarcinoma and normal mucosa of the colon were studied and showed markedly greater emission intensity from cancerous cells compared to cells obtained from the surrounding normal mucosa. A proto-type multispectral imaging system optimized for ultraviolet macroscopic imaging of tissue was used to obtain autofluorescence images of surgical specimens of colonic neoplasms and normal mucosa after resection. Fluorescence images did not display the expected greater emission from the tumor as compared to the normal mucosa, most probably due to increased optical absorption and scattering in the tumors. Increased fluorescence intensity in neoplasms was observed however, once fluorescence images were corrected using reflectance images. Tryptophan fluorescence alone may be useful in differentiating normal and cancerous cells, while in tissues its autofluorescence image divided by green reflectance may be useful in displaying neoplasms.

  2. Transcription factor Runx2 knockdown regulates colon cancer transplantation tumor growth in vitro: an experimental study

    Directory of Open Access Journals (Sweden)

    Bin Xu1

    2017-05-01

    Full Text Available Objective: To study the effect of transcription factor Runx2 knockdown on colon cancer transplantation tumor growth in vitro. Methods: Colon cancer cell lines HT29 were cultured and transfected with negative control (NC - shRNA plasmids and Runx2-shRNA plasmids respectively, the colon cancer cells transfected with shRNA were subcutaneously injected into C57 nude mice, and they were included in NC group and Runx2 knockdown group respectively. 1 week, 2 weeks and 3 weeks after model establishment, serum was collected to determine the contents of tumor markers, and tumor lesions were collected to determine proliferation and apoptosis gene expression. Results: CCSA-2, CEA and CA19-9 levels in serum as well as Rac1, Wnt3a, PLD2 and FAM96B protein expression in transplantation tumor lesions of Runx2 knockdown group were significantly lower than those of NC group while MS4A12, ASPP2 and Fas protein expression in transplantation tumor lesions of Runx2 knockdown group were significantly higher than those of NC group. Conclusion: Transcription factor Runx2 knockdown could inhibit the colon cancer transplantation tumor growth in vitro.

  3. Fluorescently labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model.

    Science.gov (United States)

    Metildi, Cristina A; Kaushal, Sharmeela; Luiken, George A; Talamini, Mark A; Hoffman, Robert M; Bouvet, Michael

    2014-04-01

    The aim of this study was to evaluate a new fluorescently labeled chimeric anti-CEA antibody for improved detection and resection of colon cancer. Frozen tumor and normal human tissue samples were stained with chimeric and mouse antibody-fluorophore conjugates for comparison. Mice with patient-derived orthotopic xenografts (PDOX) of colon cancer underwent fluorescence-guided surgery (FGS) or bright-light surgery (BLS) 24 hr after tail vein injection of fluorophore-conjugated chimeric anti-CEA antibody. Resection completeness was assessed using postoperative images. Mice were followed for 6 months for recurrence. The fluorophore conjugation efficiency (dye/mole ratio) improved from 3-4 to >5.5 with the chimeric CEA antibody compared to mouse anti-CEA antibody. CEA-expressing tumors labeled with chimeric CEA antibody provided a brighter fluorescence signal on frozen human tumor tissues (P = 0.046) and demonstrated consistently lower fluorescence signals in normal human tissues compared to mouse antibody. Chimeric CEA antibody accurately labeled PDOX colon cancer in nude mice, enabling improved detection of tumor margins for more effective FGS. The R0 resection rate increased from 86% to 96% with FGS compared to BLS. Improved conjugating efficiency and labeling with chimeric fluorophore-conjugated antibody resulted in better detection and resection of human colon cancer in an orthotopic mouse model. © 2013 Wiley Periodicals, Inc.

  4. CHARACTERISTICS OF CLINICAL COURSE OF METASTATIC AND PRIMARY OVARIAN TUMORS IN COLON CANCER

    Directory of Open Access Journals (Sweden)

    I. A. Dzhanyan

    2015-01-01

    Full Text Available The aim of this study was to investigate clinical pecuiliarities of ovarian tumors in colon cancer patients and determination of complex diagnostic methods.Subject and methods. Russian N.N.  Blokhin Cancer Research Center archives were used for retrospective study, patients, who underwent treatment during 1989–2013  were included. Colon cancer patients with ovarian metastases and with synchronous or metachronous tumors were included.Results. 141 patients were included: 91 patients had colon cancer with ovarian metastases (group 1 and 50 patients had synchronous or metachronous ovarian tumours (group 2. Ovarian tumors were diagnosed during the 1 year in 74 (81.3 % patients in group 1 and in 23 (46 % in group 2. Patients in group 2 less frequently had children (9 (18.0 % vs 5 (5.5 + 2.3 %, р < 0.05, family history of cancer (3 (6 % vs 16 (17.6 %, р < 0.05 and concomitant diseases. Median CA 125 level in group 1 was 64.96 ng/ml and 180 ng/ml in group 2. Ovarian tumors had solid and cystic structure during US examination in 66 (73 % patients in group 1 and 31 (62 % patients in group 2 had solid ovarian tumors on US examination.Conclusions. The differential diagnostics of primary and metastatic ovarian tumors must include CEA, CA 19–9 and CA 125 serum levels and pelvic US.

  5. Combined adenocarcinoma-carcinoid tumor of transverse colon

    Directory of Open Access Journals (Sweden)

    Prosanta Kumar Bhattacharjee

    2013-01-01

    Full Text Available A 65-year-old male presented with painless hematochezia associated with episodic cramps in upper abdomen, watery diarrhea, and a slowly growing mass in upper abdomen. Examination revealed a firm 6 x 5 cm, intra-abdominal, epigastric mass. Colonoscopy up to 90 cm showed a stenosing, ulcero-proliferative lesion in the transverse colon. No synchronous lesion was detected. Biopsy revealed mucin secreting adenocarcinoma. Exploration showed the growth involving the transverse colon proximal to the splenic flexure with a part of ileum, approximately three feet proximal to ileo-caecal junction, adherent to it. No significant mesenteric lymph node enlargement was evident. The patient underwent resection of the growth along with the segment of adherent ileum. Continuity was re-established by a colo-colic and ileo-ileal anastomosis respectively. Patient received adjuvant chemotherapy. Post-operative histopathology demonstrated a composite histological pattern with an admixture of carcinoid tumor and adenocarcinoma, invasion of ileal serosa and adenocarcinomatous deposits in mesocolic lymph nodes, the tumor staging being (T4, N0, M0/Stage II for carcinoid and (T4, N1, M0/Stage III for adenocarcinoma. Patient was followed-up for a year and was doing well without any evidence of recurrence.

  6. Elderly patients with colon cancer have unique tumor characteristics and poor survival.

    Science.gov (United States)

    Patel, Supriya S; Nelson, Rebecca; Sanchez, Julian; Lee, Wendy; Uyeno, Lori; Garcia-Aguilar, Julio; Hurria, Arti; Kim, Joseph

    2013-02-15

    The incidence of colon cancer increases with age, and colon cancer predominantly affects individuals >65 years old. However, there are limited data regarding clinical and pathologic factors, treatment characteristics, and survival of older patients with colon cancer. The objective of this study was to determine the effects of increasing age on colon cancer. Patients diagnosed with colon cancer between 1988 and 2006 were identified through the Los Angeles County Cancer Surveillance Program, in Southern California. Patients were stratified into 4 age groups: 18-49, 50-64, 65-79, and ≥80 years. Clinical and pathologic characteristics and disease-specific and overall survival were compared between patients from different age groups. A total of 32,819 patients were assessed. Patients aged 18 to 49 and 65 to 79 years represented the smallest and largest groups, respectively. A near equal number of males and females were diagnosed with colon cancer in the 3 youngest age groups, whereas patients who were ≥80 years old were more commonly white and female. Tumor location was different between groups, and the frequency of larger tumors (>5 cm) was greatest in youngest patients (18-49 years). The oldest patients (≥80 years) were administered chemotherapy at the lowest frequency, and disease-specific and overall survival rates decreased with increasing age. This investigation demonstrates that older age is associated with alterations in clinical and pathologic characteristics and decreased survival. This suggests that the phenotype of colon cancer and the efficacy of colon cancer therapies may be dependent on the age of patients. Copyright © 2012 American Cancer Society.

  7. Effects of the differentiating agents sodium butyrate and N-methylformamide on the oxygen enhancement ratio of human colon tumor cells

    International Nuclear Information System (INIS)

    Hallows, K.R.; Bliven, S.F.; Leith, J.T.

    1988-01-01

    We have previously shown that chronic adaptation of human tumor cells to the differentiation-inducing agents N-methylformamide (NMF) and sodium butyrate (NAB) increases the sensitivity of oxic cells to graded single doses of X rays. These studies were carried out to define the sensitivity of hypoxic cells after adaptation. Clone A colon tumor cells were grown for three passages in medium containing 170 mM NMF or 2 mM NAB and irradiated in suspension culture, after gassing with either oxygen (60 min) or ultrapure nitrogen (90 min), and complete survival curves were generated. Using the linear-quadratic equation to describe the data, it was found that NMF and NAB produced increased X-ray killing of hypoxic cells. At the 10% level of survival, the dose-modifying factors were about 1.20 and 1.25 for NMF- and NAB-adapted hypoxic cells, respectively, as compared to hypoxic control cells. However, since both oxic and hypoxic cells exhibited increased sensitivity after NMF and NAB adaptation, there was no major change in the oxygen enhancement ratio

  8. Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells

    International Nuclear Information System (INIS)

    Simms, Neka A K; Rajput, Ashwani; Sharratt, Elizabeth A; Ongchin, Melanie; Teggart, Carol A; Wang, Jing; Brattain, Michael G

    2012-01-01

    TGFβ signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFβ signaling. To test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging. Abrogation of TGFβ signaling through introduction of a dominant negative TGFβ receptor II (TGFβRII) in non-metastatic FETα human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFβ signaling in FETα-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGFβ signaling is a metastasis suppressor, we rescued TGFβ signaling in CBS metastatic colon cancer cells that had lost TGFβ receptor expression due to epigenetic repression. Restoration of TGFβ signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFβ signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma. The observations presented here indicate a metastasis suppressor role for TGF

  9. Anti-proliferative effects of Bifidobacterium adolescentis SPM0212 extract on human colon cancer cell lines

    International Nuclear Information System (INIS)

    Lee, Do Kyung; Jang, Seok; Kim, Mi Jin; Kim, Jung Hyun; Chung, Myung Jun; Kim, Kyung Jae; Ha, Nam Joo

    2008-01-01

    Lactic acid bacteria (LAB) are beneficial probiotic organisms that contribute to improved nutrition, microbial balance, and immuno-enhancement of the intestinal tract, as well as anti-tumor activity. The aim of the present work was to study the growth inhibition of tumor cells by butanol extract of Bifidobacterium adolescentis isolated from healthy young Koreans. The anti-proliferative activity of B. adolescentis isolates was assessed by XTT assays on three human colon cancer cell lines (Caco-2, HT-29, and SW480). The effects of B. adolescentis SPM0212 butanol extract on tumor necrosis factor-α (TNF-α) and nitric oxide (NO) production were tested using the murine macrophage RAW 264.7 cell line. The butanol extract of B. adolescentis SPM0212 dose-dependently inhibited the growth of Caco-2, HT-29, and SW480 cells by 70%, 30%, and 40%, respectively, at 200 μg/mL. Additionally, the butanol extract of B. adolescentis SPM0212 induced macrophage activation and significantly increased the production of TNF-α and NO, which regulate immune modulation and are cytotoxic to tumor cells. The butanol extract of B. adolescentis SPM0212 increased activity of the host immune system and may improve human health by helping to prevent colon cancer as a biological response modifier

  10. Fem1b, a proapoptotic protein, mediates proteasome inhibitor-induced apoptosis of human colon cancer cells.

    Science.gov (United States)

    Subauste, M Cecilia; Sansom, Owen J; Porecha, Nehal; Raich, Natacha; Du, Liqin; Maher, Joseph F

    2010-02-01

    In the treatment of colon cancer, the development of resistance to apoptosis is a major factor in resistance to therapy. New molecular approaches to overcome apoptosis resistance, such as selectively upregulating proapoptotic proteins, are needed in colon cancer therapy. In a mouse model with inactivation of the adenomatous polyposis coli (Apc) tumor suppressor gene, reflecting the pathogenesis of most human colon cancers, the gene encoding feminization-1 homolog b (Fem1b) is upregulated in intestinal epithelium following Apc inactivation. Fem1b is a proapoptotic protein that interacts with apoptosis-inducing proteins Fas, tumor necrosis factor receptor-1 (TNFR1), and apoptotic protease activating factor-1 (Apaf-1). Increasing Fem1b expression induces apoptosis of cancer cells, but effects on colon cancer cells have not been reported. Fem1b is a homolog of feminization-1 (FEM-1), a protein in Caenorhabditis elegans that is regulated by proteasomal degradation, but whether Fem1b is likewise regulated by proteasomal degradation is unknown. Herein, we found that Fem1b protein is expressed in primary human colon cancer specimens, and in malignant SW620, HCT-116, and DLD-1 colon cancer cells. Increasing Fem1b expression, by transfection of a Fem1b expression construct, induced apoptosis of these cells. We found that proteasome inhibitor treatment of SW620, HCT-116, and DLD-1 cells caused upregulation of Fem1b protein levels, associated with induction of apoptosis. Blockade of Fem1b upregulation with morpholino antisense oligonucleotide suppressed the proteasome inhibitor-induced apoptosis of these cells. In conclusion, the proapoptotic protein Fem1b is downregulated by the proteasome in malignant colon cancer cells and mediates proteasome inhibitor-induced apoptosis of these cells. Therefore, Fem1b could represent a novel molecular target to overcome apoptosis resistance in therapy of colon cancer.

  11. High Endogenous Expression of Chitinase 3-Like 1 and Excessive Epithelial Proliferation with Colonic Tumor Formation in MOLF/EiJ Mice.

    Directory of Open Access Journals (Sweden)

    Daren Low

    Full Text Available Colorectal cancer (CRC development is mediated by uncontrolled survival and proliferation of tumor progenitor cells. Using animal models to identify and study host-derived factors that underlie this process can aid interventions in preventing tumor expansion and metastasis. In healthy steady states in humans and mice (e.g. C57BL/6 strain, colonic Chitinase 3-like 1 (CHI3L1 gene expression is undetectable. However, this expression can be induced during intestinal inflammation and tumorigenesis where CHI3L1 plays an important role in tissue restitution and cell proliferation. Here, we show that a wild-derived mouse strain MOLF/EiJ expresses high levels of colonic epithelial CHI3L1 at the steady state due to several nucleotide polymorphisms in the proximal promoter regions of the CHI3L1 gene. Interestingly, these mice spontaneously developed polypoid nodules in the colon with signs of immune cell infiltrations at steady state. The CHI3L1 positive colonic epithelial cells were highly proliferative and exhibited malignant transformation and expansion when exposed in vivo to azoxymethane, one of the well-known colonic carcinogens.

  12. Use of a combination of CEA and tumor budding to identify high-risk patients with stage II colon cancer.

    Science.gov (United States)

    Du, Changzheng; Xue, Weicheng; Dou, Fangyuan; Peng, Yifan; Yao, Yunfeng; Zhao, Jun; Gu, Jin

    2017-07-24

    High-risk patients with stage II colon cancer may benefit from adjuvant chemotherapy, but identifying this patient population can be difficult. We assessed the prognosis value for predicting tumor progression in patients with stage II colon cancer, of a panel of 2 biomarkers for colon cancer: tumor budding and preoperative carcinoembryonic antigen (CEA). Consecutive patients (N = 134) with stage II colon cancer who underwent curative surgery from 2000 to 2007 were included. Multivariate analysis was used to evaluate the association of CEA and tumor budding grade with 5-year disease-free survival (DFS). The prognostic accuracy of CEA, tumor budding grade and the combination of both (CEA-budding panel) was determined. The study found that both CEA and tumor budding grade were associated with 5-year DFS. The prognostic accuracy for disease progression was higher for the CEA-budding panel (82.1%) than either CEA (70.9%) or tumor budding grade (72.4%) alone. The findings indicate that the combination of CEA levels and tumor budding grade has greater prognostic value for identifying patients with stage II colon cancer who are at high-risk for disease progression, than either marker alone.

  13. Differentiation between benign and malignant colon tumors using fast dynamic gadolinium-enhanced MR colonography; a feasibility study

    International Nuclear Information System (INIS)

    Achiam, M.P.; Andersen, L.P.H.; Klein, M.; Logager, V.; Chabanova, E.; Thomsen, H.S.; Rosenberg, J.

    2010-01-01

    Background: Colorectal cancer will present itself as a bowel obstruction in 16-23% of all cases. However, not all obstructing tumors are malignant and the differentiation between a benign and a malignant tumor can be difficult. The purpose of our study was to determine whether fast dynamic gadolinium-enhanced MR imaging combined with MR colonography could be used to differentiate a benign from a malignant obstructing colon tumor. Methods: Patients with benign colon tumor stenosis, based on diverticulitis, were asked to participate in the study. The same number of patients with verified colorectal cancer was included. Both groups had to be scheduled for surgery to be included. Two blinded observers analyzed the tumors on MR by placing a region of interest in the tumor and a series of parameters were evaluated, e.g. wash-in, wash-out and time-to-peak. Results: 14 patients were included. The wash-in and wash-out rates were significantly different between the benign and malignant tumors, and a clear distinction between benign and malignant disease was therefore possible by looking only at the MR data. Furthermore, MR colography evaluating the rest of the colon past the stenosis was possible with all patients. Conclusion: The results showed the feasibility of using fast dynamic gadolinium-enhanced MR imaging to differentiate between benign and malignant colonic tumors. With a high intra-class correlation and significant differences found on independent segments of the tumor, the method appears to be reproducible. Furthermore, the potential is big in performing a full preoperative colon evaluation even in patients with obstructing cancer. Trial number: (NCT00114829).

  14. Differentiation between benign and malignant colon tumors using fast dynamic gadolinium-enhanced MR colonography; a feasibility study

    Energy Technology Data Exchange (ETDEWEB)

    Achiam, M.P., E-mail: achiam1@dadlnet.d [Department of Diagnostic Radiology, Copenhagen University Hospital Herlev, Herlev Ringvej, DK-2730 Herlev (Denmark); Department of Surgical Gastroenterology D, Copenhagen University Hospital Herlev, Herlev Ringvej, DK-2730 Herlev (Denmark); Department of Diagnostic Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen (Denmark); Andersen, L.P.H.; Klein, M. [Department of Surgical Gastroenterology D, Copenhagen University Hospital Herlev, Herlev Ringvej, DK-2730 Herlev (Denmark); Department of Diagnostic Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen (Denmark); Logager, V.; Chabanova, E.; Thomsen, H.S. [Department of Diagnostic Radiology, Copenhagen University Hospital Herlev, Herlev Ringvej, DK-2730 Herlev (Denmark); Department of Diagnostic Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen (Denmark); Rosenberg, J. [Department of Surgical Gastroenterology D, Copenhagen University Hospital Herlev, Herlev Ringvej, DK-2730 Herlev (Denmark); Department of Diagnostic Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen (Denmark)

    2010-06-15

    Background: Colorectal cancer will present itself as a bowel obstruction in 16-23% of all cases. However, not all obstructing tumors are malignant and the differentiation between a benign and a malignant tumor can be difficult. The purpose of our study was to determine whether fast dynamic gadolinium-enhanced MR imaging combined with MR colonography could be used to differentiate a benign from a malignant obstructing colon tumor. Methods: Patients with benign colon tumor stenosis, based on diverticulitis, were asked to participate in the study. The same number of patients with verified colorectal cancer was included. Both groups had to be scheduled for surgery to be included. Two blinded observers analyzed the tumors on MR by placing a region of interest in the tumor and a series of parameters were evaluated, e.g. wash-in, wash-out and time-to-peak. Results: 14 patients were included. The wash-in and wash-out rates were significantly different between the benign and malignant tumors, and a clear distinction between benign and malignant disease was therefore possible by looking only at the MR data. Furthermore, MR colography evaluating the rest of the colon past the stenosis was possible with all patients. Conclusion: The results showed the feasibility of using fast dynamic gadolinium-enhanced MR imaging to differentiate between benign and malignant colonic tumors. With a high intra-class correlation and significant differences found on independent segments of the tumor, the method appears to be reproducible. Furthermore, the potential is big in performing a full preoperative colon evaluation even in patients with obstructing cancer. Trial number: (NCT00114829).

  15. IL33 Promotes Colon Cancer Cell Stemness via JNK Activation and Macrophage Recruitment

    Science.gov (United States)

    Fang, Min; Li, Yongkui; Huang, Kai; Qi, Shanshan; Zhang, Jian; Zgodzinski, Witold; Majewski, Marek; Wallner, Grzegorz; Gozdz, Stanislaw; Macek, Pawel; Kowalik, Artur; Pasiarski, Marcin; Grywalska, Ewelina; Vatan, Linda; Nagarsheth, Nisha; Li, Wei; Zhao, Lili; Kryczek, Ilona; Wang, Guobin; Wang, Zheng; Zou, Weiping; Wang, Lin

    2018-01-01

    The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. PMID:28249897

  16. Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression.

    Science.gov (United States)

    Zakraoui, Ons; Marcinkiewicz, Cezary; Aloui, Zohra; Othman, Houcemeddine; Grépin, Renaud; Haoues, Meriam; Essafi, Makram; Srairi-Abid, Najet; Gasmi, Ammar; Karoui, Habib; Pagès, Gilles; Essafi-Benkhadir, Khadija

    2017-01-01

    Lebein, is an heterodimeric disintegrin isolated from Macrovipera lebetina snake venom that was previously characterized as an inhibitor of ADP-induced platelet aggregation. In this study, we investigated the effect of Lebein on the p53-dependent growth of human colon adenocarcinoma cell lines. We found that Lebein significantly inhibited LS174 (p53wt), HCT116 (p53wt), and HT29 (p53mut) colon cancer cell viability by inducing cell cycle arrest through the modulation of expression levels of the tumor suppression factor p53, cell cycle regulating proteins cyclin D1, CDK2, CDK4, retinoblastoma (Rb), CDK1, and cyclin-dependent kinase inhibitors p21 and p27. Interestingly, Lebein-induced apoptosis of colon cancer cells was dependent on their p53 status. Thus, in LS174 cells, cell death was associated with PARP cleavage and the activation of caspases 3 and 8 while in HCT116 cells, Lebein induced caspase-independent apoptosis through increased expression of apoptosis inducing factor (AIF). In LS174 cells, Lebein triggers the activation of the MAPK ERK1/2 pathway through induction of reactive oxygen species (ROS). It also decreased cell adhesion and migration to fibronectin through down regulation of α5β1 integrin. Moreover, Lebein significantly reduced the expression of two angiogenesis stimulators, Vascular Endothelial Growth Factor (VEGF) and Neuropilin 1 (NRP1). It inhibited the VEGF-induced neovascularization process in the quail embryonic CAM system and blocked the development of human colon adenocarcinoma in nude mice. Overall, our work indicates that Lebein may be useful to design a new therapy against colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Lectin histochemistry of 1,2-dimethylhydrazine-induced rat colon neoplasia.

    Science.gov (United States)

    Freeman, H J

    1983-10-01

    Lectins linked to fluorescein were used as carbohydrate probes to examine the goblet cell mucin and epithelial cell surface glycoconjugate alterations in an experimental rodent model of colonic neoplasia induced with parenteral 1,2-dimethylhydrazine dihydrochloride. Lectins derived from Triticum vulgare (WGA), Ricinus communis (RCA1), and Limulus polyphemus (LPA) showed reduced labeling of goblet cell mucin in these tumors, while binding with peanut lectin from Arachis hypogaea (PNA), a lectin ordinarily failing to bind to mucin in normal colon, was positive. In addition, RCA1 and LPA showed increased cell surface labeling of neoplastic epithelial cells. Finally, alterations were observed in lectin binding to "transitional" colonic mucosa adjacent to colonic tumors from carcinogen-treated rats. These findings indicate that significant alterations in both membrane and mucin glycoconjugates occur in colonic tumors and mucosa adjacent to tumors in a chemically induced experimental animal model of human colon cancer.

  18. Human wound colonization by Lucilia eximia and Chrysomya rufifacies (Diptera: Calliphoridae): myiasis, perimortem, or postmortem colonization?

    Science.gov (United States)

    Sanford, Michelle R; Whitworth, Terry L; Phatak, Darshan R

    2014-05-01

    The infestation of human or animal tissues by fly larvae has been given distinctive terminology depending on the timing and location of colonization. Wounds and orifices colonized by Diptera in a living human or animal are typically referred to as myiasis. When the colonization occurs after death, it is referred to as postmortem colonization and can be used to estimate the minimum postmortem interval. What happens when the human, as in the case presented here, has a necrotic limb while the human remains alive, at least for a short period of time? The case presented here documents perimortem wound colonization by Lucilia eximia (Wiedemann) and Chrysomya rufifacies (Macquart) and the considerations for approximating development temperatures and estimating the time of colonization (TOC). This represents the first record of L. eximia in human myiasis in the United States and the first record of the co-occurrence of L. eximia and C. rufifacies in human myiasis in the United States. The TOC was estimated using both ambient and body temperature. Insect colonization before death complicates the estimation of TOC and minimum postmortem interval and illustrates the problem of temperature approximation in forensic entomology casework.

  19. Decreased Polyunsaturated Fatty Acid Content Contributes to Increased Survival in Human Colon Cancer

    Directory of Open Access Journals (Sweden)

    Manuela Oraldi

    2009-01-01

    Full Text Available Among diet components, some fatty acids are known to affect several stages of colon carcinogenesis, whereas others are probably helpful in preventing tumors. In light of this, our aim was to determine the composition of fatty acids and the possible correlation with apoptosis in human colon carcinoma specimens at different Duke's stages and to evaluate the effect of enriching human colon cancer cell line with the possible reduced fatty acid(s. Specimens of carcinoma were compared with the corresponding non-neoplastic mucosa: a significant decrease of arachidonic acid, PPARα, Bad, and Bax and a significant increase of COX-2, Bcl-2, and pBad were found. The importance of arachidonic acid in apoptosis was demonstrated by enriching a Caco-2 cell line with this fatty acid. It induced apoptosis in a dose- and time-dependent manner via induction of PPARα that, in turn, decreased COX-2. In conclusion, the reduced content of arachidonic acid is likely related to carcinogenic process decreasing the susceptibility of cancer cells to apoptosis.

  20. Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.

    Directory of Open Access Journals (Sweden)

    Pawan Kaler

    2010-07-01

    Full Text Available We recently reported that colon tumor cells stimulate macrophages to release IL-1beta, which in turn inactivates GSK3beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1beta by neutralizing IL-1beta antibody, or silencing of IL-1beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1beta was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Delta psi and activation of caspases were prevented by macrophages or by recombinant IL-1beta. Pharmacological inhibition of IL-1beta release from macrophages by vitamin D(3, a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1beta failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIkappaB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1beta stabilized Snail in tumor cells in an NF-kappaB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1beta, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.We have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1beta, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D(3 halts this amplifying loop by interfering with the release of IL-1beta from macrophages. Accordingly, vitamin D(3 sensitizes tumor cells to TRAIL

  1. Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line

    Energy Technology Data Exchange (ETDEWEB)

    Vendramini-Costa, Débora Barbosa, E-mail: vendramini.debora@gmail.com [Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, SP (Brazil); Chemical, Biological and Agricultural Pluridisciplinary Research Center (CPQBA), University of Campinas, Campinas, SP (Brazil); Alcaide, Antonio [Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville (Spain); Pelizzaro-Rocha, Karin Juliane [Department of Biochemistry, Institute of Biology, University of Campinas, Campinas, SP (Brazil); Talero, Elena; Ávila-Román, Javier [Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville (Spain); Garcia-Mauriño, Sofia [Department of Plant Biology and Ecology, Faculty of Biology, University of Seville, Seville (Spain); Pilli, Ronaldo Aloise [Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, SP (Brazil); Carvalho, João Ernesto de [Chemical, Biological and Agricultural Pluridisciplinary Research Center (CPQBA), University of Campinas, Campinas, SP (Brazil); Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, SP (Brazil); Motilva, Virginia [Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville (Spain)

    2016-06-01

    Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10 μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer. - Highlights: • Goniothalamin (GTN) inhibits the development of TNBS-induced colitis in rats. • Moreover, GTN prevents the development of spontaneous colitis in IL-10 deficient mice. • This activity relies on downregulation of TNF-α and upregulation of SIRT-1 expression

  2. Metallothioneins in human tumors and potential roles in carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Cherian, M. George; Jayasurya, A.; Bay, Boon-Huat

    2003-12-10

    Metallothioneins (MT) are a group of low-molecular weight, cysteine rich intracellular proteins, which are encoded by a family of genes containing at least 10 functional isoforms in human. The expression and induction of these proteins have been associated with protection against DNA damage, oxidative stress and apoptosis. Moreover, MT may potentially activate certain transcriptional factors by donating zinc. Although MT is a cytosolic protein in resting cells, it can be translocated transiently to the cell nucleus during cell proliferation and differentiation. A number of studies have shown an increased expression of MT in various human tumors of the breast, colon, kidney, liver, lung, nasopharynx, ovary, prostate, salivary gland, testes, thyroid and urinary bladder. However, MT is down-regulated in certain tumors such as hepatocellular carcinoma and liver adenocarcinoma. Hence, the expression of MT is not universal to all human tumors, but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. In certain tumors such as germ cell carcinoma, the expression of MT is closely related to the tumor grade and proliferative activity. Increased expression of MT has also been observed in less differentiated tumors. Thus, expression of MT may be a potential prognostic marker for certain tumors. There are few reports on the expression of the different isoforms of MT which have been analyzed by specific gene probes. They reveal that certain isoforms are expressed in specific cell types. The factors which can influence MT induction in human tumors are not yet understood. Down-regulation of MT synthesis in hepatic tumors may be related to hypermethylation of the MT-promoter or mutation of other genes such as the p53 tumor suppressor gene. In vitro studies using human cancer cells suggest a possible role for p53 and the estrogen-receptor on the expression and induction of MT in epithelial neoplastic cells

  3. Metallothioneins in human tumors and potential roles in carcinogenesis

    International Nuclear Information System (INIS)

    Cherian, M. George; Jayasurya, A.; Bay, Boon-Huat

    2003-01-01

    Metallothioneins (MT) are a group of low-molecular weight, cysteine rich intracellular proteins, which are encoded by a family of genes containing at least 10 functional isoforms in human. The expression and induction of these proteins have been associated with protection against DNA damage, oxidative stress and apoptosis. Moreover, MT may potentially activate certain transcriptional factors by donating zinc. Although MT is a cytosolic protein in resting cells, it can be translocated transiently to the cell nucleus during cell proliferation and differentiation. A number of studies have shown an increased expression of MT in various human tumors of the breast, colon, kidney, liver, lung, nasopharynx, ovary, prostate, salivary gland, testes, thyroid and urinary bladder. However, MT is down-regulated in certain tumors such as hepatocellular carcinoma and liver adenocarcinoma. Hence, the expression of MT is not universal to all human tumors, but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. In certain tumors such as germ cell carcinoma, the expression of MT is closely related to the tumor grade and proliferative activity. Increased expression of MT has also been observed in less differentiated tumors. Thus, expression of MT may be a potential prognostic marker for certain tumors. There are few reports on the expression of the different isoforms of MT which have been analyzed by specific gene probes. They reveal that certain isoforms are expressed in specific cell types. The factors which can influence MT induction in human tumors are not yet understood. Down-regulation of MT synthesis in hepatic tumors may be related to hypermethylation of the MT-promoter or mutation of other genes such as the p53 tumor suppressor gene. In vitro studies using human cancer cells suggest a possible role for p53 and the estrogen-receptor on the expression and induction of MT in epithelial neoplastic cells

  4. Detection of human papillomavirus infection by molecular tests and its relation to colonic polyps and colorectal cancer

    Directory of Open Access Journals (Sweden)

    Faten Gazzaz

    2016-03-01

    Full Text Available Objectives: To prospectively examine the association between human papilloma virus (HPV colonization of the colonic mucosa and the development of colorectal polyps (CRPs, and colorectal cancer (CRC in Saudi Arabia. Methods: A case control study was performed between January 2013 and December 2014. All eligible patients underwent standard diagnostic colonoscopy. Patients with polyps or colorectal cancer were considered cases, while those with any other endoscopic findings were controls. Biopsy samples from polyps and tumors, and/or from normal colonic mucosa were acquired. Human papilloma virus colonization was detected using a hybrid capture technique of samples taken from both normal tissue, and CRPs and CRC. The association between HPV and CRPs/CRC was evaluated. Results: A total of 132 patients were recruited. The mean age was 53 (±15.9 years. Sixty patients had endoscopically detectable CRPs/CRC, and 72 had either inflammation or normal endoscopic evaluations. Only 4 (0.8% of the 132 samples that were collected and analyzed were positive for the HPV gene. Statistical analysis did not identify any significant association between HPV colonization and the presence of CRPs/CRC. The only significant predictor of detecting CRPs/CRC on colonoscopy was symptomatic presentation (odds ratio=11.072, 95% confidence interval 4.7-26.2, p<0.001. Conclusion: Human papilloma virus colonic colonization is rare in Saudi Arabia. An association between HPV colonization and CRP/CRC development could not be identified in this cohort of patients.

  5. Cell surface glycopeptides from human intestinal epithelial cell lines derived from normal colon and colon adenocarcinomas

    International Nuclear Information System (INIS)

    Youakim, A.; Herscovics, A.

    1985-01-01

    The cell surface glycopeptides from an epithelial cell line (CCL 239) derived from normal human colon were compared with those from three cell lines (HCT-8R, HCT-15, and CaCo-2) derived independently from human colonic adenocarcinomas. Cells were incubated with D-[2- 3 H]mannose or L-[5,6- 3 H]fucose for 24 h and treated with trypsin to release cell surface components which were then digested exhaustively with Pronase and fractionated on Bio-Gel P-6 before and after treatment with endo-beta-N-acetylglucosaminidase H. The most noticeable difference between the labeled glycopeptides from the tumor and CCL 239 cells was the presence in the former of an endo-beta-N-acetylglucosaminidase H-resistant high molecular weight glycopeptide fraction which was eluted in the void volume of Bio-Gel P-6. This fraction was obtained with both labeled mannose and fucose as precursors. However, acid hydrolysis of this fraction obtained after incubation with [2- 3 H]mannose revealed that as much as 60-90% of the radioactivity was recovered as fucose. Analysis of the total glycopeptides (cell surface and cell pellet) obtained after incubation with [2- 3 H]mannose showed that from 40-45% of the radioactivity in the tumor cells and less than 10% of the radioactivity in the CCL 239 cells was recovered as fucose. After incubation of the HCT-8R cells with D-[1,6- 3 H]glucosamine and L-[1- 14 C]fucose, strong acid hydrolysis of the labeled glycopeptide fraction excluded from Bio-Gel P-6 produced 3 H-labeled N-acetylglucosamine and N-acetylgalactosamine

  6. MicroRNA-320a suppresses human colon cancer cell proliferation by directly targeting β-catenin

    International Nuclear Information System (INIS)

    Sun, Jian-Yong; Huang, Yi; Li, Ji-Peng; Zhang, Xiang; Wang, Lei; Meng, Yan-Ling; Yan, Bo; Bian, Yong-Qian; Zhao, Jing; Wang, Wei-Zhong

    2012-01-01

    Highlights: ► miR-320a is downregulated in human colorectal carcinoma. ► Overexpression of miR-320a inhibits colon cancer cell proliferation. ► β-Catenin is a direct target of miR-320a in colon cancer cells. ► miR-320a expression inversely correlates with mRNA expression of β-catenin’s target genes in human colon carcinoma. -- Abstract: Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-320a) in human colorectal carcinoma. However, its expression pattern and underlying mechanisms in the development and progression of colorectal carcinoma has not been elucidated clearly. Here, we performed real-time PCR to examine the expression levels of miR-320a in colon cancer cell lines and tumor tissues. And then, we investigated its biological functions in colon cancer cells by a gain of functional strategy. Further more, by the combinational approaches of bioinformatics and experimental validation, we confirmed target associations of miR-320a in colorectal carcinoma. Our results showed that miR-320a was frequently downregulated in cancer cell lines and colon cancer tissues. And we demonstrated that miR-320a restoration inhibited colon cancer cell proliferation and β-catenin, a functionally oncogenic molecule was a direct target gene of miR-320a. Finally, the data of real-time PCR showed the reciprocal relationship between miR-320a and β-catenin’s downstream genes in colon cancer tissues. These findings indicate that miR-320a suppresses the growth of colon cancer cells by directly targeting β-catenin, suggesting its application in prognosis prediction and cancer treatment.

  7. MicroRNA-320a suppresses human colon cancer cell proliferation by directly targeting {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Jian-Yong [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi' an (China); Huang, Yi [Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, 710032 Xi' an (China); Li, Ji-Peng [State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi' an (China); Zhang, Xiang; Wang, Lei [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Meng, Yan-Ling [Department of Immunology, Fourth Military Medical University, 710032 Xi' an (China); Yan, Bo [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Bian, Yong-Qian [State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi' an (China); Zhao, Jing [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Wang, Wei-Zhong, E-mail: weichang@fmmu.edu.cn [State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi' an (China); and others

    2012-04-20

    Highlights: Black-Right-Pointing-Pointer miR-320a is downregulated in human colorectal carcinoma. Black-Right-Pointing-Pointer Overexpression of miR-320a inhibits colon cancer cell proliferation. Black-Right-Pointing-Pointer {beta}-Catenin is a direct target of miR-320a in colon cancer cells. Black-Right-Pointing-Pointer miR-320a expression inversely correlates with mRNA expression of {beta}-catenin's target genes in human colon carcinoma. -- Abstract: Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-320a) in human colorectal carcinoma. However, its expression pattern and underlying mechanisms in the development and progression of colorectal carcinoma has not been elucidated clearly. Here, we performed real-time PCR to examine the expression levels of miR-320a in colon cancer cell lines and tumor tissues. And then, we investigated its biological functions in colon cancer cells by a gain of functional strategy. Further more, by the combinational approaches of bioinformatics and experimental validation, we confirmed target associations of miR-320a in colorectal carcinoma. Our results showed that miR-320a was frequently downregulated in cancer cell lines and colon cancer tissues. And we demonstrated that miR-320a restoration inhibited colon cancer cell proliferation and {beta}-catenin, a functionally oncogenic molecule was a direct target gene of miR-320a. Finally, the data of real-time PCR showed the reciprocal relationship between miR-320a and {beta}-catenin's downstream genes in colon cancer tissues. These findings indicate that miR-320a suppresses the growth of colon cancer cells by directly targeting {beta}-catenin, suggesting its application in prognosis prediction and cancer treatment.

  8. A 36-year-old female with Krukenberg tumor from a colonic carcinoma.

    Science.gov (United States)

    Umakanthan, Srikanth; Bukelo, Maryann M; Hardik, Khandelwal

    2015-01-01

    Krukenberg tumor is bilateral ovarian carcinoma's metastasizing most commonly from a gastric primary followed by a colon. We report a case of 36-year-old female with bilateral ovarian mass diagnosed as Krukenberg with a work up for locating the primary site. In this case, we discuss widely the clinical aspects with histopathological features and literature review of Krukenberg tumor.

  9. Fatty acid and lipidomic data in normal and tumor colon tissues of rats fed diets with and without fish oil

    Directory of Open Access Journals (Sweden)

    Zora Djuric

    2017-08-01

    Full Text Available Data is provided to show the detailed fatty acid and lipidomic composition of normal and tumor rat colon tissues. Rats were fed either a Western fat diet or a fish oil diet, and half the rats from each diet group were treated with chemical carcinogens that induce colon cancer (azoxymethane and dextran sodium sulfate. The data show total fatty acid profiles of sera and of all the colon tissues, namely normal tissue from control rats and both normal and tumor tissues from carcinogen-treated rats, as obtained by gas chromatography with mass spectral detection. Data from lipidomic analyses of a representative subset of the colon tissue samples is also shown in heat maps generated from hierarchical cluster analysis. These data display the utility lipidomic analyses to enhance the interpretation of dietary feeding studies aimed at cancer prevention and support the findings published in the companion paper (Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors, Djuric et al., 2017 [1].

  10. Perivascular Interstitial Cells of Cajal in Human ColonSummary

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    Yuan-An Liu

    2015-01-01

    Full Text Available Background & Aims: Interstitial cells of Cajal (ICC closely associate with nerves and smooth muscles to modulate gut motility. In the ICC microenvironment, although the circulating hormones/factors have been shown to influence ICC activities, the association between ICC and microvessels in the gut wall has not been described. We applied three-dimensional (3D vascular histology with c-kit staining to identify the perivascular ICC and characterize their morphologic and population features in the human colon wall. Methods: Full-thickness colons were obtained from colectomies performed for colorectal cancer. We targeted the colon wall away from the tumor site. Confocal microscopy with optical clearing (use of immersion solution to reduce scattering in optical imaging was performed to simultaneously reveal the ICC and vascular networks in space. 3D image rendering and projection were digitally conducted to illustrate the ICC–vessel contact patterns. Results: Perivascular ICC were identified in the submucosal border, myenteric plexus, and circular and longitudinal muscles via high-definition 3D microscopy. Through in-depth image projection, we specified two contact patterns—the intimate cell body-to-vessel contact (type I, 18% of ICC in circular muscle and the long-distance process-to-vessel contact (type II, 16%—to classify perivascular ICC. Particularly, type I perivascular ICC were detected with elevated c-kit staining levels and were routinely found in clusters, making them readily distinguishable from other ICC in the network. Conclusions: We propose a new subclass of ICC that closely associates with microvessels in the human colon. Our finding suggests a functional relationship between these mural ICC and microvessels based on the morphologic proximity. Keywords: 3D Histology, c-kit, ICC, Mural Cells

  11. Functional Imaging of Proteolysis: Stromal and Inflammatory Cells Increase Tumor Proteolysis

    Directory of Open Access Journals (Sweden)

    Mansoureh Sameni

    2003-07-01

    Full Text Available The underlying basement membrane is degraded during progression of breast and colon carcinoma. Thus, we imaged degradation of a quenched fluorescent derivative of basement membrane type IV collagen (DQ-collagen IV by living human breast and colon tumor spheroids. Proteolysis of DQ-collagen IV by HCT 116 and HKh-2 human colon tumor spheroids was both intracellular and pericellular. In contrast, proteolysis of DQ-collagen IV by BT20 human breast tumor spheroids was pericellular. As stromal elements can contribute to proteolytic activities associated with tumors, we also examined degradation of DQ-collagen IV by human monocytes/macrophages and colon and breast fibroblasts. Fibroblasts themselves exhibited a modest amount of pericellular degradation. Degradation was increased 4–17-fold in cocultures of fibroblasts and tumor cells as compared to either cell type alone. Inhibitors of matrix metalloproteinases, plasmin, and the cysteine protease, cathepsin B, all reduced degradation in the cocultures. Monocytes did not degrade DQ-collagen IV; however, macrophages degraded DQ-collagen IV intracellularly. In coculture of tumor cells, fibroblasts, and macrophages, degradation of DQ-collagen IV was further increased. Imaging of living tumor and stromal cells has, thus, allowed us to establish that tumor proteolysis occurs pericellularly and intracellularly and that tumor, stromal, and inflammatory cells all contribute to degradative processes.

  12. A 36-year-old female with Krukenberg tumor from a colonic carcinoma

    Directory of Open Access Journals (Sweden)

    Srikanth Umakanthan

    2015-01-01

    Full Text Available Krukenberg tumor is bilateral ovarian carcinoma′s metastasizing most commonly from a gastric primary followed by a colon. We report a case of 36-year-old female with bilateral ovarian mass diagnosed as Krukenberg with a work up for locating the primary site. In this case, we discuss widely the clinical aspects with histopathological features and literature review of Krukenberg tumor.

  13. Colonic spirochetosis in animals and humans.

    Science.gov (United States)

    Smith, James L

    2005-07-01

    Colonic spirochetosis is a disease caused by the gram-negative bacteria Brachyspira aalborgi and Brachyspira pilosicoli. B. pilosicoli induces disease in both humans and animals, whereas B. aalborgi affects only humans and higher primates. Symptoms in humans include diarrhea, rectal bleeding, and abdominal cramps. Colonic spirochetosis is common in third world countries; however, in developed countries, the disease is observed mainly in homosexual males. Terminally ill patients infected with Brachyspira are particularly at risk for developing spirochetemia. Diarrhea, poor growth performance, and decreased feed-to-gain efficiency is seen in pigs with colonic spirochetosis. The disease in chickens is characterized by delayed and/or reduced egg production, diarrhea, poor feed conversion, and retarded growth. Thus, colonic spirochetosis can represent a serious economic loss in the swine and poultry industries. The organisms are transmitted by the fecal-oral route, and several studies have demonstrated that human, primate, pig, dog, or bird strains of B. pilosicoli can be transmitted to pigs, chickens, and mice. B. pilosicoli may be a zoonotic pathogen, and although it has not been demonstrated, there is a possibility that both B. pilosicoli and B. aalborgi can be transferred to humans via contact with the feces of infected animals, meat from infected animals, or food contaminated by food handlers. Neither B. pilosicoli nor B. aalborgi has been well characterized in terms of basic cellular functions, pathogenicity, or genetics. Studies are needed to more thoroughly understand these Brachyspira species and their disease mechanisms.

  14. A Ketogenic Formula Prevents Tumor Progression and Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice

    Directory of Open Access Journals (Sweden)

    Kentaro Nakamura

    2018-02-01

    Full Text Available Low-carbohydrate, high-fat diets (ketogenic diets might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR, tumor-bearing (TB, and ketogenic formula (KF groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KF ad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia.

  15. Biosynthesis of human colonic mucin: Muc2 is the prominent secretory mucin

    NARCIS (Netherlands)

    Tytgat, K. M.; Büller, H. A.; Opdam, F. J.; Kim, Y. S.; Einerhand, A. W.; Dekker, J.

    1994-01-01

    Human colonic epithelium produces large amounts of mucin. The aim of this study was to examine mucin biosynthesis in the human colon. Human colonic mucin was isolated using CsCl density gradients, and polyclonal antiserum was raised. Biosynthesis of colonic mucins was studied by labeling colonic

  16. [Right Hemi-Colectomy for a Metastatic Transverse Colon Tumor from Breast Cancer Following Bilateral Breast Cancer Resection - A Case Report].

    Science.gov (United States)

    Okamura, Shu; Yanagisawa, Tetsu; Ohishi, Kazuhito; Murata, Kohei; Nushijima, Yoichiro; Hamano, Rie; Fukuchi, Nariaki; Ebisui, Chikara; Yokouchi, Hideoki; Kinuta, Masakatsu

    2016-11-01

    We herein report the case of a 75-year-old female patient who underwent 4 surgeries for bilateral breast cancer and its recurrence. When she presented at a clinic with an irritable colon, a fist-sized tumor was palpated in the right upper abdomen at her first medical examination. Abdominal CT scan at the clinic revealed a tumor with a maximum diameter of 10 cm on the right side of the transverse colon and multiple swollen mesenteric lymph nodes. Therefore, the patient was referred to our hospital for surgery. Colonoscopy revealed stenosis of the same lesion with an edematous mucosa and sclerosis. Using immunohistochemistry, a biopsy specimen from the lesion tested positive for CK AE1+AE3, and negative for CD20(-)and CD3 (-). As a result, the tumor was diagnosed as a poorly differentiated adenocarcinoma. We performed right hemicolectomy to avoid her intestinal obstruction. Tumor cells were mainly present at the subserosa, according to HEstaining. Using immunostaining, the cells were tested for the following markers: CDX2(-), GCDFP15(weakly positive), CK7(strongly positive), CD20(partially positive), E R(+), PgR(-), and HER2(1+), characterizing the tumor as metastasis of breast cancer. Although gastro-intestinal metastasis from breast cancer is rare, and colon metastasis is even rarer, it might be necessary to rule out the possibility of a metastatic colon tumor from breast cancer when treating patients with a colon tumor who have undergone surgery for breast cancer.

  17. Effects of Tumor Necrosis Factor-α on Morphology and Mechanical Properties of HCT116 Human Colon Cancer Cells Investigated by Atomic Force Microscopy.

    Science.gov (United States)

    Liu, Huiqing; Wang, Nan; Zhang, Zhe; Wang, Hongda; Du, Jun; Tang, Jilin

    2017-01-01

    Chronic inflammation orchestrates the tumor microenvironment and is strongly associated with cancer. Tumor necrosis factor- α (TNF α ) is involved in tumor invasion and metastasis by inducing epithelial to mesenchymal transition (EMT). This process is defined by the loss of epithelial characteristics and gain of mesenchymal traits. The mechanisms of TNF α -induced EMT in cancer cells have been well studied. However, mechanical properties have not yet been probed. In this work, atomic force microscopy (AFM) was applied to investigate the morphology and mechanical properties of EMT in HCT116 human colon cancer cells. A remarkable morphological change from cobblestone shape to spindle-like morphology was observed. In parallel, AFM images showed that the cellular cytoskeleton was rearranged from a cortical to a stress-fiber pattern. Moreover, cell stiffness measurements indicated that Young's modulus of cells gradually reduced from 1 to 3 days with TNF α -treatment, but it has an apparent increase after 4 days of treatment compared with that for 3 days. Additionally, Young's modulus of the cells treated with TNF α for 4 days is slightly larger than that for 1 or 2 days, but still less than that of the untreated cells. Our work contributes to a better understanding of colorectal cancer metastasis induced by inflammation.

  18. Effects of Tumor Necrosis Factor-α on Morphology and Mechanical Properties of HCT116 Human Colon Cancer Cells Investigated by Atomic Force Microscopy

    Directory of Open Access Journals (Sweden)

    Huiqing Liu

    2017-01-01

    Full Text Available Chronic inflammation orchestrates the tumor microenvironment and is strongly associated with cancer. Tumor necrosis factor-α (TNFα is involved in tumor invasion and metastasis by inducing epithelial to mesenchymal transition (EMT. This process is defined by the loss of epithelial characteristics and gain of mesenchymal traits. The mechanisms of TNFα-induced EMT in cancer cells have been well studied. However, mechanical properties have not yet been probed. In this work, atomic force microscopy (AFM was applied to investigate the morphology and mechanical properties of EMT in HCT116 human colon cancer cells. A remarkable morphological change from cobblestone shape to spindle-like morphology was observed. In parallel, AFM images showed that the cellular cytoskeleton was rearranged from a cortical to a stress-fiber pattern. Moreover, cell stiffness measurements indicated that Young’s modulus of cells gradually reduced from 1 to 3 days with TNFα-treatment, but it has an apparent increase after 4 days of treatment compared with that for 3 days. Additionally, Young’s modulus of the cells treated with TNFα for 4 days is slightly larger than that for 1 or 2 days, but still less than that of the untreated cells. Our work contributes to a better understanding of colorectal cancer metastasis induced by inflammation.

  19. [Evaluation of knowledge about colon cancer prevention versus other tumors].

    Science.gov (United States)

    Sanguinetti, José María; Henry, Nicolás; Ocaña, Domingo; Polesel, Julio Lotero

    2015-06-01

    In Argentina almost 7% of deaths are due to different cancers with screening strategies. Evaluate knowledge about cancer prevention compared with other tumors. Materials. A descriptive and comparative study. A survey between April and June 2013 in Salta City, province of Salta, Argentina. Correct answers were considered. Statistical analysis: Descriptive (mean and percentage), comparative Chi square Test (significance level Pmama and cervix. 20% (CI 0,13-0,28) knew that colon cancer has a genetic predisposition and 58% (CI 0,48-0,67) about mama. 73% (CI 0,63-0,8) received information about cancer prevention. The main source of information was the physician. 46% (CI 0,36-0,55) received medical care in private institutions. Those who had social security, higher educational levels and medical care in private institutions had better knowledge about cancer prevention except in colon cancer. The global results showed levels below 70% in general but extremely low in colon cancer. Not having social security, receiving medical care in public institutions and having a low educational level are related with poor knowledge about cancer prevention except for colon and prostate cancer.

  20. KITENIN is associated with tumor progression in human gastric cancer.

    Science.gov (United States)

    Ryu, Ho-Seong; Park, Young-Lan; Park, Su-Jin; Lee, Ji-Hee; Cho, Sung-Bum; Lee, Wan-Sik; Chung, Ik-Joo; Kim, Kyung-Keun; Lee, Kyung-Hwa; Kweon, Sun-Seog; Joo, Young-Eun

    2010-09-01

    KAI1 COOH-terminal interacting tetraspanin (KITENIN) promotes tumor cell migration, invasion and metastasis in colon, bladder, head and neck cancer. The aims of current study were to evaluate whether KITENIN affects tumor cell behavior in human gastric cancer cell line and to document the expression of KITENIN in a well-defined series of gastric tumors, including complete long-term follow-up, with special reference to patient prognosis. To evaluate the impact of KITENIN knockdown on behavior of a human gastric cancer cell line, AGS, migration, invasion and proliferation assays using small-interfering RNA were performed. The expression of activator protein-1 (AP-1) target genes and AP-1 transcriptional activity were evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and luciferase reporter assay. The expression of KITENIN and AP-1 target genes by RT-PCR and Western blotting or immunohistochemistry was also investigated in human gastric cancer tissues. The knockdown of KITENIN suppressed tumor cell migration, invasion and proliferation in AGS cells. The mRNA expression of matrix metalloproteinase-1 (MMP-1), MMP-3, cyclooxygenase-2 (COX-2), and CD44 was reduced by knockdown of KITENIN in AGS. AP-1 transcriptional activity was significantly decreased by knockdown of KITENIN in AGS cells. KITENIN expression was significantly increased in human cancer tissues at RNA and protein levels. Expression of MMP-1, MMP-3, COX-2 and CD44 were significantly increased in human gastric cancer tissues. Immunostaining of KITENIN was predominantly identified in the cytoplasm of cancer cells. Expression of KITENIN was significantly associated with tumor size, Lauren classification, depth of invasion, lymph node metastasis, tumor stage and poor survival. These results indicate that KITENIN plays an important role in human gastric cancer progression by AP-1 activation.

  1. Zebrafish Axenic Larvae Colonization with Human Intestinal Microbiota.

    Science.gov (United States)

    Arias-Jayo, Nerea; Alonso-Saez, Laura; Ramirez-Garcia, Andoni; Pardo, Miguel A

    2018-04-01

    The human intestine hosts a vast and complex microbial community that is vital for maintaining several functions related with host health. The processes that determine the gut microbiome composition are poorly understood, being the interaction between species, the external environment, and the relationship with the host the most feasible. Animal models offer the opportunity to understand the interactions between the host and the microbiota. There are different gnotobiotic mice or rat models colonized with the human microbiota, however, to our knowledge, there are no reports on the colonization of germ-free zebrafish with a complex human intestinal microbiota. In the present study, we have successfully colonized 5 days postfertilization germ-free zebrafish larvae with the human intestinal microbiota previously extracted from a donor and analyzed by high-throughput sequencing the composition of the transferred microbial communities that established inside the zebrafish gut. Thus, we describe for first time which human bacteria phylotypes are able to colonize the zebrafish digestive tract. Species with relevant interest because of their linkage to dysbiosis in different human diseases, such as Akkermansia muciniphila, Eubacterium rectale, Faecalibacterium prausnitzii, Prevotella spp., or Roseburia spp. have been successfully transferred inside the zebrafish digestive tract.

  2. Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX Colon Cancer Assay.

    Science.gov (United States)

    Clark-Langone, Kim M; Sangli, Chithra; Krishnakumar, Jayadevi; Watson, Drew

    2010-12-23

    The Oncotype DX Colon Cancer Assay is a new diagnostic test for determining the likelihood of recurrence in stage II colon cancer patients after surgical resection using fixed paraffin embedded (FPE) primary colon tumor tissue. Like the Oncotype DX Breast Cancer Assay, this is a high complexity, multi-analyte, reverse transcription (RT) polymerase chain reaction (PCR) assay that measures the expression levels of specific cancer-related genes. By capturing the biology underlying each patient's tumor, the Oncotype DX Colon Cancer Assay provides a Recurrence Score (RS) that reflects an individualized risk of disease recurrence. Here we describe its analytical performance using pre-determined performance criteria, which is a critical component of molecular diagnostic test validation. All analytical measurements met pre-specified performance criteria. PCR amplification efficiency for all 12 assays was high, ranging from 96% to 107%, while linearity was demonstrated over an 11 log2 concentration range for all assays. Based on estimated components of variance for FPE RNA pools, analytical reproducibility and precision demonstrated low SDs for individual genes (0.16 to 0.32 CTs), gene groups (≤ 0.05 normalized/aggregate CTs) and RS (≤ 1.38 RS units). Analytical performance characteristics shown here for both individual genes and gene groups in the Oncotype DX Colon Cancer Assay demonstrate consistent translation of specific biology of individual tumors into clinically useful diagnostic information. The results of these studies illustrate how the analytical capability of the Oncotype DX Colon Cancer Assay has enabled clinical validation of a test to determine individualized recurrence risk after colon cancer surgery.

  3. Assessment of serum tumor markers, tumor cell apoptosis and immune response in patients with advanced colon cancer after DC-CIK combined with intravenous chemotherapy

    Directory of Open Access Journals (Sweden)

    Lei-Fan Li

    2016-12-01

    Full Text Available Objective: To study the effect of DC-CIK combined with intravenous chemotherapy on serum tumor markers, tumor cell apoptosis and immune response in patients with advanced colon cancer. Methods: A total of 79 patients with advanced colon cancer conservatively treated in our hospital between May 2012 and October 2015 were retrospectively studied and divided into DC-CIK group and intravenous chemotherapy group according to different therapeutic regimens, DC-CIK group received DC-CIK combined with intravenous chemotherapy and intravenous chemotherapy group received conventional intravenous chemotherapy. After three cycles of chemotherapy, the content of tumor markers in serum, expression levels of apoptotic molecules in tumor lesions as well as immune function indexes were determined. Results: After 3 cycles of chemotherapy, CEA, CA199, CA242, HIF-1α, IL-4, IL-5 and IL-10 content in serum of DC-CIK group were significantly lower than those of intravenous chemotherapy group; p53, FAM96B, PTEN, PHLPP, ASPP2 and RASSF10 mRNA content in tumor lesions of DC-CIK group were significantly higher than those of intravenous chemotherapy group; the fluorescence intensity of CD3, CD4 and CD56 on peripheral blood mononuclear cell surface of DC-CIK group were significantly higher than those of intravenous chemotherapy group while the fluorescence intensity of CD8 and CD25 were significantly lower than those of intravenous chemotherapy group; IL-2 and IFN-γ content in serum of DC-CIK group were significantly higher than those of intravenous chemotherapy group while IL-4, IL-5 and IL-10 content were significantly lower than those of intravenous chemotherapy group. Conclusions: DC-CIK combined with intravenous chemotherapy has better effect on killing colon cancer cells and inducing colon cancer cell apoptosis than conventional intravenous chemotherapy, and can also improve the body's anti-tumor immune response.

  4. Increased mRNA expression of a laminin-binding protein in human colon carcinoma: Complete sequence of a full-length cDNA encoding the protein

    International Nuclear Information System (INIS)

    Yow, Hsiukang; Wong, Jau Min; Chen, Hai Shiene; Lee, C.; Steele, G.D. Jr.; Chen, Lanbo

    1988-01-01

    Reliable markers to distinguish human colon carcinoma from normal colonic epithelium are needed particularly for poorly differentiated tumors where no useful marker is currently available. To search for markers the authors constructed cDNA libraries from human colon carcinoma cell lines and screened for clones that hybridize to a greater degree with mRNAs of colon carcinomas than with their normal counterparts. Here they report one such cDNA clone that hybridizes with a 1.2-kilobase (kb) mRNA, the level of which is ∼9-fold greater in colon carcinoma than in adjacent normal colonic epithelium. Blot hybridization of total RNA from a variety of human colon carcinoma cell lines shows that the level of this 1.2-kb mRNA in poorly differentiated colon carcinomas is as high as or higher than that in well-differentiated carcinomas. Molecular cloning and complete sequencing of cDNA corresponding to the full-length open reading frame of this 1.2-kb mRNA unexpectedly show it to contain all the partial cDNA sequence encoding 135 amino acid residues previously reported for a human laminin receptor. The deduced amino acid sequence suggests that this putative laminin-binding protein from human colon carcinomas consists of 295 amino acid residues with interesting features. There is an unusual C-terminal 70-amino acid segment, which is trypsin-resistant and highly negatively charged

  5. Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro

    International Nuclear Information System (INIS)

    Yang, Zi-Rong; Liu, Meng; Peng, Xiu-Lan; Lei, Xiao-Fei; Zhang, Ji-Xiang; Dong, Wei-Guo

    2012-01-01

    Highlights: ► Noscapine inhibited cell viability of colon cancer in a time- and dose- dependent manner. ► G 2 /M phase arrest and chromatin condensation and nuclear fragmentation were induced. ► Noscapine promoted apoptosis via mitochondrial pathways. ► Tumorigenicity was inhibited by noscapine. -- Abstract: Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC 50 = 75 μM). This cytotoxicity was reflected by cell cycle arrest at G 2 /M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer.

  6. Isolation and in vitro expansion of human colonic stem cells

    NARCIS (Netherlands)

    Jung, P.; Sato, T.; Merlos-Suarez, A.; Barriga, F.M.; Iglesias, M.; Rossell, D.; Auer, H.; Gallardo, M.; Blasco, M.A.; Sancho, E.; Clevers, H.; Batlle, E.

    2011-01-01

    Here we describe the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of ephrin type-B receptor 2 (EPHB2) allows the purification of different cell types from human colon mucosa biopsies. The highest EPHB2 surface levels correspond to epithelial colonic

  7. Prehistoric human colonization of India

    Indian Academy of Sciences (India)

    Unknown

    J. Biosci. | Vol. 26 | No. 4 | Suppl. | November 2001. V N Misra. 492 ... humans differ from the other apes in their upright posture, ... characterized by Levallois flakes and blades and by the ... and the coastal region running parallel to them, northeast ..... November 2001. Prehistoric human colonization of India. 497. Figure 1.

  8. [A case of polymyositis associated with transverse colon cancer that responded to tumor resection and chemotherapy].

    Science.gov (United States)

    Uchida, Yuichiro; Okabe, Michio; Kawamoto, Yusuke; Tsukumo, Yuta; Ito, Tadashi

    2015-04-01

    A 72-year-old woman was admitted to our hospital because of muscle weakness and was diagnosed as having polymyositis. Whole-body evaluation revealed advanced transverse colon cancer, and we therefore considered it likely that the patient had paraneoplastic myositis. We performed a curative surgical resection for colon cancer, after which her serum creatine phosphokinase(CPK)level greatly decreased. Steroid therapy was administered postoperatively. However, her CPK levels remained persistently high, even after steroid pulse therapy, and we considered that this was due to steroid-resistance myositis. We administered chemotherapy for colon cancer using 5-fluorouracil plus Leucovorin(5-FU/LV), after which the CPK levels gradually decreased. There have been few previous reports of polymyositis associated with colon cancer and a standard treatment for paraneoplastic myositis has not been established. Most clinicians believe that treatment of the primary tumor may contribute to an improvement of myositis, and in our case, tumor resection and chemotherapy were effective.

  9. Hepatoduodenal lymph node metastasis mimicking Klatskin tumor in a patient with sigmoid colon mucinous cancer

    Directory of Open Access Journals (Sweden)

    Hovhannes Vardevanyan, PhD

    2017-09-01

    Full Text Available We report a case of a 48-year-old female patient, who presented with abdominal pain, jaundice, and lack of appetite. Ultrasound showed intrahepatic biliary dilatation with retroperitoneal lymphadenopathy. Further magnetic resonance cholangiopancreatography detected Klatskin tumor. Computed tomography (CT confirmed the Klatskin tumor with liver metastases and retroperitoneal lymphadenopathy. Biopsy from the hepatic lesion identified mucinous adenocarcinoma, likely originating from bile ducts. Endoscopic retrograde cholangiopancreatography was performed 3 times with stents placed in the left and right hepatic bile ducts. Later the patient had hematochezia and was referred to colonoscopy. Tubulovillous adenoma with dysplasia was diagnosed with signs of in situ cancer. Preoperative CT was done for further staging: new pulmonary metastases were discovered. Sigmoid colon was resected. Histopathology verified a poorly differentiated mucinous adenocarcinoma within the tubulovillous adenoma. Intraoperative biopsies of porta hepatis mass resembled metastatic lymph nodes in hepatoduodenal ligament, mimicking Klatskin tumor. Retrospective analysis of CT data demonstrated presence of sigmoid colon tumor.

  10. Traditional Chinese Medicine Curcumin Sensitizes Human Colon Cancer to Radiation by Altering the Expression of DNA Repair-related Genes.

    Science.gov (United States)

    Yang, Guangen; Qiu, Jianming; Wang, Dong; Tao, Yong; Song, Yihuan; Wang, Hongtao; Tang, Juping; Wang, Xing; Sun, Y U; Yang, Zhijian; Hoffman, Robert M

    2018-01-01

    The aim of the present study was to investigate the radio-sensitizing efficacy of curcumin, a traditional Chinese medicine (TCM) on colon cancer cells in vitro and in vivo. Human colon cancer HT-29 cells were treated with curcumin (2.5 μM), irradiation (10 Gy) and the combination of irradiation and curcumin. Cell proliferation was assessed using the MTT assay. Apoptotic cells were detected by Annexin V-PE/7-AAD analysis. PCR was performed to determine differential-expression profiling of 95 DNA-repair genes in irradiated cells and cells treated with both irradiation and curcumin. Differentially-expressed genes were confirmed by Western blotting. In vivo radio-sensitizing efficacy of curcumin was assessed in a xenograft mouse model of HT-29 colon cancer. Curcumin was administrated daily by intraperitoneal injection at 20 mg/kg/dose. Mice received irradiation (10 Gy) twice weekly. Apoptosis of the cancer cells following treatment was determined by TUNEL staining. Irradiation induced proliferation inhibition and apoptosis of HT-29 cells in vitro. Concurrent curcumin treatment sensitized the HT-29 tumor to irradiation (pcurcumin and irradiation compared with irradiation alone (pcurcumin and irradiation resulted in a significantly greater tumor-growth inhibition and apoptosis compared to irradiation treatment alone (pCurcumin sensitizes human colon cancer in vitro and in vivo to radiation. Downregulation of LIG4 and PNKP and upregulation of XRCC5 and CCNH DNA-repair-related genes were involved in the radio-sensitizing efficacy of curcumin in colon cancer. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  11. Localization by whole-body autoradiography of intact and fragmented radiolabeled antibodies in a metastatic human colonic cancer model

    International Nuclear Information System (INIS)

    Fand, Irwin; Sharkey, R.M.; Grundy, J.P.; Goldenberg, D.M.

    1992-01-01

    In this report, we have employed macroautoradiography to compare the tumor targeting of 125 I-labeled anti-carcinoembryonic antigen (CEA) MAb (NP-4) to 125 I-labeled anti-colon-specific antigen-p (CSAp) MAb (Mu-9) and their labeled F(ab') 2 and Fab' fragments, in nude mice each bearing large dorsal human colonic tumor xenografts, and small nodular tumors in the liver and lungs. Using intact MAbs (NP-4 and Mu-9), clearance of background radioactivity was delayed to 3-7 days post-treatment. Treatment with F(ab') 2 and Fab' fragments of both NP-4 and Mu-9 MAbs, however, promoted clearance of background 125 I-radioactivity which was well advanced by 6-24 h and complete by 24-48 h after injection. Localization of 125 I-radioactivity in large and micrometastatic tumor perimeters was the most characteristic uptake pattern observed for both intact and fragmented MAbs. Qualitative analysis of macroautoradiographic images and quantitative densitometry indicated that the higher tumor-to-blood ratios achieved with labeled F(ab') 2 and Fab' fragments at early time points, compared to labeled whole immunoglobulin, appeared to be more a function of rapid plasma clearance, tumor mass, location of xenografts and specific tumor growth patterns than increased tumor penetrance by lower molecular weight univalent and bivalent immune fragments. (Author)

  12. Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

    NARCIS (Netherlands)

    Erk, M.J. van; Teuling, E.; Staal, Y.C.M.; Huybers, S.; Bladeren, P.J. van; Aarts, J.M.M.J.G.; Ommen, B. van

    2004-01-01

    Background. Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an

  13. Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

    NARCIS (Netherlands)

    Erk, van M.J.; Teuling, E.; Staal, Y.C.M.; Huybers, S.; Bladeren, van P.J.; Aarts, J.M.M.J.G.; Ommen, van B.

    2004-01-01

    Background: Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an

  14. Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

    NARCIS (Netherlands)

    Van Erk, Marjan J; Teuling, Eva; Staal, Yvonne C. M.; Huybers, Sylvie; Van Bladeren, Peter J; Aarts, Jac MMJG; Van Ommen, Ben

    2004-01-01

    BACKGROUND: Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an

  15. Can the localization of primary colonic tumors be improved by staging CT without specific bowel preparation compared to optical colonoscopy?

    International Nuclear Information System (INIS)

    Feuerlein, Sebastian; Grimm, Lars J.; Davenport, Matthew S.; Haystead, Clare M.; Miller, Chad M.; Neville, Amy M.; Jaffe, Tracy A.

    2012-01-01

    Objectives: To investigate the ability of staging computed tomography (CT) without bowel preparation to accurately localize colonic tumors compared to optical colonoscopy. Methods: The local institutional review board approved this retrospective and HIPAA-compliant study. Forty-six patients with colonic adenocarcinoma, preoperative colonoscopy, and staging CT within 60 days of resection were included. Patients underwent contrast enhanced CT imaging without bowel preparation or oral contrast. The colon was divided into four segments with the operative reports used as the standard. Rectal and cecal cancers were excluded. CT scans were reviewed by 5 readers in a segmental binary fashion using a 5-point confidence scale in two sessions blinded and unblinded to the colonoscopy report. Results: At surgery 49 tumors were found in 46 patients. Readers detected 86.1%, 74.3%, and 66.9% of lesions with 92.0%, 94.1%, and 95.4% accuracy for confidence scores of ≥3, ≥4, and 5. CT interobserver agreement was good (κ = 0.82) for the unblinded and moderate (κ = 0.60) for the blinded read. Colonoscopic localization was only 78.7% accurate with 2 tumors undiscovered. Colonoscopic accuracy was low in the descending colon (57.1%) and the transverse colon (55.6%). Conclusions: Preoperative staging CT is more accurate than colonoscopy in the localization of colonic tumors

  16. Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival.

    Science.gov (United States)

    Fink, Stephen P; Myeroff, Lois L; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K V; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S; Wang, Zhenghe; Markowitz, Sanford D

    2015-10-13

    Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target.

  17. Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX® Colon Cancer Assay

    International Nuclear Information System (INIS)

    Clark-Langone, Kim M; Sangli, Chithra; Krishnakumar, Jayadevi; Watson, Drew

    2010-01-01

    The Oncotype DX ® Colon Cancer Assay is a new diagnostic test for determining the likelihood of recurrence in stage II colon cancer patients after surgical resection using fixed paraffin embedded (FPE) primary colon tumor tissue. Like the Oncotype DX Breast Cancer Assay, this is a high complexity, multi-analyte, reverse transcription (RT) polymerase chain reaction (PCR) assay that measures the expression levels of specific cancer-related genes. By capturing the biology underlying each patient's tumor, the Oncotype DX Colon Cancer Assay provides a Recurrence Score (RS) that reflects an individualized risk of disease recurrence. Here we describe its analytical performance using pre-determined performance criteria, which is a critical component of molecular diagnostic test validation. All analytical measurements met pre-specified performance criteria. PCR amplification efficiency for all 12 assays was high, ranging from 96% to 107%, while linearity was demonstrated over an 11 log 2 concentration range for all assays. Based on estimated components of variance for FPE RNA pools, analytical reproducibility and precision demonstrated low SDs for individual genes (0.16 to 0.32 C T s), gene groups (≤0.05 normalized/aggregate C T s) and RS (≤1.38 RS units). Analytical performance characteristics shown here for both individual genes and gene groups in the Oncotype DX Colon Cancer Assay demonstrate consistent translation of specific biology of individual tumors into clinically useful diagnostic information. The results of these studies illustrate how the analytical capability of the Oncotype DX Colon Cancer Assay has enabled clinical validation of a test to determine individualized recurrence risk after colon cancer surgery

  18. Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX® Colon Cancer Assay

    Directory of Open Access Journals (Sweden)

    Krishnakumar Jayadevi

    2010-12-01

    Full Text Available Abstract Background The Oncotype DX® Colon Cancer Assay is a new diagnostic test for determining the likelihood of recurrence in stage II colon cancer patients after surgical resection using fixed paraffin embedded (FPE primary colon tumor tissue. Like the Oncotype DX Breast Cancer Assay, this is a high complexity, multi-analyte, reverse transcription (RT polymerase chain reaction (PCR assay that measures the expression levels of specific cancer-related genes. By capturing the biology underlying each patient's tumor, the Oncotype DX Colon Cancer Assay provides a Recurrence Score (RS that reflects an individualized risk of disease recurrence. Here we describe its analytical performance using pre-determined performance criteria, which is a critical component of molecular diagnostic test validation. Results All analytical measurements met pre-specified performance criteria. PCR amplification efficiency for all 12 assays was high, ranging from 96% to 107%, while linearity was demonstrated over an 11 log2 concentration range for all assays. Based on estimated components of variance for FPE RNA pools, analytical reproducibility and precision demonstrated low SDs for individual genes (0.16 to 0.32 CTs, gene groups (≤0.05 normalized/aggregate CTs and RS (≤1.38 RS units. Conclusions Analytical performance characteristics shown here for both individual genes and gene groups in the Oncotype DX Colon Cancer Assay demonstrate consistent translation of specific biology of individual tumors into clinically useful diagnostic information. The results of these studies illustrate how the analytical capability of the Oncotype DX Colon Cancer Assay has enabled clinical validation of a test to determine individualized recurrence risk after colon cancer surgery.

  19. Inhibition of phospholipaseD2 increases hypoxia-induced human colon cancer cell apoptosis through inactivating of the PI3K/AKT signaling pathway.

    Science.gov (United States)

    Liu, Maoxi; Fu, Zhongxue; Wu, Xingye; Du, Kunli; Zhang, Shouru; Zeng, Li

    2016-05-01

    Hypoxia is a common feature of solid tumor, and is a direct stress that triggers apoptosis in many human cell types. As one of solid cancer, hypoxia exists in the whole course of colon cancer occurrence and progression. Our previous studies shown that hypoxia induce high expression of phospholipase D2 (PLD2) and survivin in colon cancer cells. However, the correlation between PLD2 and survivin in hypoxic colon cancer cells remains unknown. In this study, we observed significantly elevated PLD2 and survivin expression levels in colon cancer tissues and cells. This is a positive correlation between of them, and co-expression of PLD2 and survivin has a positive correlation with the clinicpatholic features including tumor size, TNM stage, and lymph node metastasis. We also found that hypoxia induced the activity of PLD increased significant mainly caused by PLD2 in colon cancer cells. However, inhibition the activity of PLD2 induced by hypoxia promotes the apoptosis of human colon cancer cells, as well as decreased the expression of apoptosis markers including survivin and bcl2. Moreover, the pharmacological inhibition of PI3K/AKT supported the hypothesis that promotes the apoptosis of hypoxic colon cancer cells by PLD2 activity inhibition may through inactivation of the PI3K/AKT signaling pathway. Furthermore, interference the PLD2 gene expression leaded to the apoptosis of hypoxic colon cancer cells increased and also decreased the expression level of survivin and bcl2 may through inactivation of PI3K/AKT signaling pathway. These results indicated that PLD2 play antiapoptotic role in colon cancer under hypoxic conditions, inhibition of the activity, or interference of PLD2 gene expression will benefit for the treatment of colon cancer patients.

  20. Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Zi-Rong; Liu, Meng; Peng, Xiu-Lan; Lei, Xiao-Fei; Zhang, Ji-Xiang [Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province (China); Dong, Wei-Guo, E-mail: dongwg1966@yahoo.com.cn [Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province (China)

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Noscapine inhibited cell viability of colon cancer in a time- and dose- dependent manner. Black-Right-Pointing-Pointer G{sub 2}/M phase arrest and chromatin condensation and nuclear fragmentation were induced. Black-Right-Pointing-Pointer Noscapine promoted apoptosis via mitochondrial pathways. Black-Right-Pointing-Pointer Tumorigenicity was inhibited by noscapine. -- Abstract: Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC{sub 50} = 75 {mu}M). This cytotoxicity was reflected by cell cycle arrest at G{sub 2}/M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase-9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer.

  1. A genome editing approach to study cancer stem cells in human tumors.

    Science.gov (United States)

    Cortina, Carme; Turon, Gemma; Stork, Diana; Hernando-Momblona, Xavier; Sevillano, Marta; Aguilera, Mònica; Tosi, Sébastien; Merlos-Suárez, Anna; Stephan-Otto Attolini, Camille; Sancho, Elena; Batlle, Eduard

    2017-07-01

    The analysis of stem cell hierarchies in human cancers has been hampered by the impossibility of identifying or tracking tumor cell populations in an intact environment. To overcome this limitation, we devised a strategy based on editing the genomes of patient-derived tumor organoids using CRISPR/Cas9 technology to integrate reporter cassettes at desired marker genes. As proof of concept, we engineered human colorectal cancer (CRC) organoids that carry EGFP and lineage-tracing cassettes knocked in the LGR5 locus. Analysis of LGR5-EGFP + cells isolated from organoid-derived xenografts demonstrated that these cells express a gene program similar to that of normal intestinal stem cells and that they propagate the disease to recipient mice very efficiently. Lineage-tracing experiments showed that LGR5 + CRC cells self-renew and generate progeny over long time periods that undergo differentiation toward mucosecreting- and absorptive-like phenotypes. These genetic experiments confirm that human CRCs adopt a hierarchical organization reminiscent of that of the normal colonic epithelium. The strategy described herein may have broad applications to study cell heterogeneity in human tumors. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  2. Complex of MUC1, CIN85 and Cbl in Colon Cancer Progression and Metastasis

    International Nuclear Information System (INIS)

    Cascio, Sandra; Finn, Olivera J.

    2015-01-01

    We previously reported that CIN85, an 85 KDa protein known to be involved in tumor cell migration and metastasis through its interaction with Cbl, associates with MUC1 in tumor cells. MUC1/CIN85 complex also regulates migration and invasion of tumor cells in vitro. Here, we examined specifically human colon carcinoma tissue microarrays (TMA) by immunohistochemistry for the expression of MUC1 and CIN85 and their potential role in cancer progression and metastasis. We detected a significant increase in expression of both MUC1 and CIN85 associated with advanced tumor stage and lymph node metastasis. We further investigated if Cbl could also be present in the MUC1/CIN85 complex. Co-immunoprecipitation assay showed that Cbl co-localized both with CIN85 and with MUC1 in a human colon cancer cell line. To begin to investigate the in vivo relevance of MUC1 overexpression and association with CIN85 and Cbl in cancer development and progression, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, the association of MUC1, CIN85 and Cbl was detected in colon tissues of AOM/DSS-treated MUC1 transgenic mice. MUC1/CIN85/Cbl complex appears to contribute to promotion and progression of colon cancer and thus increased expression of MUC1, CIN85 and Cbl in early stage colon cancer might be predictive of poor prognosis

  3. Complex of MUC1, CIN85 and Cbl in Colon Cancer Progression and Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Cascio, Sandra, E-mail: sac131@pitt.edu [Department of Immunology, University of Pittsburgh School of Medicine, E1040 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Fondazione Ri.Med, via Bandiera, Palermo 90133 (Italy); Finn, Olivera J., E-mail: sac131@pitt.edu [Department of Immunology, University of Pittsburgh School of Medicine, E1040 Biomedical Science Tower, Pittsburgh, PA 15261 (United States)

    2015-02-10

    We previously reported that CIN85, an 85 KDa protein known to be involved in tumor cell migration and metastasis through its interaction with Cbl, associates with MUC1 in tumor cells. MUC1/CIN85 complex also regulates migration and invasion of tumor cells in vitro. Here, we examined specifically human colon carcinoma tissue microarrays (TMA) by immunohistochemistry for the expression of MUC1 and CIN85 and their potential role in cancer progression and metastasis. We detected a significant increase in expression of both MUC1 and CIN85 associated with advanced tumor stage and lymph node metastasis. We further investigated if Cbl could also be present in the MUC1/CIN85 complex. Co-immunoprecipitation assay showed that Cbl co-localized both with CIN85 and with MUC1 in a human colon cancer cell line. To begin to investigate the in vivo relevance of MUC1 overexpression and association with CIN85 and Cbl in cancer development and progression, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, the association of MUC1, CIN85 and Cbl was detected in colon tissues of AOM/DSS-treated MUC1 transgenic mice. MUC1/CIN85/Cbl complex appears to contribute to promotion and progression of colon cancer and thus increased expression of MUC1, CIN85 and Cbl in early stage colon cancer might be predictive of poor prognosis.

  4. Adenocarcinoma mucoproductor de colon con infiltración de estómago y metástasis ováricas (tumor de Krukenberg Colon mucoproducing adenocarcinoma with stomach infiltration and ovarian metastases (Krukenberg's tumor

    Directory of Open Access Journals (Sweden)

    Orestes Noel Mederos Curbelo

    2011-12-01

    Full Text Available Se presenta una paciente femenina de 29 años, operada de urgencia por presentar un gran tumor que incluía cuerpo gástrico y colon trasverso, con una perforación gástrica. Se realizó una gastrectomía subtotal con colectomía trasversa en bloque que incluyó el epiplón mayor. El diagnóstico histológico fue adenocarcinoma túbulo papilar mucoproductor de origen colónico, que infiltra hasta la serosa y pared gástrica. Se realizó tratamiento adyuvante con poliquimioterapia. Diez meses después presenta un tumor en hipogastrio, que al tacto vaginal, correspondía a los órganos genitales, sospecha clínica que confirman el ultrasonido abdominal y la tomografía axial computarizada. El hallazgo transoperatorio fueron tumores voluminosos de ambos ovarios, y otro tumor que afectaba la unión rectosigmoide. Se realizó una histerectomía radical con ooforectomía bilateral y sigmoidectomía, se reseca la porción proximal del recto, y se cierra tipo Hartman. El diagnóstico histológico final fue metástasis en serosa uterina e intestinal, y en ambos ovarios de adenocarcinoma mucoproductor, túbulo papilar de intestino previamente diagnosticado (tumor de Krukenberg. Se complementó el tratamiento con poliquimioterapia adyuvante.This is the case of a woman aged 29 operated on of emergency due to a tumor involving gastric body and transverse colon with gastric perforation. A subtotal gastrectomy with block transverse colectomy including the greater omentum was carried out. The histological diagnosis was a mucoproducing papillary tubular adenocarcinoma of colonic origin infiltrating to serosa and gastric wall. An adjuvant treatment was applied with poly-chemotherapy. Ten months later appears a hypogastric tumor which at vaginal manual examination corresponding to genital organs, clinical suspicion confirmed by abdominal ultrasound and computerized axial tomography. The transoperative findings were bulky tumors of both ovaries and another tumor

  5. Role of a Cyclooxygenase Inhibitor and Luteolin in the Regression of Colon Tumors in Irradiated Rats

    International Nuclear Information System (INIS)

    Ahmed, E.S.A.

    2015-01-01

    Colon carcinogenesis is a devastating problem leading to morbidity and mortality in developed countries. Colon cancer is a complex multi-step process involving progressive disruption of homeostatic mechanisms controlling intestinal epithelial proliferation/inflammation, differentiation and programmed cell death. Colon cancer is the third most common malignant neoplasm worldwide. Its incidence strongly varies globally and is closely linked to elements of a so-called western lifestyle. In Egypt reports showed that colon cancer was detected in 11–15% of patients who underwent colonoscopy and diagnosed in 29–31% of patients aged 40 years or younger. The present study was planned to evaluate the effect of a cyclooxygenase inhibitor (aspirin) and a natural product (luteolin) and on colon cancer induced by 1, 2 dimethylhydrazine (DMH), beside studying the effects of luteolin and aspirin either alone or combined with fractionated low doses of γ- irradiation as a route of cancer therapy. Seventy adult male Wistar rats were divided into seven groups 10 animals each and treated as follows: 1. Control group (G1): rats of this group received distilled water via gavages for 15 weeks. 2. Colon tumor induction group (G2): rats of this group were injected subcutaneously with DMH (20 mg/kg body weight) once a week for 15 weeks. 3. Colon tumor + irradiation group (G3): these rats were injected subcutaneously with DMH (20 mg/kg body weight) once a week for 15 weeks then at the beginning of the 8th week they were exposed to γ-radiation at a dose level of 0.5 Gy/week x 8 and continued during DMH treatment. 4. Colon tumor + aspirin treatment group (G4): rats of this group gavaged aspirin (50 mg/kg/ week) and injected subcutaneously with DMH for 15 weeks. 5. Colon tumor + luteolin treatment group (G5): these rats were treated orally with LUT (0.2 mg/kg body weight/ day) and injected subcutaneously with DMH (20 mg/kg body weight/ week) for 15 weeks. 6. Colon tumor + aspirin

  6. A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites.

    Science.gov (United States)

    Zhang, Yan; Ma, Junli; Zhang, Sai; Deng, Ganlu; Wu, Xiaoling; He, Jingxuan; Pei, Haiping; Shen, Hong; Zeng, Shan

    2015-09-01

    Stage III colon cancer is currently treated as an entity with a unified therapeutic principle. The aim of the retrospective study is to explore the clinicopathological characteristics and outcomes of site-specific stage III colon cancers and the influences of tumor location on prognosis. Eight hundred ninety-five patients with stage III colon cancer treated with radical operation and subsequent adjuvant chemotherapy (5-fluorouracil/oxaliplatin) were divided into seven groups according to colon segment (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon). Expression of excision repair cross-complementing group 1 (ERCC1) and thymidylate synthase (TS) was examined by immunohistochemistry. We assessed if differences exist in patient characteristics and clinic outcomes between the seven groups. There were significant differences in tumor differentiation (P Cancer (AJCC) tumor-node-metastasis (TNM) stage (P colon. Cox regression analyses identified that tumor location was an independent prognostic factor for RFS and OS. Stage III colon cancer located proximally carried a poorer survival than that located distally. Different efficacies of FOLFOX adjuvant chemotherapy may be an important factor affecting survival of site-specific stage III colon cancers.

  7. Tumor lysis syndrome in a patient with metastatic colon cancer after treatment with oxaliplatin and 5-Fu

    Directory of Open Access Journals (Sweden)

    Ruo-Han Tseng

    2016-12-01

    Full Text Available Tumor lysis syndrome in solid tumors is a rare occurrence, with a poor prognosis. We present the case of a patient of recurrent colon cancer who received chemotherapy with FOLFOX regimen (lencovorin, fluorouracil, and oxaliplatin with subsequent tumor lysis. We present a recurrent rectal cancer patient suffered from tumor lysis syndrome after salvage FOLFOX regimen. After treat with CVVH with improved conscious status. In this case report, we had review the tumor lysis in solid tumor.

  8. Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials.

    Science.gov (United States)

    Aoyama, Toru; Kashiwabara, Kosuke; Oba, Koji; Honda, Michitaka; Sadahiro, Sotaro; Hamada, Chikuma; Maeda, Hiromichi; Mayanagi, Shuhei; Kanda, Mitsuro; Sakamoto, Junichi; Saji, Shigetoyo; Yoshikawa, Takaki

    2017-11-01

    The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020-1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  9. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147.

    Science.gov (United States)

    Gonsalves, Wilson I; Mahoney, Michelle R; Sargent, Daniel J; Nelson, Garth D; Alberts, Steven R; Sinicrope, Frank A; Goldberg, Richard M; Limburg, Paul J; Thibodeau, Stephen N; Grothey, Axel; Hubbard, Joleen M; Chan, Emily; Nair, Suresh; Berenberg, Jeffrey L; McWilliams, Robert R

    2014-07-01

    KRAS and BRAF (V600E) mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF (V600E) mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. KRAS (35%) and BRAF (V600E) (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P characteristics are associated with KRAS and BRAF (V600E) mutations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Emigrating Beyond Earth Human Adaptation and Space Colonization

    CERN Document Server

    Smith, Cameron M

    2012-01-01

    For four million years humankind has been actively expanding geographically and in doing so has adapted to a wide variety of hostile environments. Now we are looking towards the ultimate adaptation - the colonization of space. Emigrating Beyond Earth illustrates that this is not a technocratic endeavor, but a natural continuation of human evolution; a journey not just for the engineer and rocket scientist, but for everyman. Based on the most current understanding of our universe, human adaptation and evolution, the authors explain why space colonization must be planned as an adaptation to, rather than the conquest of, space. Emigrating Beyond Earth argues that space colonization is an insurance policy for our species, and that it isn't about rockets and robots, it's about humans doing what we've been doing for four million years: finding new places and new ways to live. Applying a unique anthropological approach, the authors outline a framework for continued human space exploration and offer a glimpse of a po...

  11. Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX? Colon Cancer Assay

    OpenAIRE

    Clark-Langone, Kim M; Sangli, Chithra; Krishnakumar, Jayadevi; Watson, Drew

    2010-01-01

    Abstract Background The Oncotype DX® Colon Cancer Assay is a new diagnostic test for determining the likelihood of recurrence in stage II colon cancer patients after surgical resection using fixed paraffin embedded (FPE) primary colon tumor tissue. Like the Oncotype DX Breast Cancer Assay, this is a high complexity, multi-analyte, reverse transcription (RT) polymerase chain reaction (PCR) assay that measures the expression levels of specific cancer-related genes. By capturing the biology unde...

  12. Radioimmunotherapy of human colon cancer xenografts by using 131I labeled-CAb1 F(ab')2

    International Nuclear Information System (INIS)

    Li Ling; Xu Huiyun; Mi Li; Bian Huijie; Qin Jun; Xiong Hua; Feng Qiang; Wen Ning; Tian Rong; Xu Liqing; Shen Xiaomei; Tang Hao; Chen Zhinan

    2006-01-01

    Purpose: Therapeutic efficacy, suitable dose, and administration times of 131 I-CAb 1 F(ab') 2 , a new monoclonal antibody therapeutics specifically directed against a cell surface-associated glycoprotein of colon cancer, were investigated in this article. Methods and Materials: In human colon cancer xenografts, 131 I-CAb 1 F(ab') 2 at the dose of 125 μCi, 375 μCi, and 1125 μCi were administrated intraperitoneally on Days 6 and 18 after implantation of HR8348 cells with CAb 1 high reactivity. Survival time and tumor growth inhibition rate were used to evaluate the efficacy and safety of 131 I-CAb 1 F(ab') 2 in treatment of colon cancer xenografts. Results: Treatment of 125, 375, and 1125 μCi 131 I-CAb1 F(ab') 2 did not significantly decrease the mean survival time of nude mice when compared with nontreated groups (p = 0.276, 0.865, 0.582, respectively). Moreover, the mean survival times of nude mice receiving 375 μCi and 1125 μCi 131 I-CAb1 F(ab') 2 were significantly longer than that of 5-FU-treated groups (p 0.018 and 0.042). Tumor growth inhibition rates of the first therapy were 35.67% and 41.37%, with corresponding 131 I-labeled antibody dosage of 375 μCi and 1125 μCi. After single attack dosage, second reinforcement therapy may rise efficacy significantly. Tumor growth inhibition rates of 125 μCi, 375 μCi, and 1125 μCi 131 I-labeled antibody on Day 20 posttherapy were 42.65%, 56.56%, and 84.41%, respectively. Histopathology examination revealed that tissue necrosis of various degrees was found in 131 I-CAb1 F(ab') 2 -treated groups. Conclusion: 131 I-CAb 1 F(ab') 2 is safe and effective for colon cancer. It may be a novel and potentially adjuvant therapeutics for colon cancer

  13. Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states

    International Nuclear Information System (INIS)

    Sarver, Aaron L; Cunningham, Julie M; Subramanian, Subbaya; Wang, Liang; Smyrk, Tom C; Rodrigues, Cecilia MP; Thibodeau, Stephen N; Steer, Clifford J; French, Amy J; Borralho, Pedro M; Thayanithy, Venugopal; Oberg, Ann L; Silverstein, Kevin AT; Morlan, Bruce W; Riska, Shaun M; Boardman, Lisa A

    2009-01-01

    Colon cancer arises from the accumulation of multiple genetic and epigenetic alterations to normal colonic tissue. microRNAs (miRNAs) are small, non-coding regulatory RNAs that post-transcriptionally regulate gene expression. Differential miRNA expression in cancer versus normal tissue is a common event and may be pivotal for tumor onset and progression. To identify miRNAs that are differentially expressed in tumors and tumor subtypes, we carried out highly sensitive expression profiling of 735 miRNAs on samples obtained from a statistically powerful set of tumors (n = 80) and normal colon tissue (n = 28) and validated a subset of this data by qRT-PCR. Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. Significant differences were also seen in 6 miRNAs including miR-31 and miR-592, in the direct comparison of tumors that were deficient or proficient for mismatch repair. Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance. A network of interactions between these miRNAs and genes associated with colon cancer provided evidence for the role of these miRNAs as oncogenes by attenuation of tumor suppressor genes. Colon tumors show differential expression of miRNAs depending on mismatch repair status. miRNA expression in colon tumors has an epigenetic component and altered expression that may reflect a reversion to regulatory programs characteristic of undifferentiated proliferative developmental states

  14. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model.

    Science.gov (United States)

    Mukherjee, P; Pathangey, L B; Bradley, J B; Tinder, T L; Basu, G D; Akporiaye, E T; Gendler, S J

    2007-02-19

    A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan-helper-peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-gamma-producing CD4(+) helper and CD8(+) cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

  15. Colon cancer associated transcripts in human cancers.

    Science.gov (United States)

    Chen, Yincong; Xie, Haibiao; Gao, Qunjun; Zhan, Hengji; Xiao, Huizhong; Zou, Yifan; Zhang, Fuyou; Liu, Yuchen; Li, Jianfa

    2017-10-01

    Long non-coding RNAs serve as important regulators in complicated cellular activities, including cell differentiation, proliferation and death. Dysregulation of long non-coding RNAs occurs in the formation and progression of cancers. The family of colon cancer associated transcripts, long non-coding RNAs colon cancer associated transcript-1 and colon cancer associated transcript-2 are known as oncogenes involved in various cancers. Colon cancer associated transcript-1 is a novel lncRNA located in 8q24.2, and colon cancer associated transcript-2 maps to the 8q24.21 region encompassing rs6983267. Colon cancer associated transcripts have close associations with clinical characteristics, such as lymph node metastasis, high TNM stage and short overall survival. Knockdown of them can reverse the malignant phenotypes of cancer cells, including proliferation, migration, invasion and apoptosis. Moreover, they can increase the expression level of c-MYC and oncogenic microRNAs via activating a series of complex mechanisms. In brief, the family of colon cancer associated transcripts may serve as potential biomarkers or therapeutic targets for human cancers. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. IGF-II transgenic mice display increased aberrant colon crypt multiplicity and tumor volume after 1,2-dimethylhydrazine treatment

    Directory of Open Access Journals (Sweden)

    Oesterle Doris

    2006-01-01

    Full Text Available Abstract In colorectal cancer insulin-like growth factor II (IGF-II is frequently overexpressed. To evaluate, whether IGF-II affects different stages of tumorigenesis, we induced neoplastic alterations in the colon of wild-type and IGF-II transgenic mice using 1,2-dimethylhydrazine (DMH. Aberrant crypt foci (ACF served as markers of early lesions in the colonic mucosa, whereas adenomas and carcinomas characterized the endpoints of tumor development. DMH-treatment led initially to significantly more ACF in IGF-II transgenic than in wild-type mice. This increase in ACF was especially prominent for those consisting of ≥three aberrant crypts (AC. Nevertheless, adenomas and adenocarcinomas of the colon, present after 34 weeks in both genetic groups, were not found at different frequency. Tumor volumes, however, were significantly higher in IGF-II transgenic mice and correlated with serum IGF-II levels. Immunohistochemical staining for markers of proliferation and apoptosis revealed increased cell proliferation rates in tumors of IGF-II transgenic mice without significant affection of apoptosis. Increased proliferation was accompanied by elevated localization of β-catenin in the cytosol and cell nuclei and reduced appearance at the inner plasma membrane. In conclusion, we provide evidence that IGF-II, via activation of the β-catenin signaling cascade, promotes growth of ACF and tumors without affecting tumor numbers.

  17. [A Case with Metastatic Huge Ovarian Tumor from Transverse Colon Cancer, Who Underwent Systemic Chemotherapy after Bilateral Oophorectomy and Right Hemi Colectomy].

    Science.gov (United States)

    Miyanari, Shun; Nagasaki, Toshiya; Minami, Hironori; Fukuoka, Hironori; Murahashi, Satoshi; Suzuki, Shinsuke; Ushigome, Hajime; Akiyoshi, Takashi; Konishi, Tsuyoshi; Fujimoto, Yoshiya; Nagayama, Satoshi; Fukunaga, Yosuke; Ueno, Masashi

    2017-11-01

    Metastatic ovarian tumors from colon cancer would be resistant to chemotherapy, and compromising quality of life(QOL) of these patients was caused by acute enlargement of the tumors. A 37-year-old woman with abdominal distension was diagnosed with transverse colon cancer, bilateral ovarian metastases, liver metastases, and peritoneal dissemination at prior hospital. Two courses of chemotherapy(FOLFOX)were administered, but metastaticovarian tumors enlarged. Chemotherapy was discontinued and she was referred to our institution. To achieve symptom relief, improving QOL, and to resume chemotherapy, we planned bilateral oophorectomy and primary tumor resection if other stenotic lesion was not present. As a result, we safely performed open bilateral oophorectomy and right hemi colectomy, and the patient discharged on postoperative day 11 without complications. Chemotherapy was resumed and continued for 7 months up to this time. Even though, curative resection could not be achieved, oophorectomy should be performed in patients with enlarged metastatic ovarian tumor from colon cancer, in spite of administration of chemotherapy.

  18. Green tea, phytic acid, and inositol in combination reduced the incidence of azoxymethane-induced colon tumors in Fisher 344 male rats.

    Science.gov (United States)

    Khatiwada, Janak; Verghese, Martha; Davis, Shurrita; Williams, Leonard L

    2011-11-01

    Experimental as well as epidemiologic studies in human populations provide evidence that consumption of phytochemicals reduces the incidence of degenerative diseases. Green tea (GT) catechins are known for their antioxidative potential. Phytic acid (PA) also acts as a natural antioxidant and may have numerous health benefits. This experiment was designed to investigate the inhibitory effects of combinations of 1% and 2% GT, PA, and inositol (I) in reducing the incidence of azoxymethane-induced colon tumors in Fisher 344 male rats. After an acclimatization period of 1 week, nine groups of rats (15 rats per group) were initially assigned to consume AIN 93 G diet and later AIN 93 M diet after 20 weeks of age. Treatments were given in drinking water. All rats received azoxymethane injections (16 mg/kg of body weight) subcutaneously at 7 and 8 weeks of age. Rats were killed at 45 weeks of age by CO(2) euthanasia. Tumor incidence (93.76%) and the number of tumors per tumor-bearing rat ratio (2.25) were significantly (P<.05) higher in the control group compared with treatment groups. Glutathione S-transferase activity was significantly (P<.05) higher in rats fed combinations of 2% GT+PA+I and GT+PA (33.25 ± 1.23 and 29.83 ± 1.10 μmol/mL, respectively) compared with other groups. These findings suggest that the synergistic effect of the 2% level of GT, PA, and I may reduce the incidence of colon tumors and therefore have potential as a chemopreventive agent.

  19. Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K.

    Directory of Open Access Journals (Sweden)

    Alexander E Yueh

    Full Text Available The phosphoinositide 3-kinase (PI3K signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin, indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling.

  20. Positive detection of exfoliated colon cancer cells on linear stapler cartridges was associated with depth of tumor invasion and preoperative bowel preparation in colon cancer.

    Science.gov (United States)

    Ikehara, Kishiko; Endo, Shungo; Kumamoto, Kensuke; Hidaka, Eiji; Ishida, Fumio; Tanaka, Jun-Ichi; Kudo, Shin-Ei

    2016-08-31

    The aim of this study was to investigate exfoliated cancer cells (ECCs) on linear stapler cartridges used for anastomotic sites in colon cancer. We prospectively analyzed ECCs on linear stapler cartridges used for anastomosis in 100 colon cancer patients who underwent colectomy. Having completed the functional end-to-end anastomosis, the linear stapler cartridges were irrigated with saline, which was collected for cytological examination and cytological diagnoses were made by board-certified pathologists based on Papanicolaou staining. The detection rate of ECCs on the linear stapler cartridges was 20 %. Positive detection of ECCs was significantly associated with depth of tumor invasion (p = 0.012) and preoperative bowel preparation (p = 0.003). There were no marked differences between ECC-positive and ECC-negative groups in terms of the operation methods, tumor location, histopathological classification, and surgical margins. Since ECCs were identified on the cartridge of the linear stapler used for anastomosis, preoperative mechanical bowel preparation using polyethylene glycol solution and cleansing at anastomotic sites using tumoricidal agents before anastomosis may be necessary to decrease ECCs in advanced colon cancer.

  1. Assessment of a novel VEGF targeted agent using patient-derived tumor tissue xenograft models of colon carcinoma with lymphatic and hepatic metastases.

    Directory of Open Access Journals (Sweden)

    Ketao Jin

    Full Text Available The lack of appropriate tumor models of primary tumors and corresponding metastases that can reliably predict for response to anticancer agents remains a major deficiency in the clinical practice of cancer therapy. It was the aim of our study to establish patient-derived tumor tissue (PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastases useful for testing of novel molecularly targeted agents. PDTT of primary colon carcinoma, lymphatic and hepatic metastases were used to create xenograft models. Hematoxylin and eosin staining, immunohistochemical staining, genome-wide gene expression analysis, pyrosequencing, qRT-PCR, and western blotting were used to determine the biological stability of the xenografts during serial transplantation compared with the original tumor tissues. Early passages of the PDTT xenograft models of primary colon carcinoma, lymphatic and hepatic metastases revealed a high degree of similarity with the original clinical tumor samples with regard to histology, immunohistochemistry, genes expression, and mutation status as well as mRNA expression. After we have ascertained that these xenografts models retained similar histopathological features and molecular signatures as the original tumors, drug sensitivities of the xenografts to a novel VEGF targeted agent, FP3 was evaluated. In this study, PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis have been successfully established. They provide appropriate models for testing of novel molecularly targeted agents.

  2. KRAS detection in colonic tumors by DNA extraction from FTA paper: the molecular touch-prep.

    Science.gov (United States)

    Petras, Melissa L; Lefferts, Joel A; Ward, Brian P; Suriawinata, Arief A; Tsongalis, Gregory J

    2011-12-01

    DNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue is usually more degraded and contains more polymerase chain reaction (PCR) inhibitors than DNA isolated from nonfixed tissue. In addition, the tumor size and cellular heterogeneity found in tissue sections can often impact testing for molecular biomarkers. As a potential remedy to this situation, we evaluated the use of Whatman FTA paper cards for collection of colorectal tumor samples before tissue fixation and for isolation of DNA for use in a real-time PCR-based KRAS mutation assay. Eleven colon tumor samples were collected by making a cut into the fresh tumor and applying the Whatman FTA paper to the cut surface. Matched FFPE tissue blocks from these tumors were also collected for comparison. KRAS mutation analysis was carried out using the Applied Biosystems 7500 Fast Real-time PCR System using 7 independent custom TaqMan PCR assays. Of the 11 colon tumors sampled, 6 were positive for KRAS mutations in both the Whatman FTA paper preparations and corresponding FFPE samples. Whatman FTA paper cards for collection of colorectal tumor samples before tissue fixation and for isolation of DNA have many advantages including ease of use, intrinsic antimicrobial properties, long storage potential (stability of DNA over time), and a faster turnaround time for results. Extracted DNA should be suitable for most molecular diagnostic assays that use PCR techniques. This novel means of DNA preservation from surgical specimens would benefit from additional study and validation as a dependable and practical technique to preserve specimens for molecular testing.

  3. Deciphering the colon cancer genes--report of the InSiGHT-Human Variome Project Workshop, UNESCO, Paris 2010.

    Science.gov (United States)

    Kohonen-Corish, Maija R J; Macrae, Finlay; Genuardi, Maurizio; Aretz, Stefan; Bapat, Bharati; Bernstein, Inge T; Burn, John; Cotton, Richard G H; den Dunnen, Johan T; Frebourg, Thierry; Greenblatt, Marc S; Hofstra, Robert; Holinski-Feder, Elke; Lappalainen, Ilkka; Lindblom, Annika; Maglott, Donna; Møller, Pål; Morreau, Hans; Möslein, Gabriela; Sijmons, Rolf; Spurdle, Amanda B; Tavtigian, Sean; Tops, Carli M J; Weber, Thomas K; de Wind, Niels; Woods, Michael O

    2011-04-01

    The Human Variome Project (HVP) has established a pilot program with the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) to compile all inherited variation affecting colon cancer susceptibility genes. An HVP-InSiGHT Workshop was held on May 10, 2010, prior to the HVP Integration and Implementation Meeting at UNESCO in Paris, to review the progress of this pilot program. A wide range of topics were covered, including issues relating to genotype-phenotype data submission to the InSiGHT Colon Cancer Gene Variant Databases (chromium.liacs.nl/LOVD2/colon_cancer/home.php). The meeting also canvassed the recent exciting developments in models to evaluate the pathogenicity of unclassified variants using in silico data, tumor pathology information, and functional assays, and made further plans for the future progress and sustainability of the pilot program. © 2011 Wiley-Liss, Inc.

  4. 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis.

    Science.gov (United States)

    Myung, Seung-Jae; Rerko, Ronald M; Yan, Min; Platzer, Petra; Guda, Kishore; Dotson, Angela; Lawrence, Earl; Dannenberg, Andrew J; Lovgren, Alysia Kern; Luo, Guangbin; Pretlow, Theresa P; Newman, Robert A; Willis, Joseph; Dawson, Dawn; Markowitz, Sanford D

    2006-08-08

    15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a prostaglandin-degrading enzyme that is highly expressed in normal colon mucosa but is ubiquitously lost in human colon cancers. Herein, we demonstrate that 15-PGDH is active in vivo as a highly potent suppressor of colon neoplasia development and acts in the colon as a required physiologic antagonist of the prostaglandin-synthesizing activity of the cyclooxygenase 2 (COX-2) oncogene. We first show that 15-PGDH gene knockout induces a marked 7.6-fold increase in colon tumors arising in the Min (multiple intestinal neoplasia) mouse model. Furthermore, 15-PGDH gene knockout abrogates the normal resistance of C57BL/6J mice to colon tumor induction by the carcinogen azoxymethane (AOM), conferring susceptibility to AOM-induced adenomas and carcinomas in situ. Susceptibility to AOM-induced tumorigenesis is mediated by a marked induction of dysplasia, proliferation, and cyclin D1 expression throughout microscopic aberrant crypt foci arising in 15-PGDH null colons and is concomitant with a doubling of prostaglandin E(2) in 15-PGDH null colonic mucosa. A parallel role for 15-PGDH loss in promoting the earliest steps of colon neoplasia in humans is supported by our finding of a universal loss of 15-PGDH expression in microscopic colon adenomas recovered from patients with familial adenomatous polyposis, including adenomas as small as a single crypt. These models thus delineate the in vivo significance of 15-PGDH-mediated negative regulation of the COX-2 pathway and moreover reveal the particular importance of 15-PGDH in opposing the neoplastic progression of colonic aberrant crypt foci.

  5. Assessment of cytotoxicity of Portulaca oleracea Linn. against human colon adenocarcinoma and vero cell line

    Science.gov (United States)

    Mali, Prashant Y.

    2015-01-01

    Background: Portulaca oleracea Linn. (Portulacaceae) is commonly known as purslane in English. In traditional system it is used to cure diarrhea, dysentery, leprosy, ulcers, asthma, and piles, reduce small tumors and inflammations. Aim: To assess cytotoxic potential of chloroform extract of P. oleracea whole plant against human colon adenocarcinoma (HCT-15) and normal (Vero) cell line. Materials and Methods: Characterization of chloroform extract of P. oleracea by Fourier transform infrared (FTIR) spectroscopy was performed. Cytotoxicity (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay was used for assessment of cytotoxic potential of chloroform extract of P. oleracea. The concentrations of 1000–0.05 μg/ml were used in the experiment. Doxorubicin was considered as standard reference drug. Results: FTIR spectrum showed the peak at 1019.52 and 1396.21 center. The 50% cell growth inhibition (IC50) of chloroform extract of P. oleracea and doxorubicin was 1132.02 μg/ml and 460.13 μg/ml against human colon adenocarcinoma and 767.60 μg/ml and 2392.71 μg/ml against Vero cell line, respectively. Conclusion: Chloroform extract of P. oleracea whole plant was less efficient or does not have cytotoxic activity against human colon adenocarcinoma cell line. It was not safe to normal Vero cell line. But, there is a need to isolate, identify, and confirm the phytoconstituents present in extract by sophisticated analytical techniques. PMID:27833374

  6. Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity

    International Nuclear Information System (INIS)

    Qi, Wentao; Weber, Christopher R; Wasland, Kaarin; Savkovic, Suzana D

    2011-01-01

    Soy consumption is associated with a lower incidence of colon cancer which is believed to be mediated by one of its of components, genistein. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation, but mechanisms are not well understood. Epidermal growth factor (EGF)-induced proliferation of colon cancer cells plays an important role in colon cancer progression and is mediated by loss of tumor suppressor FOXO3 activity. The aim of this study was to assess if genistein exerts anti-proliferative properties by attenuating the negative effect of EGF on FOXO3 activity. The effect of genistein on proliferation stimulated by EGF-mediated loss of FOXO3 was examined in human colonic cancer HT-29 cells. EGF-induced FOXO3 phosphorylation and translocation were assessed in the presence of genistein. EGF-mediated loss of FOXO3 interactions with p53 (co-immunoprecipitation) and promoter of p27kip1 (ChIP assay) were examined in presence of genistein in cells with mutated p53 (HT-29) and wild type p53 (HCT116). Silencing of p53 determined activity of FOXO3 when it is bound to p53. Genistein inhibited EGF-induced proliferation, while favoring dephosphorylation and nuclear retention of FOXO3 (active state) in colon cancer cells. Upstream of FOXO3, genistein acts via the PI3K/Akt pathway to inhibit EGF-stimulated FOXO3 phosphorylation (i.e. favors active state). Downstream, EGF-induced disassociation of FOXO3 from mutated tumor suppressor p53, but not wild type p53, is inhibited by genistein favoring FOXO3-p53(mut) interactions with the promoter of the cell cycle inhibitor p27kip1 in colon cancer cells. Thus, the FOXO3-p53(mut) complex leads to elevated p27kip1 expression and promotes cell cycle arrest. These novel anti-proliferative mechanisms of genistein suggest a possible role of combining genistein with other chemoreceptive agents for the treatment of colon cancer

  7. MicroRNA, SND1, and alterations in translational regulation in colon carcinogenesis

    International Nuclear Information System (INIS)

    Tsuchiya, Naoto; Nakagama, Hitoshi

    2010-01-01

    Post-transcriptional regulation of gene expression by microRNA (miRNA) has recently attracted major interest in relation to its involvement in cancer development. miRNA is a member of small non-coding RNA, consists of 22-24 nucleotides and regulates expression of target mRNA species in a post-transcriptional manner by being incorporated with RNA-induced silencing complex (RISC). Staphylococcal nuclease homology domain containing 1 (SND1), a component of RISC, is frequently up-regulated in human colon cancers and also chemically induced colon cancers in animals. We here showed that SDN1 is involved in miRNA-mediated gene suppression and overexpression of SND1 in colon cancer cells causes down-regulation of APC without altering APC mRNA levels. As for the miRNA expression profile in human colon cancer, miR-34a was among the list of down-regulated miRNA. Expression of miR-34a is tightly regulated by p53, and ectopic expression of miR-34a in colon cancer cells causes remarkable reduction of cell proliferation and induces senescence-like phenotypes. MiR-34a also participates in the positive feedback loop of the p53 tumor suppressor network. This circuitry mechanism for p53 activation is of interest in understanding the tumor suppressive function of miR-34a in colon carcinogenesis. miRNA should also be considered as novel anti-cancer agents in tumor suppressive therapeutic applications.

  8. Extravirgin olive oil up-regulates CB₁ tumor suppressor gene in human colon cancer cells and in rat colon via epigenetic mechanisms.

    Science.gov (United States)

    Di Francesco, Andrea; Falconi, Anastasia; Di Germanio, Clara; Micioni Di Bonaventura, Maria Vittoria; Costa, Antonio; Caramuta, Stefano; Del Carlo, Michele; Compagnone, Dario; Dainese, Enrico; Cifani, Carlo; Maccarrone, Mauro; D'Addario, Claudio

    2015-03-01

    Extravirgin olive oil (EVOO) represents the typical lipid source of the Mediterranean diet, an eating habit pattern that has been associated with a significant reduction of cancer risk. Diet is the more studied environmental factor in epigenetics, and many evidences suggest dysregulation of epigenetic pathways in cancer. The aim of our study was to investigate the effects of EVOO and its phenolic compounds on endocannabinoid system (ECS) gene expression via epigenetic regulation in both human colon cancer cells (Caco-2) and rats exposed to short- and long-term dietary EVOO. We observed a selective and transient up-regulation of CNR1 gene - encoding for type 1 cannabinoid receptor (CB₁) - that was evoked by exposure of Caco-2 cells to EVOO (100 ppm), its phenolic extracts (OPE, 50 μM) or authentic hydroxytyrosol (HT, 50 μM) for 24 h. None of the other major elements of the ECS (i.e., CB₂; GPR55 and TRPV1 receptors; and NAPE-PLD, DAGL, FAAH and MAGL enzymes) was affected at any time point. The stimulatory effect of OPE and HT on CB₁ expression was inversely correlated to DNA methylation at CNR1 promoter and was associated with reduced proliferation of Caco-2 cells. Interestingly, CNR1 gene was less expressed in Caco-2 cells when compared to normal colon mucosa cells, and again this effect was associated with higher level of DNA methylation at CNR1. Moreover, in agreement with the in vitro studies, we also observed a remarkable (~4-fold) and selective increase in CB₁ expression in the colon of rats receiving dietary EVOO supplementation for 10 days. Consistently, CpG methylation of rat Cnr1 promoter, miR23a and miR-301a, previously shown to be involved in the pathogenesis of colorectal cancer and predicted to target CB₁ mRNA, was reduced after EVOO administration down to ~50% of controls. Taken together, our findings demonstrating CB₁ gene expression modulation by EVOO or its phenolic compounds via epigenetic mechanism, both in vitro and in vivo, may

  9. Urotensin-II receptor is over-expressed in colon cancer cell lines and in colon carcinoma in humans.

    Science.gov (United States)

    Federico, Alessandro; Zappavigna, Silvia; Romano, Marco; Grieco, Paolo; Luce, Amalia; Marra, Monica; Gravina, Antonietta Gerarda; Stiuso, Paola; D'Armiento, Francesco Paolo; Vitale, Giovanni; Tuccillo, Concetta; Novellino, Ettore; Loguercio, Carmela; Caraglia, Michele

    2014-01-01

    Urotensin (U)-II receptor (UTR) has been previously reported to be over-expressed in a number of tumours. Whether UTR-related pathway plays a role in colon carcinogenesis is unknown. We evaluated UTR protein and mRNA expression in human epithelial colon cancer cell lines and in normal colon tissue, adenomatous polyps and colon cancer. U-II protein expression was assessed in cancer cell lines. Moreover, we evaluated the effects of U-II(4-11) (an UTR agonist), antagonists and knockdown of UTR protein expression through a specific shRNA, on proliferation, invasion and motility of human colon cancer cells. Cancer cell lines expressed U-II protein and UTR protein and mRNA. By immunohistochemistry, UTR was expressed in 5-30% of epithelial cells in 45 normal controls, in 30-48% in 21 adenomatous polyps and in 65-90% in 48 colon adenocarcinomas. UTR mRNA expression was increased by threefold in adenomatous polyps and eightfold in colon cancer, compared with normal colon. U-II(4-11) induced a 20-40% increase in cell growth while the blockade of the receptor with specific antagonists caused growth inhibition of 20-40%. Moreover, the knock down of UTR with a shRNA or the inhibition of UTR with the antagonist urantide induced an approximately 50% inhibition of both motility and invasion. UTR appears to be involved in the regulation of colon cancer cell invasion and motility. These data suggest that UTR-related pathway may play a role in colon carcinogenesis and that UTR may function as a target for therapeutic intervention in colon cancer. © 2013 Stichting European Society for Clinical Investigation Journal Foundation.

  10. Tumor location and patient characteristics of colon and rectal adenocarcinomas in relation to survival and TNM classes

    International Nuclear Information System (INIS)

    Hemminki, Kari; Santi, Irene; Weires, Marianne; Thomsen, Hauke; Sundquist, Jan; Bermejo, Justo Lorenzo

    2010-01-01

    Old age at diagnosis is associated with poor survival in colorectal cancer (CRC) for unknown reasons. Recent data show that colonoscopy is efficient in preventing left-sided cancers only. We examine the association of Tumor Node Metastasis (TNM) classes with diagnostic age and patient characteristics. The Swedish Family-Cancer Database has data on TNM classes on 6,105 CRC adenocarcinoma patients. Ordinal logistic regression analysis was performed to model tumor characteristics according to age at diagnosis, tumor localization, gender, socioeconomic status, medical region and family history. The results were compared to results from survival analysis. The only parameters systematically associated with TNM classes were age and tumor localization. Young age at diagnosis was a risk factor for aggressive CRC, according to stage, N and M with odds ratios (ORs) ranging from 1.80 to 1.93 for diagnosis before age 50 years compared to diagnosis at 80+ years. All tumor characteristics, particularly T, were worse for colon compared to rectal tumors. Right-sided tumors showed worse characteristics for all classifiers but M. The survival analysis on patients diagnosed since 2000 showed a hazard ratio of 0.55 for diagnosis before age 50 years compared to diagnosis at over 80 years and a modestly better prognosis for left-sided compared to right-sided tumors. The results showed systematically more aggressive tumors in young compared to old patients. The poorer survival of old patients in colon cancer was not related to the available tumor characteristics. However, these partially agreed with the limited colonoscopic success with right-sided tumors

  11. BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-κB.

    Science.gov (United States)

    Du, Jipei; Wang, Yufang; Chen, Degao; Ji, Guangyu; Ma, Qizhao; Liao, Shiping; Zheng, Yanjiang; Zhang, Ji; Hou, Yiping

    2016-12-28

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is well known for its ability to preferentially induce apoptosis in malignant cells without causing damage to most normal cells. However, inherent and acquired resistance of tumor to TRAIL-induced apoptosis limits its therapeutic applicability. Here we show that the orally available tyrosine kinase inhibitor, BAY61-3606, enhances the sensitivity of human colon cancer cells, especially those harboring active mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene, to TRAIL-induced apoptosis in vitro and in vivo. The sensitization was achieved by up-regulating death receptor 4 (DR4) and the tumor suppressor p53. BAY61-3606-induced the up-regulation of DR4 is p53-dependent. Knockout of p53 decreased BAY61-3606-induced DR4 expression and inhibited the effect of BAY61-3606 on TRAIL-induced apoptosis. In addition, BAY61-3606 suppressed activity of NF-κB and regulated its gene products, which might also contribute to TRAIL-induced apoptosis. In conclusion, our results showed that BAY61-3606 sensitizes colon cancer cells to TRAIL-induced apoptosis via up-regulating DR4 expression in p53-dependent manner and inhibiting NF-κB activity, suggesting that the combination of TRAIL and BAY61-3606 may be a promising therapeutic approach in the treatment of colon cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Persistent STAT3 Activation in Colon Cancer Is Associated with Enhanced Cell Proliferation and Tumor Growth

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    Florian M. Corvinus

    2005-06-01

    Full Text Available Colorectal carcinoma (CRC is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRCderived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth.

  13. [A Case of Intrahepatic Cholangiocarcinoma with Invasion to the Transverse Colon and Gallbladder, Forming an Intra-Tumor Abscess].

    Science.gov (United States)

    Okada, Nami; Kametaka, Hisashi; Koyama, Takashi; Seike, Kazuhiro; Makino, Hironobu; Fukada, Tadaomi; Sato, Yutaka; Miyazaki, Masaru

    2015-11-01

    An 81-year-old man was referred to our institution for evaluation of high fever and a liver tumor that had been detected by ultrasonography. Computed tomography revealed a low-density mass with peripheral ring-like enhancement in S5 of the liver. The liver mass was in contact with the gallbladder, and the boundary between the mass and the gallbladder was unclear. On the suspicion of liver abscess, percutaneous transhepatic drainage was performed. The cavity of the abscess communicated with the gallbladder. Because the cavity had no tendency to reduce in size, we performed surgical resection under a preoperative diagnosis of liver abscess or primary liver carcinoma invading to the gallbladder. Intraoperative findings revealed a liver tumor invading the transverse colon and gallbladder. Subsegmentectomy of S4a and S5 of the liver combined with gallbladder and transverse colon resection was performed. Histopathological findings indicated the growth of a mass forming type intrahepatic cholangiocarcinoma with invasion to the transverse colon and gallbladder, and the pathological stage of the tumor was pT3N0M0, fStage Ⅲ. Thus far, the patient is alive without recurrence 9 months after surgery. Here, we report an extremely rare case of intrahepatic cholangiocarcinoma that invaded other organs and was associated with an intra-tumor abscess.

  14. Neural control of colonic cell proliferation.

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1980-03-15

    The mitotic rate in rat colonic crypts and in dimethylhydrazine-induced colonic carcinomas was measured using a stathmokinetic technique. In sympathectomized animals cell proliferation was retarded in the crypts but not in the tumors, whereas in animals treated with Metaraminol, a drug which releases norepinephrine from nerve terminals, crypt cell but not tumor cell proliferation was accelerated. Blockade of alpha-adrenoceptors also inhibited crypt cell proliferation. However, stimulation of beta-adrenoceptors inhibited and blockade of beta-adrenoceptors accelerated tumor cell proliferation without influencing crypt cell proliferation. Injection of either serotonin or histamine stimulated tumor but not crypt cell proliferation and blockade or serotonin receptors or histamine H2-receptors inhibited tumor cell proliferation. It is postulated that cell proliferation in the colonic crypts, like that in the jejunal crypts, is under both endocrine and autonomic neural control whereas colonic tumor cell division is subject to endocrine regulation alone.

  15. The tumor suppressor CDX2 opposes pro-metastatic biomechanical modifications of colon cancer cells through organization of the actin cytoskeleton.

    Science.gov (United States)

    Platet, Nadine; Hinkel, Isabelle; Richert, Ludovic; Murdamoothoo, Devadarssen; Moufok-Sadoun, Ahlam; Vanier, Marie; Lavalle, Philippe; Gaiddon, Christian; Vautier, Dominique; Freund, Jean-Noel; Gross, Isabelle

    2017-02-01

    The vast majority of cancer deaths are caused by the formation of metastases rather than the primary tumor itself. Despite this clinical importance, the molecular and cellular events that support the dissemination of cancer cells are not yet fully unraveled. We have previously shown that CDX2, a homeotic transcription factor essential for gut development, acts as a colon-specific tumor suppressor and opposes metastasis. Here, using a combination of biochemical, biophysical, and immunofluorescence techniques, we further investigated the mechanisms promoted by CDX2 that might antagonize tumor cell dissemination. We found that CDX2 expression regulates the transcription of RHO GEFs, thereby activating RHO signaling cascades that lead to reorganization of the actin cytoskeleton and enhanced adherent junctions. Accordingly, we observed by atomic force microscopy (AFM) that colon cancer cells expressing CDX2 are less deformable, a feature that has been shown to correlate with poor metastatic potential. Thus, this study illustrates how the loss of expression of a transcription factor during colon cancer progression modifies the biomechanical characteristics of tumor cells and hence facilitates invasion and metastasis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

    Directory of Open Access Journals (Sweden)

    van Erk Marjan J

    2004-05-01

    Full Text Available Abstract Background Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an anti-oxidant and it can act as an anti-inflammatory agent. The aim of this study was to elucidate mechanisms and effect of curcumin in colon cancer cells using gene expression profiling. Methods Gene expression changes in response to curcumin exposure were studied in two human colon cancer cell lines, using cDNA microarrays with four thousand human genes. HT29 cells were exposed to two different concentrations of curcumin and gene expression changes were followed in time (3, 6, 12, 24 and 48 hours. Gene expression changes after short-term exposure (3 or 6 hours to curcumin were also studied in a second cell type, Caco-2 cells. Results Gene expression changes (>1.5-fold were found at all time points. HT29 cells were more sensitive to curcumin than Caco-2 cells. Early response genes were involved in cell cycle, signal transduction, DNA repair, gene transcription, cell adhesion and xenobiotic metabolism. In HT29 cells curcumin modulated a number of cell cycle genes of which several have a role in transition through the G2/M phase. This corresponded to a cell cycle arrest in the G2/M phase as was observed by flow cytometry. Functional groups with a similar expression profile included genes involved in phase-II metabolism that were induced by curcumin after 12 and 24 hours. Expression of some cytochrome P450 genes was downregulated by curcumin in HT29 and Caco-2 cells. In addition, curcumin affected expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis. Conclusions This study has extended knowledge on pathways or processes already reported to be affected by curcumin (cell cycle arrest, phase

  17. Imaging Matrix Metalloproteases in Spontaneous Colon Tumors: Validation by Correlation with Histopathology.

    Science.gov (United States)

    Hensley, Harvey; Cooper, Harry S; Chang, Wen-Chi L; Clapper, Margie L

    2017-01-01

    The use of fluorescent probes in conjunction with white-light colonoscopy is a promising strategy for improving the detection of precancerous colorectal lesions, in particular flat (sessile) lesions that do not protrude into the lumen of the colon. We describe a method for determining the sensitivity and specificity of an enzymatically activated near-infrared probe (MMPSense680) for the detection of colon lesions in a mouse model (APC +/Min-FCCC ) of spontaneous colorectal cancer. Fluorescence intensity correlates directly with the activity of matrix metalloproteinases (MMPs). Overexpression of MMPs is an early event in the development of colorectal lesions. Although the probe employed serves as a reporter of the activity of MMPs, our method can be applied to any fluorescent probe that targets an early molecular event in the development of colorectal tumors.

  18. Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice.

    Science.gov (United States)

    Morioka, Takamitsu; Miyoshi-Imamura, Tomoko; Blyth, Benjamin J; Kaminishi, Mutsumi; Kokubo, Toshiaki; Nishimura, Mayumi; Kito, Seiji; Tokairin, Yutaka; Tani, Shusuke; Murakami-Murofushi, Kimiko; Yoshimi, Naoki; Shimada, Yoshiya; Kakinuma, Shizuko

    2015-03-01

    Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  19. Proteogenomic characterization of human colon and rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Bing; Wang, Jing; Wang, Xiaojing; Zhu, Jing; Liu, Qi; Shi, Zhiao; Chambers, Matthew C.; Zimmerman, Lisa J.; Shaddox, Kent F.; Kim, Sangtae; Davies, Sherri; Wang, Sean; Wang, Pei; Kinsinger, Christopher; Rivers, Robert; Rodriguez, Henry; Townsend, Reid; Ellis, Matthew; Carr, Steven A.; Tabb, David L.; Coffey, Robert J.; Slebos, Robbert; Liebler, Daniel

    2014-09-18

    We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Protein sequence variants encoded by somatic genomic variations displayed reduced expression compared to protein variants encoded by germline variations. mRNA transcript abundance did not reliably predict protein expression differences between tumors. Proteomics identified five protein expression subtypes, two of which were associated with the TCGA "MSI/CIMP" transcriptional subtype, but had distinct mutation and methylation patterns and associated with different clinical outcomes. Although CNAs showed strong cis- and trans-effects on mRNA expression, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. Our analyses identified HNF4A, a novel candidate driver gene in tumors with chromosome 20q amplifications. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords novel insights into cancer biology.

  20. Radioimmunoimaging of human colon carcinoma grafted into nudemice using 131I-labeled monoclonal anticea antibody and its F(ab')2 fragments

    International Nuclear Information System (INIS)

    Liu Guangda

    1988-01-01

    131 I-labeled monoclonal anti-CEA antibody and its F(ab') 2 fragments were injected into nude mice bearing human colon carcinoma xenografts for tumor localization and radioimmunoimaging studies. Transplanted tumors were visualized in 12 hours after injection of the labeled anti-CEA or its F(ab') 2 by gamma camera. Biodistribution data indicated that F(ab') 2 fragments were cleared more rapidly from blood (T 1/2 = 13.3 h for F(ab') 2 , T 1/2 = 21.1 h for intact antibody) over 6-24 h and had higher tumor blood ratios. The intact antibody was concentrated in the tumor better than F(ab') 2 . In double-label experiments, a nonspecific localization of the control ( 125 I-labeled anti-HCG) in the tumor was also observed

  1. Colonic Fermentation: A Neglected Topic in Human Physiology Education

    Science.gov (United States)

    Valeur, Jorgen; Berstad, Arnold

    2010-01-01

    Human physiology textbooks tend to limit their discussion of colonic functions to those of absorbing water and electrolytes and storing waste material. However, the colon is a highly active metabolic organ, containing an exceedingly complex society of microbes. By means of fermentation, gastrointestinal microbes break down nutrients that cannot be…

  2. Increased expression and activity of group IIA and X secretory phospholipase A2 in peritumoral versus central colon carcinoma tissue

    DEFF Research Database (Denmark)

    Tribler, Line; Jensen, Lotte T.; Jørgensen, Kent

    2007-01-01

    Secretory phospholipase A2 (sPLA2) type IIA and X was analyzed in tumors from 22 patients with colon adenocarcinomas in order to determine the involvement and activity of sPLA2 in colon cancer. Evaluation of immunoreactive sPLA2 IIA by Western blotting showed a significantly higher level...... in the periphery of the tumors, compared to central tumor regions. Increased levels of sPLA2 IIA protein correlated with a two-fold increase in sPLA2 enzymatic activity in the peripheral regions compared to central regions. Nineteen out of 22 tumors showed high levels of sPLA2 IIA, whereas 7 out of the 22 tumors...... showed sPLA2 type X. These data demonstrate that both sPLA2 type IIA and X are present in human colon cancer and suggest a role for sPLA2 in colon cancer tumor immunology and tumorigenesis....

  3. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    International Nuclear Information System (INIS)

    Raufman, Jean-Pierre; Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng

    2011-01-01

    Highlights: ► Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. ► Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. ► Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers – this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre-treatment with anti-MMP1 antibody. This study contributes to understanding

  4. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Raufman, Jean-Pierre, E-mail: jraufman@medicine.umaryland.edu [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States); Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. Black-Right-Pointing-Pointer Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. Black-Right-Pointing-Pointer Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre

  5. Dome-type carcinoma of the colon; a rare variant of adenocarcinoma resembling a submucosal tumor: a case report

    Directory of Open Access Journals (Sweden)

    Yamada Masayoshi

    2012-03-01

    Full Text Available Abstract Background Dome-type carcinoma (DC is a distinct variant of colorectal adenocarcinoma and less than 10 cases have been described in the literature. Most of the previously reported cases were early lesions and no endoscopic observations have been described so far. We herein report a case of a DC invading the subserosal layer, including endoscopic findings. Case presentation A highly elevated lesion in the transverse colon was diagnosed by colonoscopy in a 77-year-old man. The tumor appeared to be similar to a submucosal tumor (SMT, however, a demarcated area of reddish and irregular mucosa was observed at the top of the tumor. There were no erosions or ulcers. Laparoscopic-assisted right hemicolectomy was performed and pathological examination revealed a well-circumscribed tumor invading the subserosal layer. The tumor was a well-differentiated adenocarcinoma associated with a dense lymphocytic infiltration and showed expansive growth. The overlying mucosal layer showed high-grade dysplasia. Conclusion The present lesion was diagnosed as a DC of the colon invading the subserosal layer. Because the association of mucosal dysplasia is common in DCs, the detection of dysplastic epithelium would be important to discriminate DCs from SMTs.

  6. [A Case of Transverse Colon Cancer with Liver Metastasis and Tumor Thrombosis of Portal Vein Effectively Treated with Chemotherapy].

    Science.gov (United States)

    Aida, Toshiaki; Shiobara, Masayuki; Wakatsuki, Kazuo; Arai, Shuka; Suda, Kosuke; Miyazawa, Kotaro; Miyoshi, Tetsutaro; Takahashi, Yoshihisa; Yoshioka, Shigeru

    2018-02-01

    The patient was a 70-year-old man. He was diagnosed with advanced transverse colon cancer. A computed tomography (CT)revealed liver metastasis and tumor thrombosis of portal vein. We started combination chemotherapy with capecita- bine/oxaliplatin(CapeOX). Perforation of the tumor was observed 5 days after CapeOX therapy was started. Treatment with abscess drainage and ileostmy, infection was controlled and general condition was improved. After 9 courses of CapeOX, we changed chemotherapy regimen to irinotecan/tegafur-gimeracil-oteracilpotassium (IRIS)due to strong side effects. In CT and FDG-PET examination after 8 courses of IRIS, the tumor of transverse colon, liver metastasis, and the tumor thrombosis of portalvein became unclear. A year and 6 months have passed since chemotherapy was started, recurrence was not observed. For the patients with unresectable colorectal cancer, it is necessary to consider multidisciplinary treatments including chemotherapy while considering the general condition of them.

  7. Differential expression of colon cancer associated transcript1 (CCAT1) along the colonic adenoma-carcinoma sequence

    International Nuclear Information System (INIS)

    Alaiyan, Bilal; Trink, Barry; Gure, Ali O; Nissan, Aviram; Ilyayev, Nadia; Stojadinovic, Alexander; Izadjoo, Mina; Roistacher, Marina; Pavlov, Vera; Tzivin, Victoria; Halle, David; Pan, Honguang

    2013-01-01

    The transition from normal epithelium to adenoma and, to invasive carcinoma in the human colon is associated with acquired molecular events taking 5-10 years for malignant transformation. We discovered CCAT1, a non-coding RNA over-expressed in colon cancer (CC), but not in normal tissues, thereby making it a potential disease-specific biomarker. We aimed to define and validate CCAT1 as a CC-specific biomarker, and to study CCAT1 expression across the adenoma-carcinoma sequence of CC tumorigenesis. Tissue samples were obtained from patients undergoing resection for colonic adenoma(s) or carcinoma. Normal colonic tissue (n = 10), adenomatous polyps (n = 18), primary tumor tissue (n = 22), normal mucosa adjacent to primary tumor (n = 16), and lymph node(s) (n = 20), liver (n = 8), and peritoneal metastases (n = 19) were studied. RNA was extracted from all tissue samples, and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR) with confirmatory in-situ hybridization (ISH). Borderline expression of CCAT1 was identified in normal tissue obtained from patients with benign conditions [mean Relative Quantity (RQ) = 5.9]. Significant relative CCAT1 up-regulation was observed in adenomatous polyps (RQ = 178.6 ± 157.0; p = 0.0012); primary tumor tissue (RQ = 64.9 ± 56.9; p = 0.0048); normal mucosa adjacent to primary tumor (RQ = 17.7 ± 21.5; p = 0.09); lymph node, liver and peritoneal metastases (RQ = 11,414.5 ± 12,672.9; 119.2 ± 138.9; 816.3 ± 2,736.1; p = 0.0001, respectively). qRT-PCR results were confirmed by ISH, demonstrating significant correlation between CCAT1 up-regulation measured using these two methods. CCAT1 is up-regulated across the colon adenoma-carcinoma sequence. This up-regulation is evident in pre-malignant conditions and through all disease stages, including advanced metastatic disease suggesting a role in both tumorigenesis and the metastatic process

  8. Expression and new exon mutations of the human Beta defensins and their association on colon cancer development.

    Directory of Open Access Journals (Sweden)

    Abdelhabib Semlali

    Full Text Available The development of cancer involves genetic predisposition and a variety of environmental exposures. Genome-wide linkage analyses provide evidence for the significant linkage of many diseases to susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Human β-defensins (hBDs are important molecules of innate immunity. This study was designed to analyze the expression and genetic variations in hBDs (hBD-1, hBD-2, hBD-3 and hBD-4 and their putative association with colon cancer. hBD gene expression and relative protein expression were evaluated by Real-Time polymerase chain reaction (qPCR and immunohistochemistry, respectively, from 40 normal patients and 40 age-matched patients with colon cancer in Saudi Arabia. In addition, hBD polymorphisms were genotyped by exon sequencing and by promoter methylation. hBD-1, hBD-2, hBD-3 and hBD-4 basal messenger RNA expression was significantly lower in tumor tissues compared with normal tissues. Several insertion mutations were detected in different exons of the analyzed hBDs. However, no methylation in any hBDs promoters was detected because of the limited number of CpG islands in these regions. We demonstrated for the first time a link between hBD expression and colon cancer. This suggests that there is a significant link between innate immunity deregulation through disruption of cationic peptides (hBDs and the potential development of colon cancer.

  9. Immunoscintigraphy of human tumors transplanted in nude mice with radiolabeled anti-ras p21 monoclonal antibodies

    International Nuclear Information System (INIS)

    Katoh, Y.; Nakata, K.; Kohno, K.; Shima, M.; Satoh, A.; Kusumoto, Y.; Ishii, N.; Kohji, T.; Shiku, H.; Nagataki, S.

    1990-01-01

    Anti-ras p21 monoclonal antibody (RASK-3) was used for immunoscintigraphy of human cancer cell lines in nude mice. Iodine-125-labeled RASK-3 was injected into nude mice with either human colon cancers (FCC-1 or BM-314) or lung cancer (KNS-62). Clear images were obtained in all three cancers 7 days after the injection of antibody. No localization of 125 I-labeled control monoclonal antibody was observed. The ratio of tissue/blood radioactivity and % ID/g in the tumor were significantly higher than other organs by Day 8. The specific localization index examined by 131 I-RASK-3 and 125 I-control monoclonal antibody was also higher in the tumor than in other tissues. In the in vitro study, binding of RASK-3 to tumor cells increased significantly by treatment of cells with either lysolecithin or periodate-lysine-paraformaldehyde, which confirmed the intracellular localization of ras p21. The mechanism by which anti-ras p21 antibodies accumulate in tumor sites could be the necrotic changes in tumor cells or changes in membrane permeability of non-necrotic cells. These results provide a strong rationale for the utilization of ras p21 as a target antigen in the imaging of a variety of human cancers

  10. The Akt inhibitor ISC-4 synergizes with cetuximab in 5-FU-resistant colon cancer.

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    Joshua E Allen

    Full Text Available Phenylbutyl isoselenocyanate (ISC-4 is an Akt inhibitor with demonstrated preclinical efficacy against melanoma and colon cancer. In this study, we sought to improve the clinical utility of ISC-4 by identifying a synergistic combination with FDA-approved anti-cancer therapies, a relevant and appropriate disease setting for testing, and biomarkers of response. We tested the activity of ISC-4 and 19 FDA-approved anticancer agents, alone or in combination, against the SW480 and RKO human colon cancer cell lines. A synergistic interaction with cetuximab was identified and validated in a panel of additional colon cancer cell lines, as well as the kinetics of synergy. ISC-4 in combination with cetuximab synergistically reduced the viability of human colon cancer cells with wild-type but not mutant KRAS genes. Further analysis revealed that the combination therapy cooperatively decreased cell cycle progression, increased caspase-dependent apoptosis, and decreased phospho-Akt in responsive tumor cells. The synergism between ISC-4 and cetuximab was retained independently of acquired resistance to 5-FU in human colon cancer cells. The combination demonstrated synergistic anti-tumor effects in vivo without toxicity and in the face of resistance to 5-FU. These results suggest that combining ISC-4 and cetuximab should be explored in patients with 5-FU-resistant colon cancer harboring wild-type KRAS.

  11. The prognostic value of simultaneous tumor and serum RAS/RAF mutations in localized colon cancer

    DEFF Research Database (Denmark)

    Brenner Thomsen, Caroline Emilie; Appelt, Ane Lindegaard; Andersen, Rikke Fredslund

    2017-01-01

    The impact of RAS/RAF mutations in localized colon cancer needs clarification. Based on analysis of tumor-specific DNA, this study aimed at elucidating the prognostic influence of mutational status in tumor and serum using an extended panel of mutations. The study retrospectively included 294.......0057), and disease-free survival (DFS) (HR = 2.18, 95%CI = 1.26-3.77, P = 0.0053). BRAF mutation in the serum and proficient mismatch repair (pMMR) protein in tumor also indicated significantly worse prognosis, OS (HR = 3.45, 95% CI = 1.52-7.85, P = 0.0032) and DFS (HR = 3.61, 95% CI = 1.70-7.67, P = 0...

  12. Middle-preserving pancreatectomy for advanced transverse colon cancer invading the duodenun and non-functioning endocrine tumor in the pancreatic tail.

    Science.gov (United States)

    Noda, Hiroshi; Kato, Takaharu; Kamiyama, Hidenori; Toyama, Nobuyuki; Konishi, Fumio

    2011-02-01

    A 73-year-old female was referred to our hospital with a diagnosis of advanced transverse colon cancer with severe anemia and body weight loss. Preoperative evaluations, including colonoscopy, gastroduodenoscopy, and computed tomography, revealed not only a transverse colon cancer massively invading the duodenum, but also a non-functioning endocrine tumor in the pancreatic tail. We performed middle-preserving pancreatectomy (MPP) with right hemicolectomy for these tumors with a curative intent. After the resection, about 6 cm of the body of the pancreas was preserved, and signs of diabetes mellitus have not appeared. The postoperative course was complicated by a grade B pancreatic fistula, but this was successfully treated with conservative management. After a 33-day hospital stay, the patient returned to daily life without signs of pancreatic exocrine insufficiency. Although the long-term follow-up of the patient is indispensable, in this case, MPP might be able to lead to the curative resection of transverse colon cancer massively invading the duodenum and non-functioning endocrine tumor in the pancreatic tail with preservation of pancreatic function.

  13. Synthesis and characterization of near IR fluorescent albumin nanoparticles for optical detection of colon cancer

    International Nuclear Information System (INIS)

    Cohen, Sarit; Pellach, Michal; Kam, Yossi; Grinberg, Igor; Corem-Salkmon, Enav; Rubinstein, Abraham; Margel, Shlomo

    2013-01-01

    Near IR (NIR) fluorescent human serum albumin (HSA) nanoparticles hold great promise as contrast agents for tumor diagnosis. HSA nanoparticles are considered to be biocompatible, non-toxic and non-immunogenic. In addition, NIR fluorescence properties of these nanoparticles are important for in vivo tumor diagnostics, with low autofluorescence and relatively deep penetration of NIR irradiation due to low absorption of biomatrices. The present study describes the synthesis of new NIR fluorescent HSA nanoparticles, by entrapment of a NIR fluorescent dye within the HSA nanoparticles, which also significantly increases the photostability of the dye. Tumor-targeting ligands such as peanut agglutinin (PNA) and anti-carcinoembryonic antigen antibodies (anti-CEA) were covalently conjugated to the NIR fluorescent albumin nanoparticles, increasing the potential fluorescent signal in tumors with upregulated corresponding receptors. Specific colon tumor detection by the NIR fluorescent HSA nanoparticles was demonstrated in a chicken embryo model and a rat model. In future work we also plan to encapsulate cancer drugs such as doxorubicin within the NIR fluorescent HSA nanoparticles for both colon cancer imaging and therapy. - Highlights: ► Near IR human serum albumin nanoparticles were synthesized and characterized. ► Nanoparticles were shown to be physically and chemically stable and photostable. ► Tumor-targeting ligands were covalently conjugated to the nanoparticles. ► Specific colon cancer tumor detection was demonstrated in chicken-embryo and rat models.

  14. Evaluation of an in vitro faecal degradation method for early assessment of the impact of colonic degradation on colonic absorption in humans.

    Science.gov (United States)

    Tannergren, Christer; Borde, Anders; Boreström, Cecilia; Abrahamsson, Bertil; Lindahl, Anders

    2014-06-16

    The objective of this study was to develop and evaluate an in vitro method to investigate bacterial-mediated luminal degradation of drugs in colon in humans. This would be a valuable tool for the assessment of drug candidates during early drug development, especially for compounds intended to be developed as oral extended release formulations. Freshly prepared faecal homogenate from healthy human volunteers (n=3-18), dog (n=6) and rat (colon and caecal content, n=3) was homogenised with 3.8 parts (w/w) physiological saline under anaerobical conditions. Four model compounds (almokalant, budesonide, ximelagatran and metoprolol) were then incubated (n=3-18) separately in the human faecal homogenate for up to 120min at 37°C. In addition, ximelagatran was also incubated in the faecal or colonic content from dog and rat. The mean (±SD) in vitro half-life for almokalant, budesonide and ximelagatran was 39±1, 68±21 and 26±12min, respectively, in the human faecal homogenate. Metoprolol was found to be stable in the in vitro model. The in vitro degradation data was then compared to literature data on fraction absorbed after direct colon administration in humans. The percentage of drug remaining after 60min of in vitro incubation correlated (R(2)=0.90) with the fraction absorbed from colon in humans. The mean in vitro half-life of ximelagatran was similar in human faeces (26±12min) and rat colon content (34±31min), but significantly (pdegradation in vivo was rapidly degraded in the faecal homogenates as well as quantitatively since a correlation was established between percentage degraded in vitro at 60min and fraction absorbed in the colon for the model drugs, which have no other absorption limiting properties. Also, the method is easy to use from a technical point of view, which suggests that the method is suitable for use in early assessment of colonic absorption of extended release formulation candidates. Further improvement of the confidence in the use of the

  15. Prognostic impact of Metadherin-SND1 interaction in colon cancer.

    Science.gov (United States)

    Wang, Nan; Du, Xilin; Zang, Li; Song, Nuan; Yang, Tao; Dong, Rui; Wu, Tao; He, Xianli; Lu, Jianguo

    2012-12-01

    The interaction between Metadherin (MTDH) and Staphylococcal nuclease homology domain containing 1 (SND1) is involved in tumorigenesis and tumor progression of several human malignancies. However, its roles in colon cancer are still unclear. To investigate the clinical value of MTDH and SND1 expression in colon cancer. Immunohistochemical staining was performed to detect the expression of MTDH and SND1 using human colon cancer and their corresponding non-cancerous colon tissues from 196 patients' biopsies. Positive expression of MTDH and SND1 were both increased in colon cancer tissues compared to paired non-cancerous colon tissues. There was a positive correlation between MTDH and SND1 expression in colon cancer tissues (r = 0.86, p colon cancer patients with positive expression of MTDH and SND1 were significantly shorter than those without their expression (both p = 0.01). Furthermore, multivariate Cox regression analysis suggested that positive expression of MTDH and SND1 was an independent poor prognostic predictor in colon cancer. Our data suggest that the increased expression of MTDH and/or SND1 is closely related to carcinogenesis, progression, and prognosis of colon cancer. The co-expression of MTDH/SND1 may be a novel distinctive marker to benefit us in prediction of the prognosis in colon cancer.

  16. Histochemical and radioautographic studies of normal human fetal colon

    International Nuclear Information System (INIS)

    Lev, R.; Orlic, D.; New York Medical Coll., N.Y.

    1974-01-01

    Twenty fetal and infant colons ranging from 10 weeks in utero to 20 months postpartum, and 12 adult human colons were examined using histochemical techniques in conjunction with in vitro radioautography using Na 2 35 SO 4 as a sulfomucin precursor. Only the sulfated components of mucus in fetal goblet cells was found to differ significantly from adult colonic mucins. In the fetus sulfomucin staining was much weaker than in the adult, and was more intense in the left colon which is the reverse of the adult pattern. Sulfomucin was concentrated in the crypts throughout the fetal colon whereas in the adult right colon it predominated in the surface cells. As in the adult, saponification liberated carboxyl groups, possibly belonging to sialic acid, and vicinal hydroxyl groups from fetal mucins suggesting that this procedure hydrolyses an ester linkage between these 2 reactive groups. During the middle trimester of fetal life the colon possesses villi whose constituent cells display alkaline phosphatase in their surface coat. These and other morphological and histochemical similarities to fetal small intestine suggest that the fetal colon may have a limited capacity to absorb materials contained within swallowed amniotic fluid during this period. (orig.) [de

  17. Localization of indium-111 in human malignant tumor xenografts and control by chelators

    International Nuclear Information System (INIS)

    Watanabe, Naoyuki; Oriuchi, Noboru; Endo, Keigo; Inoue, Tomio; Tanada, Shuji; Murata, Hajime; Kim, E. Edmund; Sasaki, Yasuhito

    1999-01-01

    The kinetics of soluble indium-111 ( 111 In) in human malignant tumor xenografts and cells was investigated in combination with chelators. Firstly, without chelator, the kinetics of 111 In-chloride was investigated in vitro and in vivo using four human malignant neuroblastoma SK-N-MC, pulmonary papillary adenocarcinoma NCI-H441, pulmonary squamous cell carcinoma PC 9, and colon adenocarcinoma LS 180 cells and xenografts. 111 In was incorporated into tumor cells in vitro to a maximum level during a 60-min incubation. A maximum level of radioactivity was demonstrated in vivo in four human malignant tumors xenografted into nude mice at 24 h postinjection of 111 In-chloride. Secondly, the effect of edetate calcium disodium (CaNa 2 EDTA) on radioactivity in 111 In-labeled tumors xenografts and cells was studied in vitro and in vivo. CaNa 2 EDTA significantly reduced 111 In-activity from the labeled tumor xenografts, whereas it had no affect on the radioactivity in the labeled cells. Thirdly, the effect of CaNa 2 EDTA on radioactivity in human malignant tumors xenografted into nude mice injected with 111 In-chloride was investigated. In one group of mice CaNa 2 EDTA administered intraperitoneally at 1, 22, 34, 46, 58, and 70 h after injection of 111 In-chloride (postadministration), the localization of 111 In at the tumors was significantly decreased at 72 h compared with the control in all four tumor types. In the other group of mice, CaNa 2 EDTA administered intraperitoneally at 12 and 1 h before injection of 111 In-chloride and 1, 22, 34, 46, 58, and 70 h postinjection (pre- and postadministration), the radioactivity of tumors was also significantly decreased at 72 h, and the reduction was greater than that with use of postadministration. In a comparative study, CaNa 3 DTPA had a more powerful effect than CaNa 2 EDTA. In conclusion, 111 In-activity in tumors consists of intracellular and extracellular components, and the extracellular 111 In may be cleared by

  18. Impact of MLH1 expression on tumor evolution after curative surgical tumor resection in a murine orthotopic xenograft model for human MSI colon cancer.

    Science.gov (United States)

    Meunier, Katy; Ferron, Marianne; Calmel, Claire; Fléjou, Jean-François; Pocard, Marc; Praz, Françoise

    2017-09-01

    Colorectal cancers (CRCs) displaying microsatellite instability (MSI) most often result from MLH1 deficiency. The aim of this study was to assess the impact of MLH1 expression per se on tumor evolution after curative surgical resection using a xenograft tumor model. Transplantable tumors established with the human MLH1-deficient HCT116 cell line and its MLH1-complemented isogenic clone, mlh1-3, were implanted onto the caecum of NOD/SCID mice. Curative surgical resection was performed at day 10 in half of the animals. The HCT116-derived tumors were more voluminous compared to the mlh1-3 ones (P = .001). Lymph node metastases and peritoneal carcinomatosis occurred significantly more often in the group of mice grafted with HCT116 (P = .007 and P = .035, respectively). Mlh1-3-grafted mice did not develop peritoneal carcinomatosis or liver metastasis. After surgical resection, lymph node metastases only arose in the group of mice implanted with HCT116 and the rate of cure was significantly lower than in the mlh1-3 group (P = .047). The murine orthotopic xenograft model based on isogenic human CRC cell lines allowed us to reveal the impact of MLH1 expression on tumor evolution in mice who underwent curative surgical resection and in mice whose tumor was left in situ. Our data indicate that the behavior of MLH1-deficient CRC is not only governed by mutations arising in genes harboring microsatellite repeated sequences but also from their defect in MLH1 as such. © 2017 Wiley Periodicals, Inc.

  19. The cardiac glycoside oleandrin induces apoptosis in human colon cancer cells via the mitochondrial pathway.

    Science.gov (United States)

    Pan, Li; Zhang, Yuming; Zhao, Wanlu; Zhou, Xia; Wang, Chunxia; Deng, Fan

    2017-07-01

    Evidence indicates that the cardiac glycoside oleandrin exhibits cytotoxic activity against several different types of cancer. However, the specific mechanisms underlying oleandrin-induced anti-tumor effects remain largely unknown. The present study examined the anti-cancer effect and underlying mechanism of oleandrin on human colon cancer cells. The cytotoxicity and IC50 of five small molecule compounds (oleandrin, neriifolin, strophanthidin, gitoxigenin, and convallatoxin) in human colon cancer cell line SW480 cells and normal human colon cell line NCM460 cells were determined by cell counting and MTT assays, respectively. Apoptosis was determined by staining cells with annexin V-FITC and propidium iodide, followed by flow cytometry. Intracellular Ca 2+ was determined using Fluo-3 AM,glutathione (GSH) levels were measured using a GSH detection kit,and the activity of caspase-3, -9 was measured using a peptide substrate. BAX, pro-caspase-3, -9, cytochrome C and BCL-2 expression were determined by Western blotting. Oleandrin significantly decreased cell viabilities in SW480, HCT116 and RKO cells. The IC50 for SW480 cells was 0.02 µM, whereas for NCM460 cells 0.56 µM. More interestingly, the results of flow cytometry showed that oleandrin potently induced apoptosis in SW480 and RKO cells. Oleandrin downregulated protein expression of pro-caspase-3, -9, but enhanced caspase-3, -9 activities. These effects were accompanied by upregulation of protein expression of cytochrome C and BAX, and downregulation of BCL-2 protein expression in a concentration-dependent manner. Furthermore, oleandrin increased intracellular Ca 2+ concentration, but decreased GSH concentration in the cells. The present results suggest that oleandrin induces apoptosis in human colorectal cancer cells via the mitochondrial pathway. Our findings provide new insight into the mechanism of anti-cancer property of oleandrin.

  20. MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Hisataka Ogawa

    Full Text Available Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

  1. Correlation between the methylation of APC gene promoter and colon cancer.

    Science.gov (United States)

    Li, Bing-Qiang; Liu, Peng-Peng; Zhang, Cai-Hua

    2017-08-01

    The present study was planned to explore the correlation between the methylation of APC (adenomatous polyposis coli) and colon carcinogenesis. Colon cancer tissues and tumor-adjacent normal tissues of 60 colon cancer patients (who received surgical operation in our hospital from January 2012 to December 2014) were collected. SW1116 cells in human colon cancer tissues were selected for culturing. 5-aza-2c-deoxycytidine (5-aza-dC) was utilized as an inhibitor of the methylation for APC gene. Methylation specific PCR (MSP) was utilized for detection of APC methylation in SW1116 cells. The MTT and Transwell assays were performed to detect the effect of the methylation of APC gene on the proliferation and invasive abilities of SW1116 cells. The correlation between the methylation of APC gene and pathological parameters of colon cancer patients was analyzed. MSP results revealed that 41 cases (68.33%) showed methylation of APC gene in colon cancer tissues. No methylation of APC gene was found in tumor-adjacent normal tissues. 5-aza-dC was able to inhibit the methylation of APC gene in SW1116 cells. APC gene methylation was correlated with tumor size, differentiation degree, lymph node metastasis and Dukes staging. In conclusion, the levels of the methylation of APC in colon cancer tissues and SW1116 cells are relatively high. The methylation of APC promoted the proliferation and invasion abilities of SW1116 cells. Furthermore, methylation is correlated with a variety of clinicopathological features of colon cancer patients.

  2. Carbohydrate plasma expanders for passive tumor targeting

    DEFF Research Database (Denmark)

    Hoffmann, Stefan; Caysa, Henrike; Kuntsche, Judith

    2013-01-01

    The objective of this study was to investigate the suitability of carbohydrate plasma volume expanders as a novel polymer platform for tumor targeting. Many synthetic polymers have already been synthesized for targeted tumor therapy, but potential advantages of these carbohydrates include inexpen...... was characterized in human colon carcinoma xenograft bearing nude mice. A tumor specific accumulation of HES 450 was observed, which proves it’s potential as carrier for passive tumor targeting....

  3. Ethanolic Extract of Traditional Chinese Medicine (TCM) Gamboge Inhibits Colon Cancer via the Wnt/Beta-Catenin Signaling Pathway in an Orthotopic Mouse Model.

    Science.gov (United States)

    Wang, Wei; Li, Youran; Chen, Yiqi; Chen, Hongjin; Zhu, Ping; Xu, Minmin; Wang, Hao; Wu, Minna; Yang, Zhijian; Hoffman, Robert M; Gu, Yunfei

    2018-04-01

    The aim of the present study was to investigate the efficacy of an ethanolic extract of gamboge (EEG), a traditional Chinese medicine (TCM), both in vitro on colon cancer cells and in vivo in an orthotopic mouse model of human colon cancer. The in vitro cytotoxicity of EEG on colon cancer cells was determined with the CCK8 proliferation assay and the Annexin V-PE/7-AAD apoptosis assay. Efficacy of EEG in vivo was evaluated in an orthotopic mouse model of human colon cancer implated with the green fluorescent protein-expressing human colon cancer cell line SW480-GFP. The tumor-bearing mice were treated with vehicle (0.2 ml/dose normal saline, po, daily), irinotecan (50 mg/kg/dose, ip, twice a week), 5-FU (15 mg/kg/dose, ip, every other day) as positive controls or EEG at doses of 12.5, 25 and 50 mg/kg/dose, po, daily. Real-time fluorescence imaging was performed to determine tumor inhibition in each treated group compared to the untreated controls. The protein expression of β-catenin, MMP-7, cyclin D1 and E-cadherin in the tumors was analyzed by immunohistochemistry. EEG significantly induced proliferation inhibition and apoptosis of SW480 colon cancer cells in vitro in a dose-dependent manner. Tumor growth in the colon-cancer orthotopic model was significantly inhibited by irinotecan, 5-FU and all three doses of EEG. The efficacy of EEG was comparable to irinotecan and 5-FU. Irinotecan, 5-FU and 50 mg/kg EEG significantly decreased the protein expression of β-catenin and MMP-7. Cyclin D1 expression was decreased and E-cadherin expression was increased by irinotecan, 5-FU and all three doses of EEG. The present study demonstrates anti-tumor efficacy of EEG on colon cancer both in vitro and in vivo through inducing proliferation inhibition and apoptosis of SW480 colon cancer cells and inhibiting tumor growth, respectively. EEG exerts anti-tumor activity at least partly via down-regulation of the Wnt/β-catenin signaling pathway. Copyright© 2018, International

  4. Scaffold-Free Coculture Spheroids of Human Colonic Adenocarcinoma Cells and Normal Colonic Fibroblasts Promote Tumorigenicity in Nude Mice

    Directory of Open Access Journals (Sweden)

    Jong-il Park

    2016-02-01

    Full Text Available The aim of this study was to form a scaffold-free coculture spheroid model of colonic adenocarcinoma cells (CACs and normal colonic fibroblasts (NCFs and to use the spheroids to investigate the role of NCFs in the tumorigenicity of CACs in nude mice. We analysed three-dimensional (3D scaffold-free coculture spheroids of CACs and NCFs. CAC Matrigel invasion assays and tumorigenicity assays in nude mice were performed to examine the effect of NCFs on CAC invasive behaviour and tumorigenicity in 3D spheroids. We investigated the expression pattern of fibroblast activation protein-α (FAP-α by immunohistochemical staining. CAC monocultures did not form densely-packed 3D spheroids, whereas cocultured CACs and NCFs formed 3D spheroids. The 3D coculture spheroids seeded on a Matrigel extracellular matrix showed higher CAC invasiveness compared to CACs alone or CACs and NCFs in suspension. 3D spheroids injected into nude mice generated more and faster-growing tumors compared to CACs alone or mixed suspensions consisting of CACs and NCFs. FAP-α was expressed in NCFs-CACs cocultures and xenograft tumors, whereas monocultures of NCFs or CACs were negative for FAP-α expression. Our findings provide evidence that the interaction between CACs and NCFs is essential for the tumorigenicity of cancer cells as well as for tumor propagation.

  5. Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tomasi, Maria Lauda [Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); The Southern California Research Center for Alcoholic and Pancreatic Diseases and Cirrhosis, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); Ryoo, Minjung; Skay, Anna [Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); Tomasi, Ivan; Giordano, Pasquale [Department of Colorectal Surgery, Whipps Cross University Hospital, London E11 1NR (United Kingdom); Mato, José M. [CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia (Spain); Lu, Shelly C., E-mail: shellylu@usc.edu [Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States); The Southern California Research Center for Alcoholic and Pancreatic Diseases and Cirrhosis, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033 (United States)

    2013-07-15

    Methionine adenosyltransferase (MAT) is an essential enzyme that is responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. MAT1A is expressed in normal liver and MAT2A is expressed in all extrahepatic tissues. MAT2A expression is increased in human colon cancer and in colon cancer cells treated with mitogens, whereas silencing MAT2A resulted in apoptosis. The aim of the current work was to examine the mechanism responsible for MAT2A-dependent growth and apoptosis. We found that in RKO (human adenocarcinoma cell line) cells, MAT2A siRNA treatment lowered cellular SAMe and putrescine levels by 70–75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100 pmol/L) raised MAT2A mRNA level to 4.3-fold of control, increased the expression of c-Jun and c-Fos and binding to an AP-1 site in the human MAT2A promoter and the promoter activity. In human colon cancer specimens, the expression levels of MAT2A, ornithine decarboxylase (ODC), c-Jun and c-Fos are all elevated as compared to adjacent non-tumorous tissues. Overexpression of ODC in RKO cells also raised MAT2A mRNA level and MAT2A promoter activity. ODC and MAT2A are also overexpressed in liver cancer and consistently, similar MAT2A-ODC-putrescine interactions and effects on growth and apoptosis were observed in HepG2 cells. In conclusion, there is a crosstalk between polyamines and MAT2A. Increased MAT2A expression provides more SAMe for polyamines biosynthesis; increased polyamine (putrescine in this case) can activate MAT2A at the transcriptional level. This along with increased ODC expression in cancer all feed forward to further enhance the proliferative capacity of the cancer cell. -- Highlights: • MAT2A knockdown depletes putrescine and leads to apoptosis. • Putrescine attenuates MAT2A knockdown-induced apoptosis and growth

  6. Prognostic values of tumor endothelial markers in patients with colorectal cancer

    OpenAIRE

    Rmali, KA; Puntis, MCA; Jiang, WG

    2005-01-01

    AIM: Tumor endothelial markers (TEMs) are a newly discovered family of endothelial markers associated with tumor specific angiogenesis. This study sought to examine the levels of expression (qualitatively and quantitatively) for TEMs in human colon cancer.

  7. Colon cancer proliferating desulfosinigrin in wasabi (Wasabia japonica).

    Science.gov (United States)

    Weil, Marvin J; Zhang, Yanjun; Nair, Muraleedharan G

    2004-01-01

    A reduced incidence of different types of cancer has been linked to consumption of Brassica vegetables, and there is evidence that glucosinolates (GSLs) and their hydrolysis products play a role in reducing cancer risk. Wasabi (Wasabia japonica) and horseradish (Armoracia rusticana), both Brassica vegetables, are widely used condiments both in Japanese cuisine and in the United States. Desulfosinigrin (DSS) (1) was isolated from a commercially available wasabi powder and from fresh wasabi roots. Sinigrin (2) was isolated from horseradish roots. DSS and sinigrin were evaluated for their inhibitory effects on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, on lipid peroxidation, and on the proliferation of human colon (HCT-116), breast (MCF-7), lung (NCIH460), and central nervous system (CNS, SF-268) cancer cell lines. DSS did not inhibit COX enzymes or lipid peroxidation at 250 microg/ml. Sinigrin inhibited lipid peroxidation by 71% at 250 microg/ml. However, DSS promoted the growth of HCT-116 (colon) and NCI H460 (lung) human cancer cells as determined by the MTT assay in a concentration-dependent manner. At 3.72 microg/ml, a 27% increase in the number of viable human HCT-116 colon cancer cells was observed; the corresponding increases at 7.50 and 15 microg/ml were 42 and 69%, respectively. At 60 microg/ml, DSS doubled the number of HCT-16 colon cancer cells. For NCI H460 human lung cancer cells, DSS at 60 microg/ml increased the cell number by 20%. Sinigrin showed no proliferating effect on the tumor cells tested. This is the first report of the tumor cell-proliferating activity by a desulfoglucosinolate, the biosynthetic precursor of GSLs found in Brassica spp.

  8. Overexpression of GRK3, Promoting Tumor Proliferation, Is Predictive of Poor Prognosis in Colon Cancer

    Directory of Open Access Journals (Sweden)

    Tao Jiang

    2017-01-01

    Full Text Available Deregulation of G protein-coupled receptor kinase 3 (GRK3, which belongs to a subfamily of kinases called GRKs, acts as a promoter mechanism in some cancer types. Our study found that GRK3 was significantly overexpressed in 162 pairs of colon cancer tissues than in the matched noncancerous mucosa (P<0.01. Based on immunohistochemistry staining of TMAs, GRK3 was dramatically stained positive in primary colon cancer (130/180, 72.22%, whereas it was detected minimally or negative in paired normal mucosa specimens (50/180, 27.78%. Overexpression of GRK3 was closely correlated with AJCC stage (P=0.001, depth of tumor invasion (P<0.001, lymph node involvement (P=0.004, distant metastasis (P=0.016, and histologic differentiation (P=0.004. Overexpression of GRK3 is an independent prognostic indicator that correlates with poor survival in colon cancer patients. Consistent with this, downregulation of GRK3 exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate, and impaired colon tumorigenicity in a xenograft model. Hence, a specific overexpression of GRK3 was observed in colon cancer, GRK3 potentially contributing to progression by mediating cancer cell proliferation and functions as a poor prognostic indicator in colon cancer and potentially represent a novel therapeutic target for the disease.

  9. IFNγ Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer.

    Science.gov (United States)

    Bardhan, Kankana; Paschall, Amy V; Yang, Dafeng; Chen, May R; Simon, Priscilla S; Bhutia, Yangzom D; Martin, Pamela M; Thangaraju, Muthusamy; Browning, Darren D; Ganapathy, Vadivel; Heaton, Christopher M; Gu, Keni; Lee, Jeffrey R; Liu, Kebin

    2015-07-01

    Short-chain fatty acids, metabolites produced by colonic microbiota from fermentation of dietary fiber, act as anti-inflammatory agents in the intestinal tract to suppress proinflammatory diseases. GPR109A is the receptor for short-chain fatty acids. The functions of GPR109A have been the subject of extensive studies; however, the molecular mechanisms underlying GPR109A expression is largely unknown. We show that GPR109A is highly expressed in normal human colon tissues, but is silenced in human colon carcinoma cells. The GPR109A promoter DNA is methylated in human colon carcinoma. Strikingly, we observed that IFNγ, a cytokine secreted by activated T cells, activates GPR109A transcription without altering its promoter DNA methylation. Colon carcinoma grows significantly faster in IFNγ-deficient mice than in wild-type mice in an orthotopic colon cancer mouse model. A positive correlation was observed between GPR109A protein level and tumor-infiltrating T cells in human colon carcinoma specimens, and IFNγ expression level is higher in human colon carcinoma tissues than in normal colon tissues. We further demonstrated that IFNγ rapidly activates pSTAT1 that binds to the promoter of p300 to activate its transcription. p300 then binds to the GPR109A promoter to induce H3K18 hyperacetylation, resulting in chromatin remodeling in the methylated GPR109A promoter. The IFNγ-activated pSTAT1 then directly binds to the methylated but hyperacetylated GPR109 promoter to activate its transcription. Overall, our data indicate that GPR109A acts as a tumor suppressor in colon cancer, and the host immune system might use IFNγ to counteract DNA methylation-mediated GPR109A silencing as a mechanism to suppress tumor development. ©2015 American Association for Cancer Research.

  10. IFNγ induces DNA methylation-silenced GPR109A expression via pSTAT1/p300 and H3K18 acetylation in colon cancer

    Science.gov (United States)

    Bardhan, Kankana; Paschall, Amy V.; Yang, Dafeng; Chen, May R.; Simon, Priscilla S.; Bhutia, Yangzom; Martin, Pamela M.; Thangaraju, Muthusamy; Browning, Darren D.; Ganapathy, Vadivel; Heaton, Christopher M.; Gu, Keni; Lee, Jeffrey R.; Liu, Kebin

    2015-01-01

    Short-chain fatty acids, metabolites produced by colonic microbiota from fermentation of dietary fiber, act as anti-inflammatory agents in the intestinal tract to suppress proinflammatory diseases. GPR109A is the receptor for short-chain fatty acids. The functions of GPR109A has been the subject of extensive studies, however, the molecular mechanisms underlying GPR109A expression is largely unknown. We show that GPR109A is highly expressed in normal human colon tissues, but is silenced in human colon carcinoma cells. The GPR109A promoter DNA is methylated in human colon carcinoma. Strikingly, we observed that IFNγ, a cytokine secreted by activated T cells, activates GPR109A transcription without altering its promoter DNA methylation. Colon carcinoma grows significantly faster in IFNγ-deficient mice than in wildtype mice in an orthotopic colon cancer mouse model. A positive correlation was observed between GPR109A protein level and tumor-infiltrating T cells in human colon carcinoma specimens, and IFNγ expression level is higher in human colon carcinoma tissues than in normal colon tissues. We further demonstrated that IFNγ rapidly activates pSTAT1 that binds to the promoter of p300 to activate its transcription. p300 then binds to the GPR109A promoters to induce H3K18 hyperacetylation, resulting in chromatin remodeling in the methylated GPR109A promoter. The IFNγ-activated pSTAT1 then directly binds to the methylated but hyperacetylated GPR109 promoters to activate its transcription. Overall, our data indicate that GPR109A acts as a tumor suppressor in colon cancer and the host immune system might use IFNγ to counteract DNA methylation-mediated GPR109A silencing as a mechanism to suppress tumor development. PMID:25735954

  11. MiR-145 regulates PAK4 via the MAPK pathway and exhibits an antitumor effect in human colon cells

    International Nuclear Information System (INIS)

    Wang, Zhigang; Zhang, Xiaoping; Yang, Zhili; Du, Hangxiang; Wu, Zhenqian; Gong, Jianfeng; Yan, Jun; Zheng, Qi

    2012-01-01

    Highlights: ► MiR-145 targets a putative binding site in the 3′UTR of PAK4. ► MiR-145 played an important role in inhibiting cell growth by directly targeting PAK4. ► MiR-145 may function as tumor suppressors. -- Abstract: MicroRNAs (miRNAs) are regulators of numerous cellular events; accumulating evidence indicates that miRNAs play a key role in a wide range of biological functions, such as cellular proliferation, differentiation, and apoptosis in cancer. Down-regulated expression of miR-145 has been reported in colon cancer tissues and cell lines. The molecular mechanisms underlying miR-145 and the regulation of colon carcinogenesis remain unclear. In this study, we investigated the levels of miR-145 in human colon cancer cells using qRT-PCR and found markedly decreased levels compared to normal epithelial cells. We identified PAK4 as a novel target of miR-145 using informatics screening. Additionally, we demonstrated that miR-145 targets a putative binding site in the 3′UTR of PAK4 and that its abundance is inversely associated with miR-145 expression in colon cancer cells; we confirmed this relationship using the luciferase reporter assay. Furthermore, restoration of miR-145 by mimics in SW620 cells significantly attenuated cell growth in vitro, in accordance with the inhibitory effects induced by siRNA mediated knockdown of PAK4. Taken together, these findings demonstrate that miR-145 downregulates P-ERK expression by targeting PAK4 and leads to inhibition of tumor growth.

  12. Epo receptors are not detectable in primary human tumor tissue samples.

    Directory of Open Access Journals (Sweden)

    Steve Elliott

    Full Text Available Erythropoietin (Epo is a cytokine that binds and activates an Epo receptor (EpoR expressed on the surface of erythroid progenitor cells to promote erythropoiesis. While early studies suggested EpoR transcripts were expressed exclusively in the erythroid compartment, low-level EpoR transcripts were detected in nonhematopoietic tissues and tumor cell lines using sensitive RT-PCR methods. However due to the widespread use of nonspecific anti-EpoR antibodies there are conflicting data on EpoR protein expression. In tumor cell lines and normal human tissues examined with a specific and sensitive monoclonal antibody to human EpoR (A82, little/no EpoR protein was detected and it was not functional. In contrast, EpoR protein was reportedly detectable in a breast tumor cell line (MCF-7 and breast cancer tissues with an anti-EpoR polyclonal antibody (M-20, and functional responses to rHuEpo were reported with MCF-7 cells. In another study, a functional response was reported with the lung tumor cell line (NCI-H838 at physiological levels of rHuEpo. However, the specificity of M-20 is in question and the absence of appropriate negative controls raise questions about possible false-positive effects. Here we show that with A82, no EpoR protein was detectable in normal human and matching cancer tissues from breast, lung, colon, ovary and skin with little/no EpoR in MCF-7 and most other breast and lung tumor cell lines. We show further that M-20 provides false positive staining with tissues and it binds to a non-EpoR protein that migrates at the same size as EpoR with MCF-7 lysates. EpoR protein was detectable with NCI-H838 cells, but no rHuEpo-induced phosphorylation of AKT, STAT3, pS6RP or STAT5 was observed suggesting the EpoR was not functional. Taken together these results raise questions about the hypothesis that most tumors express high levels of functional EpoR protein.

  13. Tuft (caveolated) cells in two human colon carcinoma cell lines.

    OpenAIRE

    Barkla, D. H.; Whitehead, R. H.; Foster, H.; Tutton, P. J.

    1988-01-01

    The presence of an unusual cell type in two human colon carcinoma cell lines is reported. The cells show the same morphology as "tuft" (caveolated) cells present in normal gastrointestinal epithelium. Tuft cells were seen in cell line LIM 1863 growing in vitro and in human colon carcinoma cell line LIM 2210 growing as subcutaneous solid tumour xenografts in nude mice. Characteristic morphologic features of tuft cells included a wide base, narrow apex and a tuft of long microvilli projecting f...

  14. SiRNA-mediated IGF-1R inhibition sensitizes human colon cancer SW480 cells to radiation

    International Nuclear Information System (INIS)

    Yavari, Kamal; Taghikhani, Mohammad; Mesbah-Namin, Seyed A.; Maragheh, Mohammad Ghannadi; Babaei, Mohammad Hosein; Arfaee, Ali Jabbary; Madani, Hossein; Mirzaei, Hamid Reza

    2010-01-01

    Purpose. Insulin like growth factor receptor 1 (IGF-1R) is well-documented to play a key role in radiation response and tumor radiosensitivity, thus offering an attractive clinic drug target to enhance tumor sensitivity to anti-cancer radiotherapy. Material and methods. Human colon carcinoma SW480 cells were transfected with the specific small interference RNA (siRNA) expression vector (pkD-shRNA-IGF-1R-V2) designed to target IGF-1R mRNA. The expression of IGF-1R mRNA and its protein among the transfected and untransfected cells were detected by semi-quantitative RT-PCR and ELISA assay. The changes in cell radiosensitivity were examined by MTT assay. Results. Transfection of mammalian expression vector pkD containing IGF-1R siRNA was shown to reduce IGF-1R mRNA levels by up to 95%. ELISA assay detected a similar inhibition of IGF-1R protein levels in cells transfected with IGF-1R siRNA. SW480 cells transfected with the expression vector for siRNA significantly rendered cells more sensitive to radiation and the highest radiation enhancement ratio was 2.02 ± 0.08. Conclusion. These data provide the first evidence that specific siRNA fragment (pkD-shRNA-IGF-1R-V2) targeting human IGF-1R mRNA is able to enhance colon cancer radiosensitivity. Also results indicated that, combining IGF-1R siRNA and radiation significantly enhances antitumor efficacy compared with either modality alone

  15. Synthesis and characterization of near IR fluorescent albumin nanoparticles for optical detection of colon cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, Sarit; Pellach, Michal [Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 52900 (Israel); Kam, Yossi [Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120 (Israel); Grinberg, Igor; Corem-Salkmon, Enav [Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 52900 (Israel); Rubinstein, Abraham [Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120 (Israel); Margel, Shlomo, E-mail: shlomo.margel@mail.biu.ac.il [Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan 52900 (Israel)

    2013-03-01

    Near IR (NIR) fluorescent human serum albumin (HSA) nanoparticles hold great promise as contrast agents for tumor diagnosis. HSA nanoparticles are considered to be biocompatible, non-toxic and non-immunogenic. In addition, NIR fluorescence properties of these nanoparticles are important for in vivo tumor diagnostics, with low autofluorescence and relatively deep penetration of NIR irradiation due to low absorption of biomatrices. The present study describes the synthesis of new NIR fluorescent HSA nanoparticles, by entrapment of a NIR fluorescent dye within the HSA nanoparticles, which also significantly increases the photostability of the dye. Tumor-targeting ligands such as peanut agglutinin (PNA) and anti-carcinoembryonic antigen antibodies (anti-CEA) were covalently conjugated to the NIR fluorescent albumin nanoparticles, increasing the potential fluorescent signal in tumors with upregulated corresponding receptors. Specific colon tumor detection by the NIR fluorescent HSA nanoparticles was demonstrated in a chicken embryo model and a rat model. In future work we also plan to encapsulate cancer drugs such as doxorubicin within the NIR fluorescent HSA nanoparticles for both colon cancer imaging and therapy. - Highlights: Black-Right-Pointing-Pointer Near IR human serum albumin nanoparticles were synthesized and characterized. Black-Right-Pointing-Pointer Nanoparticles were shown to be physically and chemically stable and photostable. Black-Right-Pointing-Pointer Tumor-targeting ligands were covalently conjugated to the nanoparticles. Black-Right-Pointing-Pointer Specific colon cancer tumor detection was demonstrated in chicken-embryo and rat models.

  16. Influence of a Dietary Fiber on Development of Dimethylhydrazine-Induced Aberrant Crypt Foci and Colon Tumor Incidence in Wistar Rats

    DEFF Research Database (Denmark)

    Thorup, I.; Meyer, Otto A.; Kristiansen, E.

    1994-01-01

    Formation of aberrant crypt foci (ACF) in archived colon tissue from animals in a previous study was examined. The animals were fed a semisynthetic casein-based diet in which the carbohydrate pool was substituted with a dietary beet fiber (Fibeta) as the only source of fiber. Oral doses...... experimental data. The present state of knowledge could indicate that ACF represent true preneoplastic lesions progressing into colon tumors or that ACF and colon tumors represent two parallel independent events as a consequence of the cancer initiation (i.e., the ACF not being preneoplastic lesions per se)....... between duration of intake of high-fiber diet and number of animals with ACF, as well as the total number of ACF and number of small A CF (1-3 crypts) per affected animal. The previously reported data showed no protective effect of the dietary fiber at any stage of the colorectal carcinogenic process...

  17. Physical activity counteracts tumor cell growth in colon carcinoma C26-injected muscles: an interim report

    Directory of Open Access Journals (Sweden)

    Charlotte Hiroux

    2016-06-01

    Full Text Available Skeletal muscle tissue is a rare site of tumor metastasis but is the main target of the degenerative processes occurring in cancer-associated cachexia syndrome. Beneficial effects of physical activity in counteracting cancer-related muscle wasting have been described in the last decades. Recently it has been shown that, in tumor xeno-transplanted mouse models, physical activity is able to directly affect tumor growth by modulating inflammatory responses in the tumor mass microenvironment. Here, we investigated the effect of physical activity on tumor cell growth in colon carcinoma C26 cells injected tibialis anterior muscles of BALB/c mice. Histological analyses revealed that 4 days of voluntary wheel running significantly counteracts tumor cell growth in C26-injected muscles compared to the non-injected sedentary controls. Since striated skeletal muscle tissue is the site of voluntary contraction, our results confirm that physical activity can also directly counteract tumor cell growth in a metabolically active tissue that is usually not a target for metastasis.

  18. Preparation and bioevaluation of {sup 177}Lu-labelled anti-CD44 for radioimmunotherapy of colon cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, So Young; Hong, Young Don; Jung, Sung Hee; Choi, Sun Ju [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-12-15

    CD44 is a particular adhesion molecule and facilitates both cell-cell and cell-matrix interactions. In particular, splice variants of CD44 are particularly overexpressed in a large number of malignancies and carcinomas. In this study, the {sup 177}Lu-labelled CD44 targeting antibody was prepared and bioevaluated in vitro and in vivo. Anti-CD44 was immunoconjugated with the equivalent molar ratio of cysteine-based dtPA-ncS and radioimmunoconjugated with {sup 177}Lu at room temperature within 15 minutes. the stability was tested in human serum. An in vitro study was carried out in Ht-29 human colon cancer cell lines. For the biodistribution study {sup 177}Lu-labelled anti-CD44 was injected in xenograft mice. Anti-CD44 was immunoconjugated with cysteinebased dtPA-ncS and purified by a centricon filter system having a molecular cut-off of 50 kda. radioimmunoconjugation with {sup 177}Lu was reacted for 15 min at room temperature. the radiolabeling yield was >99%, and it was stable in human serum without any fragmentation or degradation. The radioimmunoconjugate showed a high binding affinity on HT-29 colon cancer cell surfaces. In a biodistribution study, the tumor-to-blood ratio of the radioimmunoconjugate was 43 : 1 at 1 day post injection (p.i) in human colon cancer bearing mice. the anti-CD44 monoclonal antibody for the targeting of colon cancer was effectively radioimmunoconjugated with {sup 177}Lu. the in vitro high immunoactivity of this radioimmunoconjugate was determined by a cell binding assay. In addition, the antibody's tumor targeting ability was demonstrated with very high uptake in tumors. this radioimmunoconjugate is applicable to therapy in human colon cancer with highly expressed CD44.

  19. EMT is the dominant program in human colon cancer

    Directory of Open Access Journals (Sweden)

    Tollenaar Rob AEM

    2011-01-01

    Full Text Available Abstract Background Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging. Methods We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1 of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence. Results Here we report that the most dominant pattern of intrinsic gene expression in colon cancer (PC1 was tightly correlated (Pearson R = 0.92, P -135 with the EMT signature-- both in gene identity and directionality. In a global micro-RNA screen, we further identified the most anti-correlated microRNA with PC1 as MiR200, known to regulate EMT. Conclusions These data demonstrate that the biology underpinning the native, molecular classification of human colon cancer--previously thought to be highly heterogeneous-- was clarified through the lens of comprehensive transcriptome analysis.

  20. Additional prognostic factors in right colon cancer staging.

    Science.gov (United States)

    Parmeggiani, Domenico; Avenia, Nicola; Gubitosi, Adelmo; Gilio, Francesco; Atelli, Pietro Francesco; Agresti, Massimo

    2011-09-01

    Based on the theory--which is now acknowledged-of a clinical difference between proximal and distal colon cancer and on the results of recent genetic and microbiological studies, a minority of authors have assumed that also in the sphere of right-sided colon cancer, tumors at three different locations, namely, the cecum and ascending and transverse colon, can be considered to be biologically different. These studies have provided the basis for a retrospective study carried out on 50 patients admitted to our department from 1996 to 2008 for tumor pathology of the right colon. The tumor was considered to be a unified biological entity and assessed in relation to the three above-mentioned locations. The results verify that the aggressive of the tumor increases from the cecum to the transverse, with a higher percentage of cecal tumors being in I stage, more tumors in the ascending colon being in II stage, and more transverse tumors, with the largest percentage of N+ and M+, in stages III and IV. This difference in biological behavior for the three tumor locations has been also found in terms of sensitiveness, both pre- and post-operation, of tumor markers CEA, TPA, and CA19-9. Clinical data revealed a binary relationship between the transverse, cecum, and ascending tumors, which ultimately affects patient mortality, which increases in a directly proportional way from the cecum to the transverse-in the case of a tumor at one of these locations.

  1. Strategies For Human Exploration Leading To Human Colonization of Space

    Science.gov (United States)

    Smitherman, David; Everett, Harmon

    2009-01-01

    Enabling the commercial development of space is key to the future colonization of space and key to a viable space exploration program. Without commercial development following in the footsteps of exploration it is difficult to justify and maintain public interest in the efforts. NASA's exploration program has suffered from the lack of a good commercial economic strategy for decades. Only small advances in commercial space have moved forward, and only up to Earth orbit with the commercial satellite industry. A way to move beyond this phase is to begin the establishment of human commercial activities in space in partnership with the human exploration program. In 2007 and 2008, the authors researched scenarios to make space exploration and commercial space development more feasible as part of their graduate work in the Space Architecture Program at the Sasakawa International Center for Space Architecture at the University of Houston, Houston, Texas. Through this research it became apparent that the problems facing future colonization are much larger than the technology being developed or the international missions that our space agencies are pursuing. These issues are addressed in this paper with recommendations for space exploration, commercial development, and space policy that are needed to form a strategic plan for human expansion into space. In conclusion, the authors found that the current direction in space as carried out by our space agencies around the world is definitely needed, but is inadequate and incapable of resolving all of the issues that inhibit commercial space development. A bolder vision with strategic planning designed to grow infrastructures and set up a legal framework for commercial markets will go a long way toward enabling the future colonization of space.

  2. Increased colon cancer risk after severe Salmonella infection.

    Directory of Open Access Journals (Sweden)

    Lapo Mughini-Gras

    Full Text Available Colon cancer constitutes one of the most frequent malignancies. Previous studies showed that Salmonella manipulates host cell signaling pathways and that Salmonella Typhimurium infection facilitates colon cancer development in genetically predisposed mice. This epidemiological study examined whether severe Salmonella infection, usually acquired from contaminated food, is associated with increased colon cancer risk in humans.We performed a nationwide registry-based study to assess colon cancer risk after diagnosed Salmonella infection. National infectious disease surveillance records (1999-2015 for Dutch residents aged ≥20 years when diagnosed with salmonellosis (n = 14,264 were linked to the Netherlands Cancer Registry. Salmonella-infected patients were laboratory-confirmed under medical consultation after 1-2 weeks of illness. These datasets also contained information on Salmonella serovar and type of infection. Colon cancer risk (overall and per colon subsite among patients with a diagnosed Salmonella infection was compared with expected colon cancer risk in the general population. Data from the nationwide registry of histo- and cytopathology (PALGA and Statistics Netherlands (CBS allowed assessing potential effects of age, gender, latency, socioeconomic status, genetic predisposition, inflammatory bowel disease (IBD, and tumor features. We found that compared to the general population, colon cancer risk was significantly increased (standardized incidence ratio [SIR] 1.54; 95%CI 1.09-2.10 among patients with Salmonella infection diagnosed <60 years of age. Such increased risk concerned specifically the ascending/transverse colon (SIR 2.12; 95%CI 1.38-3.09 after S. Enteritidis infection (SIR 2.97; 95%CI 1.73-4.76. Salmonellosis occurred more frequently among colon cancer patients with pre-infectious IBD, a known risk factor for colon cancer. Colon tumors of patients with a history of Salmonella infection were mostly of low grade

  3. Increased colon cancer risk after severe Salmonella infection

    Science.gov (United States)

    Mooij, Sofie; Neefjes-Borst, E. Andra; van Pelt, Wilfrid; Neefjes, Jacques

    2018-01-01

    Background Colon cancer constitutes one of the most frequent malignancies. Previous studies showed that Salmonella manipulates host cell signaling pathways and that Salmonella Typhimurium infection facilitates colon cancer development in genetically predisposed mice. This epidemiological study examined whether severe Salmonella infection, usually acquired from contaminated food, is associated with increased colon cancer risk in humans. Methods and findings We performed a nationwide registry-based study to assess colon cancer risk after diagnosed Salmonella infection. National infectious disease surveillance records (1999–2015) for Dutch residents aged ≥20 years when diagnosed with salmonellosis (n = 14,264) were linked to the Netherlands Cancer Registry. Salmonella-infected patients were laboratory-confirmed under medical consultation after 1–2 weeks of illness. These datasets also contained information on Salmonella serovar and type of infection. Colon cancer risk (overall and per colon subsite) among patients with a diagnosed Salmonella infection was compared with expected colon cancer risk in the general population. Data from the nationwide registry of histo- and cytopathology (PALGA) and Statistics Netherlands (CBS) allowed assessing potential effects of age, gender, latency, socioeconomic status, genetic predisposition, inflammatory bowel disease (IBD), and tumor features. We found that compared to the general population, colon cancer risk was significantly increased (standardized incidence ratio [SIR] 1.54; 95%CI 1.09–2.10) among patients with Salmonella infection diagnosed transverse colon (SIR 2.12; 95%CI 1.38–3.09) after S. Enteritidis infection (SIR 2.97; 95%CI 1.73–4.76). Salmonellosis occurred more frequently among colon cancer patients with pre-infectious IBD, a known risk factor for colon cancer. Colon tumors of patients with a history of Salmonella infection were mostly of low grade. Conclusions Patients diagnosed with severe

  4. Soluble interleukin 6 receptor (sIL-6R) mediates colonic tumor cell adherence to the vascular endothelium: a mechanism for metastatic initiation?

    LENUS (Irish Health Repository)

    Dowdall, J F

    2012-02-03

    The mechanisms by which surgery increases metastatic proliferation remain poorly characterized, although endotoxin and immunocytes play a role. Recent evidence suggests that endothelial adherence of tumor cells may be important in the formation of metastases. Soluble receptors of interleukin-6 (sIL-6R) shed by activated neutrophils exert IL-6 effects on endothelial cells, which are unresponsive under normal circumstances. This study examined the hypothesis that sIL-6R released by surgical stress increases tumor cell adherence to the endothelium. Neutrophils (PMN) were stimulated with lipopolysaccharide, C-reactive protein (CRP), and tumor necrosis factor-alpha. Soluble IL-6R release was measured by enzyme-linked immunosorbent assay. Colonic tumor cells transfected with green fluorescent protein and endothelial cells were exposed to sIL-6R, and tumor cell adherence and transmigration were measured by fluorescence microscopy. Basal release of sIL-6R from PMN was 44.7 +\\/- 8.2 pg\\/ml at 60 min. This was significantly increased by endotoxin and CRP (131 +\\/- 16.8 and 84.1 +\\/- 5.3, respectively; both P < 0.05). However, tumor necrosis factor-alpha did not significantly alter sIL-6R release. Endothelial and tumor cell exposure to sIL-6R increased tumor cell adherence by 71.3% within 2 h but did not significantly increase transmigration, even at 6 h. Mediators of surgical stress induce neutrophil release of a soluble receptor for IL-6 that enhances colon cancer cell endothelial adherence. Since adherence to the endothelium is now considered to be a key event in metastatic genesis, these findings have important implications for colon cancer treatment strategies.

  5. Colonic complications following human bone marrow transplantation

    Directory of Open Access Journals (Sweden)

    Paulino Martínez Hernández-Magro

    2015-01-01

    Full Text Available Background: Human bone marrow transplantation (BMT becomes an accepted treatment of leukemia, aplastic anemia, immunodeficiency syndromes, and hematologic malignancies. Colorectal surgeons must know how to determine and manage the main colonic complications. Objective: To review the clinical features, clinical and pathological staging of graft vs host disease (GVHD, and treatment of patients suffering with colonic complications of human bone marrow transplantation. Patients and methods: We have reviewed the records of all patients that received an allogeneic bone marrow transplant and were evaluated at our Colon and Rectal Surgery department due to gastrointestinal symptoms, between January 2007 and January 2012. The study was carried out in patients who developed colonic complications, all of them with clinical, histopathological or laboratory diagnosis. Results: The study group was constituted by 77 patients, 43 male and 34 female patients. We identified colonic complications in 30 patients (38.9%; five patients developed intestinal toxicity due to pretransplant chemotherapy (6.4%; graft vs. host disease was present in 16 patients (20%; 13 patients (16.8% developed acute colonic GVHD, and 3 (3.8% chronic GVHD. Infection was identified in 9 patients (11.6%. Conclusions: The three principal colonic complications are the chemotherapy toxicity, GVHD, and superinfection; the onset of symptoms could help to suspect the type of complication (0–20 day chemotherapy toxicity, 20 and more GVHD, and infection could appear in any time of transplantation. Resumo: Experiência: O transplante de medula óssea humana (MOH passou a ser um tratamento adotado para leucemia, anemia aplástica, síndromes de imunodeficiência e neoplasias hematológicas. Cirurgiões colorretais devem saber como determinar e tratar as principais complicações do cólon. Objetivo: Revisar as características clínicas, estadiamentos clínico e patológico da doença do enxerto

  6. Radioimmunodetection of human melanoma tumor xenografts with human monoclonal antibodies

    International Nuclear Information System (INIS)

    Gomibuchi, Makoto; Saxton, R.E.; Lake, R.R.; Katano, Mitsuo; Irie, R.F.

    1986-01-01

    A human IgM monoclonal antibody has been established that defines a tumor-associated membrane antigen expressed on human melanoma cells. The antigen has been identified as the ganglioside GD2. In this paper, the authors describe the potential usefulness of the human monoclonal antibody for radioimaging. Nude mice bearing tumors derived from a human melanoma cell line were used as a model. Antibody activity was degradated significantly after labeling with 131 I by the use of a modified chloramine-T method. After testing various concentrations, labeled antibody of a specific activity of 2.8μCi/μg produced the best results. Balb/c nude mice bearing a GD2-positive M14 melanoma cell line were injected with 10-30μg of labeled antibody, and its radiolocalization in different organs and in the whole body were evaluated. The best tumor image was obtained on Day 6. The labeled antibody uptake ratio between tumor and muscle was 9.2:1; the ratio between tumor and liver was 1.4:1. These studies represent the first report of experimental tumor imaging with human monoclonal antibody. Human monoclonals will probably prove to be superior reagents for tumor imaging in melanoma patients if the problem of anti-body radiolysis is resolved. (author)

  7. Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation.

    Science.gov (United States)

    Cheng, Kunrong; Samimi, Roxana; Xie, Guofeng; Shant, Jasleen; Drachenberg, Cinthia; Wade, Mark; Davis, Richard J; Nomikos, George; Raufman, Jean-Pierre

    2008-09-01

    Most colon cancers overexpress M3 muscarinic receptors (M3R), and post-M3R signaling stimulates human colon cancer cell proliferation. Acetylcholine (ACh), a muscarinic receptor ligand traditionally regarded as a neurotransmitter, may be produced by nonneuronal cells. We hypothesized that ACh release by human colon cancer cells results in autocrine stimulation of proliferation. H508 human colon cancer cells, which have robust M3R expression, were used to examine effects of muscarinic receptor antagonists, acetylcholinesterase inhibitors, and choline transport inhibitors on cell proliferation. A nonselective muscarinic receptor antagonist (atropine), a selective M3R antagonist (p-fluorohexahydro-sila-difenidol hydrochloride), and a choline transport inhibitor (hemicholinum-3) all inhibited unstimulated H508 colon cancer cell proliferation by approximately 40% (P<0.005). In contrast, two acetylcholinesterase inhibitors (eserine-hemisulfate and bis-9-amino-1,2,3,4-tetrahydroacridine) increased proliferation by 2.5- and 2-fold, respectively (P<0.005). By using quantitative real-time PCR, expression of choline acetyltransferase (ChAT), a critical enzyme for ACh synthesis, was identified in H508, WiDr, and Caco-2 colon cancer cells. By using high-performance liquid chromatography-electrochemical detection, released ACh was detected in H508 and Caco-2 cell culture media. Immunohistochemistry in surgical specimens revealed weak or no cytoplasmic staining for ChAT in normal colon enterocytes (n=25) whereas half of colon cancer specimens (n=24) exhibited moderate to strong staining (P<0.005). We conclude that ACh is an autocrine growth factor in colon cancer. Mechanisms that regulate colon epithelial cell production and release of ACh warrant further investigation.

  8. Dispersal time for ancient human migrations: Americas and Europe colonization

    Science.gov (United States)

    Flores, J. C.

    2007-07-01

    I apply the recently proposed intermittence strategy to investigate the ancient human migrations in the world. That is, the Americas colonization (Bering-bridge and Pacific-coast theories) and Neanderthal replacement in Europe around 45000 years before the present. Using a mathematical equation related to diffusion and ballistic motion, I calculate the colonization time in all these cases in good agreement with archeological data (including Neolithic transition in Europe). Moreover, to support these calculations, I obtain analytically the effective speed of colonization in Europe veff=0.62 [km/yr] and related to the Aurignacian culture propagation.

  9. Regorafenib effects on human colon carcinoma xenografts monitored by dynamic contrast-enhanced computed tomography with immunohistochemical validation.

    Directory of Open Access Journals (Sweden)

    Clemens C Cyran

    Full Text Available To investigate dynamic contrast-enhanced computed tomography for monitoring the effects of regorafenib on experimental colon carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation.Colon carcinoma xenografts (HT-29 implanted subcutaneously in female athymic rats (n = 15 were imaged at baseline and after a one-week treatment with regorafenib by dynamic contrast-enhanced computed tomography (128-slice dual-source computed tomography. The therapy group (n = 7 received regorafenib daily (10 mg/kg bodyweight. Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min, endothelial permeability (PS, mL/100 mL/min, and tumor vascularity (plasma volume, % were calculated using a 2-compartment uptake model. Dynamic contrast-enhanced computed tomography parameters were validated with immunohistochemical assessments of tumor microvascular density (CD-31, tumor cell apoptosis (TUNEL, and proliferation (Ki-67.Regorafenib suppressed tumor vascularity (15.7±5.3 to 5.5±3.5%; p<0.05 and tumor perfusion (12.8±2.3 to 8.8±2.9 mL/100 mL/min; p = 0.063. Significantly lower microvascular density was observed in the therapy group (CD-31; 48±10 vs. 113±25, p<0.05. In regorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 11844±2927 vs. 5097±3463, p<0.05 were observed. Dynamic contrast-enhanced computed tomography tumor perfusion and tumor vascularity correlated significantly (p<0.05 with microvascular density (CD-31; r = 0.84 and 0.66 and inversely with apoptosis (TUNEL; r = -0.66 and -0.71.Regorafenib significantly suppressed tumor vascularity (plasma volume quantified by dynamic contrast-enhanced computed tomography in experimental colon carcinomas in rats with good-to-moderate correlations to an immunohistochemical gold standard. Tumor response biomarkers assessed by dynamic contrast-enhanced computed tomography may be a promising future

  10. Proteomic profiling of antibody-inducing immunogens in tumor tissue identifies PSMA1, LAP3, ANXA3, and maspin as colon cancer markers

    Science.gov (United States)

    Yang, Qian; Roehrl, Michael H.; Wang, Julia Y.

    2018-01-01

    We hypothesized that cancer tissue immunogens – antigens capable of inducing specific antibody production in patients – are promising targets for development of precision diagnostics and humoral immunotherapies. We developed an innovative immuno-proteomic strategy and identified new immunogenic markers of colon cancer. Proteins from cancers and matched normal tissues were separated by 2D gel electrophoresis and blotted with serum antibodies from the same patients. Antibody-reactive proteins were sequenced by mass spectrometry and validated by Western blotting and immunohistochemistry. 170 serum antibody-reactive proteins were identified only in cancerous but not matched normal. Among these, proteasome subunit alpha type 1 (PSA1), leucine aminopeptidase 3 (LAP3), annexin A3 (ANXA3), and maspin (serpin B5) were reproducibly found in tissues from three patients. Differential expression patterns were confirmed in samples from eight patients with various stages of colon adenocarcinoma and liver metastases. These tumor-resident proteins and/or their associated serum antibodies may be promising markers for colon cancer screening and early diagnosis. Furthermore, tumor tissue-specific antibodies could potentially be exploited as immunotherapeutic targets against cancer. More generally, proteomic profiling of antibody-inducing cancer-associated immunogens represents a powerful generic method for uncovering the tumor antigen-ome, i.e., the totality of immunogenic tumor-associated proteins. PMID:29423100

  11. Leukemia and colon tumor detection based on microarray data classification using momentum backpropagation and genetic algorithm as a feature selection method

    Science.gov (United States)

    Wisesty, Untari N.; Warastri, Riris S.; Puspitasari, Shinta Y.

    2018-03-01

    Cancer is one of the major causes of mordibility and mortality problems in the worldwide. Therefore, the need of a system that can analyze and identify a person suffering from a cancer by using microarray data derived from the patient’s Deoxyribonucleic Acid (DNA). But on microarray data has thousands of attributes, thus making the challenges in data processing. This is often referred to as the curse of dimensionality. Therefore, in this study built a system capable of detecting a patient whether contracted cancer or not. The algorithm used is Genetic Algorithm as feature selection and Momentum Backpropagation Neural Network as a classification method, with data used from the Kent Ridge Bio-medical Dataset. Based on system testing that has been done, the system can detect Leukemia and Colon Tumor with best accuracy equal to 98.33% for colon tumor data and 100% for leukimia data. Genetic Algorithm as feature selection algorithm can improve system accuracy, which is from 64.52% to 98.33% for colon tumor data and 65.28% to 100% for leukemia data, and the use of momentum parameters can accelerate the convergence of the system in the training process of Neural Network.

  12. Metastases of transverse colon cancer to bilateral ovaries (Krukenberg tumor) and the left breast: A case report.

    Science.gov (United States)

    Luo, Xin-Yu; Wang, Jue; Zhao, Jia; Chen, Rui; Zha, Xiao-Ming

    2017-07-01

    Breast cancer has the highest rate of incidence among all types of cancer in women. Only ~0.43% of breast malignancies occur as a result of metastatic lesions from extramammary tumors. The present study reports an extremely rare case of transverse colon cancer metastasizing to the bilateral ovaries and the left breast. The patient was a 47-year old female, who had a lump in the left breast without axillary lymphadenopathy. Specimens obtained by core needle biopsy were submitted for hematoxylin and eosin examination, and results revealed that the lump was a poorly differentiated adenocarcinoma. Since the patient had elevated levels of the carcinoembryonic antigen and a medical history of a Krukenberg tumor metastasized from colon cancer, immunohistochemical examinations were applied. Results identified that caudal-related homeobox protein 2 and cytokeratin 20 were positively stained, whilst cytokeratin 7 was negatively stained. Therefore, this patient was diagnosed as having colon cancer that had metastasized to the bilateral ovaries and the left breast. As the life expectancy of patients with cancer is increasing, types of metastases that used to be seen as rare are increasingly becoming more common. For clinicians, diagnosis should be cautious, and differential diagnosis should always be kept in mind.

  13. MiR-145 regulates PAK4 via the MAPK pathway and exhibits an antitumor effect in human colon cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zhigang [Department of General Surgery, Shanghai Jiaotong University Affiliated 6th People' s Hospital, Shanghai (China); Zhang, Xiaoping [Department of Nuclear Medicine, Shanghai 10th People' s Hospital, Tongji University School of Medicine (China); Yang, Zhili; Du, Hangxiang; Wu, Zhenqian; Gong, Jianfeng; Yan, Jun [Department of General Surgery, Shanghai Jiaotong University Affiliated 6th People' s Hospital, Shanghai (China); Zheng, Qi, E-mail: zhengqi1957@yahoo.com.cn [Department of General Surgery, Shanghai Jiaotong University Affiliated 6th People' s Hospital, Shanghai (China)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer MiR-145 targets a putative binding site in the 3 Prime UTR of PAK4. Black-Right-Pointing-Pointer MiR-145 played an important role in inhibiting cell growth by directly targeting PAK4. Black-Right-Pointing-Pointer MiR-145 may function as tumor suppressors. -- Abstract: MicroRNAs (miRNAs) are regulators of numerous cellular events; accumulating evidence indicates that miRNAs play a key role in a wide range of biological functions, such as cellular proliferation, differentiation, and apoptosis in cancer. Down-regulated expression of miR-145 has been reported in colon cancer tissues and cell lines. The molecular mechanisms underlying miR-145 and the regulation of colon carcinogenesis remain unclear. In this study, we investigated the levels of miR-145 in human colon cancer cells using qRT-PCR and found markedly decreased levels compared to normal epithelial cells. We identified PAK4 as a novel target of miR-145 using informatics screening. Additionally, we demonstrated that miR-145 targets a putative binding site in the 3 Prime UTR of PAK4 and that its abundance is inversely associated with miR-145 expression in colon cancer cells; we confirmed this relationship using the luciferase reporter assay. Furthermore, restoration of miR-145 by mimics in SW620 cells significantly attenuated cell growth in vitro, in accordance with the inhibitory effects induced by siRNA mediated knockdown of PAK4. Taken together, these findings demonstrate that miR-145 downregulates P-ERK expression by targeting PAK4 and leads to inhibition of tumor growth.

  14. Colonic transit time is related to bacterial metabolism and mucosal turnover in the human gut

    DEFF Research Database (Denmark)

    Roager, Henrik Munch; Hansen, Lea Benedicte Skov; Bahl, Martin Iain

    Little is known about how colonic transit time relates to human colonic metabolism, and its importance for host health, although stool consistency, a proxy for colonic transit time, has recently been negatively associated with gut microbial richness. To address the relationships between colonic t...... imply a healthy gut microbial ecosystem and points at colonic transit time as a highly important factor to consider in microbiome and metabolomics studies.......Little is known about how colonic transit time relates to human colonic metabolism, and its importance for host health, although stool consistency, a proxy for colonic transit time, has recently been negatively associated with gut microbial richness. To address the relationships between colonic...... transit time and the gut microbial composition and metabolism, we assessed the colonic transit time of 98 subjects using radiopaque markers, and profiled their gut microbiota by16S rRNA gene sequencing and their urine metabolome by ultra performance liquid chromatography mass spectrometry. Based...

  15. Resection of pulmonary metastases from colon and rectal cancer: factors to predict survival differ regarding to the origin of the primary tumor.

    Science.gov (United States)

    Meimarakis, G; Spelsberg, F; Angele, M; Preissler, G; Fertmann, J; Crispin, A; Reu, S; Kalaitzis, N; Stemmler, M; Giessen, C; Heinemann, V; Stintzing, S; Hatz, R; Winter, H

    2014-08-01

    The purpose of the present study was to determine differences in prognostic factors for survival of patients with pulmonary metastases resected in curative intent from colon or rectum cancer. Between 1980 and 2006, prognostic factors after resection of pulmonary metastases in 171 patients with primary rectum or colon tumor were evaluated. Survival of patients after surgical metastasectomy was compared with that of patients receiving standard chemotherapy by matched-pair analysis. Median survival after pulmonary resection was 35.2 months (confidence interval 27.3-43.2). One-, 3-, and 5-year survival for patients following R0 resection was 88.8, 52.1, and 32.9 % respectively. Complete metastasectomy (R0), UICC stage of the primary tumor, pleural infiltration, and hilar or mediastinal lymph node metastases are independent prognostic factors for survival. Matched-pair analysis confirmed that pulmonary metastasectomy significantly improved survival. Although no difference in survival for patients with pulmonary metastases from lower rectal compared to upper rectal or colon cancer was observed, factors to predict survival are different for patients with lower and middle rectal cancer (R0, mediastinal and/or hilar lymph nodes, gender, UICC stage) compared with patients with upper rectal or colon cancer (R0, number of metastases). Our results indicate that distinct prognostic factors exist for patients with pulmonary metastases from lower rectal compared with upper rectal or colon cancer. This supports the notion that colorectal cancer should not be considered as a single-tumor entity. Metastasectomy, especially after complete resection resulted in a dramatic improvement of survival compared with patients treated with chemotherapy alone.

  16. Occlusive stenosis – atypical presentation of right colon cancer

    Directory of Open Access Journals (Sweden)

    Petrişor Banu

    2018-05-01

    Full Text Available Colorectal cancers are one of the most frequent malignancies worldwide. Significant differences are described in relation to the location of tumors within the colon. Thus, between right and left colon cancer there are epidemiological, clinical, genetic, evolutionary and prognostic differences. Considering these premises, right and left colon cancers can be seen as distinct pathological entities. In right colon cancer the initial phases are often asymptomatic and the presence of symptoms is in relation to advanced phases and complications. We report the case of a 64-year-old man with no significant medical history who was admitted and operated as an emergency for stenotic and perforated tumor of the right colon. Operative exploration revealed distended small bowel loops and caecum up to the ascending colon where a stenosing tumor is found. The tumor extends to a small bowel loop and also exhibit a perforation. Right hemicolectomy was performed, with favorable postoperative evolution and discharge on 7th day.

  17. Overexpression of long non-coding RNA colon cancer-associated transcript 2 is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer.

    Science.gov (United States)

    Zhang, Junling; Jiang, Yong; Zhu, Jing; Wu, Tao; Ma, Ju; Du, Chuang; Chen, Shanwen; Li, Tengyu; Han, Jinsheng; Wang, Xin

    2017-12-01

    The aim of the present study was to explore the clinicopathological and prognostic significance of long non-coding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) expression in human colorectal cancer (CRC). Expression levels of lncRNA CCAT2 in CRC, adjacent non-tumor and healthy colon mucosa tissues were detected by quantitative polymerase chain reaction. The disease-free survival and overall survival rates were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using Cox proportional hazard analysis. The expression level of lncRNA CCAT2 in CRC tissues was increased significantly compared with adjacent normal tissues or non-cancerous tissues. CCAT2 expression was observed to be progressively increased between tumor-node-metastasis (TNM) stages I and IV. A high level of CCAT2 expression was revealed to be associated with poor cell differentiation, deeper tumor infiltration, lymph node metastasis, distance metastasis, vascular invasion and advanced TNM stage. Compared with patients with low levels of CCAT2 expression, patients with high levels of CCAT2 expression had shorter disease-free survival and overall survival times. Multivariate analyses indicated that high CCAT2 expression was an independent poor prognostic factor. Therefore, increased lncRNA CCAT2 expression maybe a potential diagnostic biomarker for CRC, and an independent predictor of prognosis in patients with CRC.

  18. Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota

    DEFF Research Database (Denmark)

    Wahlström, Annika; Kovatcheva-Datchary, Petia; Ståhlman, Marcus

    2017-01-01

    The gut microbiota influences the development and progression of metabolic diseases partly by metabolism of bile acids (BAs) and modified signaling through the farnesoid X receptor (FXR). In this study, we aimed to determine how the human gut microbiota metabolizes murine BAs and affects FXR...... signaling in colonized mice. We colonized germ-free mice with cecal content from a mouse donor or feces from a human donor and euthanized the mice after short-term (2 weeks) or long-term (15 weeks) colonization. We analyzed the gut microbiota and BA composition and expression of FXR target genes in ileum...... and liver. We found that cecal microbiota composition differed between mice colonized with mouse and human microbiota and was stable over time. Human and mouse microbiota reduced total BA levels similarly, but the humanized mice produced less secondary BAs. The human microbiota was able to reduce the levels...

  19. Human colon tissue in organ culture: calcium and multi-mineral-induced mucosal differentiation.

    Science.gov (United States)

    Dame, Michael K; Veerapaneni, Indiradevi; Bhagavathula, Narasimharao; Naik, Madhav; Varani, James

    2011-01-01

    We have recently shown that a multi-mineral extract from the marine red algae, Lithothamnion calcareum, suppresses colon polyp formation and inflammation in mice. In the present study, we used intact human colon tissue in organ culture to compare responses initiated by Ca(2+) supplementation versus the multi-mineral extract. Normal human colon tissue was treated for 2 d in culture with various concentrations of calcium or the mineral-rich extract. The tissue was then prepared for histology/immunohistochemistry, and the culture supernatants were assayed for levels of type I procollagen and type I collagen. At higher Ca(2+) concentrations or with the mineral-rich extract, proliferation of epithelial cells at the base and walls of the mucosal crypts was suppressed, as visualized by reduced Ki67 staining. E-cadherin, a marker of differentiation, was more strongly expressed at the upper third of the crypt and at the luminal surface. Treatment with Ca(2+) or with the multi-mineral extract influenced collagen turnover, with decreased procollagen and increased type I collagen. These data suggest that calcium or mineral-rich extract has the capacity to (1) promote differentiation in human colon tissue in organ culture and (2) modulate stromal function as assessed by increased levels of type I collagen. Taken together, these data suggest that human colon tissue in organ culture (supporting in vivo finding in mice) will provide a valuable model for the preclinical assessment of agents that regulate growth and differentiation in the colonic mucosa.

  20. In vivo tomographic imaging of lung colonization of tumour in mouse with simultaneous fluorescence and X-ray CT.

    Science.gov (United States)

    Zhang, Bin; Gao, Fuping; Wang, Mengjiao; Cao, Xu; Liu, Fei; Wang, Xin; Luo, Jianwen; Wang, Guangzhi; Bai, Jing

    2014-01-01

    Non-invasive in vivo imaging of diffuse and wide-spread colonization within the lungs, rather than distinct solid primary tumors, is still a challenging work. In this work, a lung colonization mouse model bearing A549 human lung tumor was simultaneously scanned by a dual-modality fluorescence molecular tomography (FMT) and X-ray computed tomography (CT) system in vivo. A two steps method which incorporates CT structural information into the FMT reconstruction procedure is employed to provide concurrent anatomical and functional information. By using the target-specific fluorescence agent, the fluorescence tomographic results show elevated fluorescence intensity deep within the lungs which is colonized with diffuse and wide-spread tumors. The results were confirmed with ex vivo fluorescence reflectance imaging and histological examination of the lung tissues. With FMT reconstruction combined with the CT information, the dual-modality FMT/micro-CT system is expected to offer sensitive and noninvasive imaging of diffuse tumor colonization within the lungs in vivo. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Evaluation of the Combined Effects of Sonodynamic and Photodynamic Therapies in a Colon Carcinoma Tumor Model (CT26

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    Ameneh Sazgarnia

    2009-12-01

    Full Text Available Introduction: Photodynamic therapy is a noninvasive therapeutic method for tumors with a maximum depth of 5 mm. On the other hand, most photosensitizers are also susceptible to ultrasound waves (the basis of sonodynamic therapy. Therefore, it is expected that a combination of the two therapeutic methods will increase effectiveness of photodynamic therapies for lower doses of sensitizer and curing deeper tumors. This study evaluates the synergistic effects of photodynamic and sonodynamic therapies.     Materials and methods: The study was conducted on a colon carcinoma tumor model in Balb/c mice. The colon carcinoma tumors were induced in the mice by subcutaneous injection. Twenty four hours after intraperitoneal injection of Zinc Phthalocyanine liposome as a sensitizer, at first ultrasound irradiation with a known frequency and intensity was performed followed by illumination of the tumor area. Evaluation of the treatment efficacy was done using daily measurement of the tumors and calculation of their relative volumes. Also, all control groups were considered to confirm the effect of each therapeutic option in the study.   Results: In the first ten days post treatment, the relative volumes of all groups decreased significantly in comparison with the main control group, but the best response was observed in the photodynamic or sonodynamic therapy groups. The longest doubling time of tumor size was related to groups under photodynamic, sonodynamic and main therapies, and the shortest belonged to the control group.   Discussion and conclusion: Zinc phthalocyanine liposome is both a photosensitizer and sonsensitizer. Photodynamic and sonodynamic therapies can be efficient in retarding tumor growth rate. In this study, combination of the two methods did not cause improved therapeutic outcomes. It is predicted that this result is related to the choice of therapeutic agents and could be optimized in future.

  2. Plant Polyphenols and Oxidative Metabolites of the Herbal Alkenylbenzene Methyleugenol Suppress Histone Deacetylase Activity in Human Colon Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Isabel Anna Maria Groh

    2013-01-01

    Full Text Available Evidence has been provided that diet and environmental factors directly influence epigenetic mechanisms associated with cancer development in humans. The inhibition of histone deacetylase (HDAC activity and the disruption of the HDAC complex have been recognized as a potent strategy for cancer therapy and chemoprevention. In the present study, we investigated whether selected plant constituents affect HDAC activity or HDAC1 protein status in the human colon carcinoma cell line HT29. The polyphenols (−-epigallocatechin-3-gallate (EGCG and genistein (GEN as well as two oxidative methyleugenol (ME metabolites were shown to inhibit HDAC activity in intact HT29 cells. Concomitantly, a significant decrease of the HDAC1 protein level was observed after incubation with EGCG and GEN, whereas the investigated ME metabolites did not affect HDAC1 protein status. In conclusion, dietary compounds were found to possess promising HDAC-inhibitory properties, contributing to epigenetic alterations in colon tumor cells, which should be taken into account in further risk/benefit assessments of polyphenols and alkenylbenzenes.

  3. Clinical Significance of Lymph Node Metastasis in the Mesentery of the Terminal Ileum in Patients With Right-sided Colon Tumors at Different Locations.

    Science.gov (United States)

    Kang, Sung Il; Kim, Duck-Woo; Shin, Eun; Kim, Myung Jo; Son, Il Tae; Oh, Heung-Kwon; Kang, Sung-Bum

    2018-06-01

    There are limited reports on peri-ileal lymph node metastasis in patients with right-sided colon cancer, and little is known about their clinical significance. This study aimed to examine the role of tumor location in the prevalence and clinical significance of peri-ileal lymph node metastasis in patients with right-sided colon cancer. This is a retrospective study from a prospective cohort database. The study was conducted at a tertiary referral hospital. Patients with right-sided colon cancer treated with radical surgery in a hospital between May 2006 and September 2016 were included. The frequency of peri-ileal lymph node metastasis in the study cohort and the role of tumor location and the clinical characteristics of patients with peri-ileal lymph node metastasis were determined. We examined 752 cases with right-sided colon cancer including 82 cecal, 554 ascending colon, and 116 hepatic flexure cancer. Twenty patients (2.7%) had peri-ileal lymph node metastasis. The incidence of metastasis to peri-ileal lymph nodes was 7.3% (6/82) in patients with cecal cancer, 2.2% (12/554) in patients with ascending colon cancer, and 1.7% (2/116) in patients with hepatic flexure cancer. Three patients had stage III cancer and 17 had stage IV. All 3 patients with positive peri-ileal lymph nodes and stage III cancer had cecal tumors. In contrast, all patients with ascending colon or hepatic flexure cancer and positive peri-ileal lymph nodes had stage IV cancer. The results were limited by the retrospective design of the study and the small number of patients with peri-ileal lymph node metastasis. Peri-ileal lymph node metastasis was rare even in right-sided colon cancer and occurred mainly in stage IV. However, it occurred in some patients with locally advanced cecal cancer. These results suggest that optimal resection of the mesentery of the terminal ileum might have clinical benefit, especially in curative surgery for cecal cancer. See Video Abstract at http

  4. Inferring human colonization history using a copying model.

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    Garrett Hellenthal

    2008-05-01

    Full Text Available Genome-wide scans of genetic variation can potentially provide detailed information on how modern humans colonized the world but require new methods of analysis. We introduce a statistical approach that uses Single Nucleotide Polymorphism (SNP data to identify sharing of chromosomal segments between populations and uses the pattern of sharing to reconstruct a detailed colonization scenario. We apply our model to the SNP data for the 53 populations of the Human Genome Diversity Project described in Conrad et al. (Nature Genetics 38,1251-60, 2006. Our results are consistent with the consensus view of a single "Out-of-Africa" bottleneck and serial dilution of diversity during global colonization, including a prominent East Asian bottleneck. They also suggest novel details including: (1 the most northerly East Asian population in the sample (Yakut has received a significant genetic contribution from the ancestors of the most northerly European one (Orcadian. (2 Native North [corrected] Americans have received ancestry from a source closely related to modern North-East Asians (Mongolians and Oroquen that is distinct from the sources for native South [corrected] Americans, implying multiple waves of migration into the Americas. A detailed depiction of the peopling of the world is available in animated form.

  5. Design of near-infrared fluorescent bioactive conjugated functional iron oxide nanoparticles for optical detection of colon cancer

    Directory of Open Access Journals (Sweden)

    Corem-Salkmon E

    2012-10-01

    Full Text Available Enav Corem-Salkmon, Benny Perlstein, Shlomo MargelThe Institute of Nanotechnology and Advanced Materials, Department of Chemistry, Bar-Ilan University, Ramat-Gan, IsraelBackground: Colon cancer is one of the major causes of death in the Western world. Early detection significantly improves long-term survival for patients with the disease. Near-infrared (NIR fluorescent nanoparticles hold great promise as contrast agents for tumor detection. NIR offers several advantages for bioimaging compared with fluorescence in the visible spectrum, ie, lower autofluorescence of biological tissues, lower absorbance, and consequently deeper penetration into biomatrices.Methods and results: NIR fluorescent iron oxide nanoparticles with a narrow size distribution were prepared by nucleation, followed by controlled growth of thin iron oxide films onto cyanine NIR dye conjugated gelatin-iron oxide nuclei. For functionalization, and in order to increase the NIR fluorescence intensity, the NIR fluorescent iron oxide nanoparticles obtained were coated with human serum albumin containing cyanine NIR dye. Leakage of the NIR dye from these nanoparticles into phosphate-buffered saline solution containing 4% albumin was not detected. The work presented here is a feasibility study to test the suitability of iron oxide-human serum albumin NIR fluorescent nanoparticles for optical detection of colon cancer. It demonstrates that encapsulation of NIR fluorescent dye within these nanoparticles significantly reduces photobleaching of the dye. Tumor-targeting ligands, peanut agglutinin and anticarcinoembryonic antigen antibodies (αCEA, were covalently conjugated with the NIR fluorescent iron oxide-human serum albumin nanoparticles via a poly(ethylene glycol spacer. Specific colon tumor detection was demonstrated in chicken embryo and mouse models for both nonconjugated and the peanut agglutinin-conjugated or αCEA-conjugated NIR fluorescent iron oxide-human serum albumin

  6. Silencing of the hTERT gene by shRNA inhibits colon cancer SW480 cell growth in vitro and in vivo.

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    Ai-Qun Liu

    Full Text Available Human telomerase reverse transcriptase (hTERT is the key enzyme responsible for synthesizing and maintaining the telomeres on the ends of chromosomes, and it is essential for cell proliferation. This has made hTERT a focus of oncology research and an attractive target for anticancer drug development. In this study, we designed a small interfering RNA (siRNA targeting the catalytic subunit of hTERT and tested its effects on the growth of telomerase-positive human colon carcinoma SW480 cells in vitro, as well as on the tumorigenicity of these cells in nude mice. Transient and stable transfection of hTERT siRNA into colon cancer SW480 cells suppressed hTERT expression, reduced telomerase activity and inhibited cell growth and proliferation. Knocking down hTERT expression in SW480 tumors xenografted into nude mice significantly slowed tumor growth and promoted tumor cell apoptosis. Our results suggest that hTERT is involved in carcinogenesis of human colon carcinoma, and they highlight the therapeutic potential of a hTERT knock-down approach.

  7. Engineering of near IR fluorescent albumin nanoparticles for in vivo detection of colon cancer

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    Cohen Sarit

    2012-08-01

    Full Text Available Abstract Background The use of near-infrared (NIR fluorescence imaging techniques has gained great interest for early detection of cancer because water and other intrinsic biomolecules display negligible absorption or autofluorescence in this region. Novel fluorescent nanoparticles with potential to improve neoplasm detection sensitivity may prove to be a valuable tool in early detection of colon tumors. Methods The present study describes the synthesis and use of NIR fluorescent albumin nanoparticles as a diagnostic tool for detection of colon cancer. These fluorescent nanoparticles were prepared by a precipitation process of human serum albumin (HSA in aqueous solution in the presence of a carboxylic acid derivative of the NIR dye IR-783 (CANIR. Tumor-targeting ligands such as peanut agglutinin (PNA, anti-carcinoembryonic antigen antibodies (anti-CEA and tumor associated glycoprotein-72 monoclonal antibodies (anti-TAG-72 were covalently conjugated to the albumin nanoparticles via the surface carboxylate groups by using the carbodiimide activation method. Results and discussion Leakage of the encapsulated dye into PBS containing 4% HSA or human bowel juice was not detected. This study also demonstrates that the encapsulation of the NIR fluorescent dye within the HSA nanoparticles reduces the photobleaching of the dye significantly. Specific colon tumor detection in a mouse model was demonstrated for PNA, anti-CEA and anti-TAG-72 conjugated NIR fluorescent HSA nanoparticles. These bioactive NIR fluorescent albumin nanoparticles also detected invisible tumors that were revealed as pathological only subsequent to histological analysis. Conclusions These results may suggest a significant advantage of NIR fluorescence imaging using NIR fluorescent nanoparticles over regular colonoscopy. In future work we plan to broaden this study by encapsulating cancer drugs, such as paclitaxel and doxorubicin, within these biodegradable NIR fluorescent HSA

  8. Engineering of near IR fluorescent albumin nanoparticles for in vivo detection of colon cancer.

    Science.gov (United States)

    Cohen, Sarit; Margel, Shlomo

    2012-08-14

    The use of near-infrared (NIR) fluorescence imaging techniques has gained great interest for early detection of cancer because water and other intrinsic biomolecules display negligible absorption or autofluorescence in this region. Novel fluorescent nanoparticles with potential to improve neoplasm detection sensitivity may prove to be a valuable tool in early detection of colon tumors. The present study describes the synthesis and use of NIR fluorescent albumin nanoparticles as a diagnostic tool for detection of colon cancer. These fluorescent nanoparticles were prepared by a precipitation process of human serum albumin (HSA) in aqueous solution in the presence of a carboxylic acid derivative of the NIR dye IR-783 (CANIR). Tumor-targeting ligands such as peanut agglutinin (PNA), anti-carcinoembryonic antigen antibodies (anti-CEA) and tumor associated glycoprotein-72 monoclonal antibodies (anti-TAG-72) were covalently conjugated to the albumin nanoparticles via the surface carboxylate groups by using the carbodiimide activation method. Leakage of the encapsulated dye into PBS containing 4% HSA or human bowel juice was not detected. This study also demonstrates that the encapsulation of the NIR fluorescent dye within the HSA nanoparticles reduces the photobleaching of the dye significantly. Specific colon tumor detection in a mouse model was demonstrated for PNA, anti-CEA and anti-TAG-72 conjugated NIR fluorescent HSA nanoparticles. These bioactive NIR fluorescent albumin nanoparticles also detected invisible tumors that were revealed as pathological only subsequent to histological analysis. These results may suggest a significant advantage of NIR fluorescence imaging using NIR fluorescent nanoparticles over regular colonoscopy. In future work we plan to broaden this study by encapsulating cancer drugs, such as paclitaxel and doxorubicin, within these biodegradable NIR fluorescent HSA nanoparticles, in order to use them for both detection as well as therapy of colon

  9. Radioimmunotoxin Therapy of Experimental Colon and Ovarian Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Buchsbaum, Donald J.; Vallera, Daniel A.

    2006-02-09

    mixed with the EpCam sFv that was synthesized without any toxin attached. The proliferation studies showed that EpCam sFv was able to block the killing of the EpCam expressing cells by DTEpCam. An irrelevant control protein, 1D10Fc was unable to block. Together, these studies indicated that EpCam was exquisitely selective. In order to produce an IT of even greater potency, we used a toxin containing the Golgi retention sequence KDEL. The same EpCam sFv was spliced to truncated PE containing the terminal KDEL sequence. The addition of KDEL enhanced the potency of the EpCam sFv IT at least 6 logs or 1000-fold with an IC50 of 2 to 7 x 10-8 nM. This conjugate was also shown to be highly selective. Taken together, all of these studies indicate that in vitro experiments have shown that we have a highly potent IT that selectively kills colon cancer cells. The next step was to show that the EpCam IT had the ability to inhibit the growth of flank tumors in vivo in nude mice. The same human colon tumor cells, HT29 used in the in vitro studies were injected into the flank of nude mice. Tumor cells were injected into groups of mice and when tumors reached the size of 0.5 cm3, we injected our best-performing EpCam IT called EpCamKDEL intratumorally. There was a significant drop in tumor size indicating that this agent was very effective against human colon cancer. Since the EpCamKDEL was injected intratumorally, it did not have to travel through the systemic circulation to find its target. Our next step will be to inject EpCamKDEL intravenously into mice with flank tumors to determine if EpCamKDEL has the ability to migrate to the tumor systemically. The next step was to radiolabel EpCamKDEL to see whether it could serve as an RIT. We radiolabeled EpCam with 111In as a surrogate for 90Y and then incubated it with HT29. The labeling efficiency was over 90% indicating that a high percentage of the protein molecules could be readily radiolabeled. However, the immunoreactivity was only

  10. Radioimmunotoxin Therapy of Experimental Colon and Ovarian Cancer

    International Nuclear Information System (INIS)

    Buchsbaum, Donald J.; Vallera, Daniel A.

    2006-01-01

    mixed with the EpCam sFv that was synthesized without any toxin attached. The proliferation studies showed that EpCam sFv was able to block the killing of the EpCam expressing cells by DTEpCam. An irrelevant control protein, 1D10Fc was unable to block. Together, these studies indicated that EpCam was exquisitely selective. In order to produce an IT of even greater potency, we used a toxin containing the Golgi retention sequence KDEL. The same EpCam sFv was spliced to truncated PE containing the terminal KDEL sequence. The addition of KDEL enhanced the potency of the EpCam sFv IT at least 6 logs or 1000-fold with an IC50 of 2 to 7 x 10-8 nM. This conjugate was also shown to be highly selective. Taken together, all of these studies indicate that in vitro experiments have shown that we have a highly potent IT that selectively kills colon cancer cells. The next step was to show that the EpCam IT had the ability to inhibit the growth of flank tumors in vivo in nude mice. The same human colon tumor cells, HT29 used in the in vitro studies were injected into the flank of nude mice. Tumor cells were injected into groups of mice and when tumors reached the size of 0.5 cm3, we injected our best-performing EpCam IT called EpCamKDEL intratumorally. There was a significant drop in tumor size indicating that this agent was very effective against human colon cancer. Since the EpCamKDEL was injected intratumorally, it did not have to travel through the systemic circulation to find its target. Our next step will be to inject EpCamKDEL intravenously into mice with flank tumors to determine if EpCamKDEL has the ability to migrate to the tumor systemically. The next step was to radiolabel EpCamKDEL to see whether it could serve as an RIT. We radiolabeled EpCam with 111In as a surrogate for 90Y and then incubated it with HT29. The labeling efficiency was over 90% indicating that a high percentage of the protein molecules could be readily radiolabeled. However, the immunoreactivity was only

  11. Overexpression of UbcH10 alternates the cell cycle profile and accelerate the tumor proliferation in colon cancer

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    Hatoh Shinji

    2009-03-01

    Full Text Available Abstract Background UbcH10 participates in proper metaphase to anaphase transition, and abrogation of UbcH10 results in the premature separation of sister chromatids. To assess the potential role of UbcH10 in colon cancer progression, we analyzed the clinicopathological relevance of UbcH10 in colon cancer. Methods We firstly screened the expression profile of UbcH10 in various types of cancer tissues as well as cell lines. Thereafter, using the colon cancer cells line, we manipulated the expression of UbcH10 and evaluated the cell cycle profile and cellular proliferations. Furthermore, the clinicopathological significance of UbcH10 was immunohistologically evaluated in patients with colon cancer. Statistical analysis was performed using the student's t-test and Chi-square test. Results Using the colon cancer cells, depletion of UbcH10 resulted in suppression of cellular growth whereas overexpression of UbcH10 promoted the cellular growth and oncogenic cellular growth. Mitotic population was markedly alternated by the manipulation of UbcH10 expression. Immunohistochemical analysis indicated that UbcH10 was significantly higher in colon cancer tissue compared with normal colon epithelia. Furthermore, the clinicopathological evaluation revealed that UbcH10 was associated with high-grade histological tumors. Conclusion The results show the clinicopathological significance of UbcH10 in the progression of colon cancer. Thus UbcH10 may act as a novel biomarker in patients with colon cancer.

  12. The first microbial colonizers of the human gut

    NARCIS (Netherlands)

    Milani, Christian; Duranti, Sabrina; Bottacini, Francesca; Casey, Eoghan; Turroni, Francesca; Mahony, Jennifer; Belzer, Clara; Palacio, Susana Delgado; Montes, Silvia Arboleya; Mancabelli, Leonardo; Lugli, Gabriele Andrea; Rodriguez, Juan Miguel; Bode, Lars; Vos, De Willem; Gueimonde, Miguel; Margolles, Abelardo; Sinderen, Van Douwe; Ventura, Marco

    2017-01-01

    The human gut microbiota is engaged in multiple interactions affecting host health during the host's entire life span. Microbes colonize the neonatal gut immediately following birth. The establishment and interactive development of this early gut microbiota are believed to be (at least partially)

  13. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium.

    Science.gov (United States)

    Sato, Toshiro; Stange, Daniel E; Ferrante, Marc; Vries, Robert G J; Van Es, Johan H; Van den Brink, Stieneke; Van Houdt, Winan J; Pronk, Apollo; Van Gorp, Joost; Siersema, Peter D; Clevers, Hans

    2011-11-01

    We previously established long-term culture conditions under which single crypts or stem cells derived from mouse small intestine expand over long periods. The expanding crypts undergo multiple crypt fission events, simultaneously generating villus-like epithelial domains that contain all differentiated types of cells. We have adapted the culture conditions to grow similar epithelial organoids from mouse colon and human small intestine and colon. Based on the mouse small intestinal culture system, we optimized the mouse and human colon culture systems. Addition of Wnt3A to the combination of growth factors applied to mouse colon crypts allowed them to expand indefinitely. Addition of nicotinamide, along with a small molecule inhibitor of Alk and an inhibitor of p38, were required for long-term culture of human small intestine and colon tissues. The culture system also allowed growth of mouse Apc-deficient adenomas, human colorectal cancer cells, and human metaplastic epithelia from regions of Barrett's esophagus. We developed a technology that can be used to study infected, inflammatory, or neoplastic tissues from the human gastrointestinal tract. These tools might have applications in regenerative biology through ex vivo expansion of the intestinal epithelia. Studies of these cultures indicate that there is no inherent restriction in the replicative potential of adult stem cells (or a Hayflick limit) ex vivo. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  14. Magnetic Resonance Imaging Quantification of Fasted State Colonic Liquid Pockets in Healthy Humans.

    Science.gov (United States)

    Murray, Kathryn; Hoad, Caroline L; Mudie, Deanna M; Wright, Jeff; Heissam, Khaled; Abrehart, Nichola; Pritchard, Susan E; Al Atwah, Salem; Gowland, Penny A; Garnett, Martin C; Amidon, Gregory E; Spiller, Robin C; Amidon, Gordon L; Marciani, Luca

    2017-08-07

    The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or "pockets". Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of

  15. Comparison of the effects of an ornithine decarboxylase inhibitor on the intestinal epithelium and on intestinal tumors.

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1986-12-01

    Ornithine decarboxylase (ODC) catalyzes the rate-limiting step in the synthesis of polyamines, it has a short half-life, and its synthesis is under hormonal control. Recently, insight into the role of ODC and thus into the physiology of polyamines has been gained by the use of an inhibitor of ODC, difluoromethylornithine (DFMO). In the present report cell proliferation was measured by a stathmokinetic method in the crypt epithelium of the jejunum and colon of normal rats and in dimethylhydrazine-induced colonic tumors. Growth of human colon tumor xenografts in immunosuppressed mice and mouse colon tumor isografts was also assessed. Cell proliferation in primary colonic tumors was substantially suppressed by a single dose of DFMO at 100 mg/kg whereas the normal crypt epithelium of the small and large intestine required two doses at 400 mg/kg to produce a similar magnitude of inhibition of cell proliferation. DFMO was also found to suppress cell proliferation in, and the growth of, the transplantable colon cancers. Because of the apparent selectivity of the antimitotic activity of DFMO towards tumors, ODC inhibitors may prove to be useful anticancer drugs.

  16. Mesenchymal Stem Cells Induce Epithelial to Mesenchymal Transition in Colon Cancer Cells through Direct Cell-to-Cell Contact

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    Hidehiko Takigawa

    2017-05-01

    Full Text Available We previously reported that in an orthotopic nude mouse model of human colon cancer, bone marrow–derived mesenchymal stem cells (MSCs migrated to the tumor stroma and promoted tumor growth and metastasis. Here, we evaluated the proliferation and migration ability of cancer cells cocultured with MSCs to elucidate the mechanism of interaction between cancer cells and MSCs. Proliferation and migration of cancer cells increased following direct coculture with MSCs but not following indirect coculture. Thus, we hypothesized that direct contact between cancer cells and MSCs was important. We performed a microarray analysis of gene expression in KM12SM colon cancer cells directly cocultured with MSCs. Expression of epithelial-mesenchymal transition (EMT–related genes such as fibronectin (FN, SPARC, and galectin 1 was increased by direct coculture with MSCs. We also confirmed the upregulation of these genes with real-time polymerase chain reaction. Gene expression was not elevated in cancer cells indirectly cocultured with MSCs. Among the EMT-related genes upregulated by direct coculture with MSCs, we examined the immune localization of FN, a well-known EMT marker. In coculture assay in chamber slides, expression of FN was seen only at the edges of cancer clusters where cancer cells directly contacted MSCs. FN expression in cancer cells increased at the tumor periphery and invasive edge in orthotopic nude mouse tumors and human colon cancer tissues. These results suggest that MSCs induce EMT in colon cancer cells via direct cell-to-cell contact and may play an important role in colon cancer metastasis.

  17. Oral Candida spp. colonization in human immunodeficiency virus-infected individuals

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    D. V. Moris

    2008-01-01

    Full Text Available Several yeast species of Candida genus can colonize the skin as well as the mucous membrane of the vagina and the digestive tract for short or long periods. Depending on the host's immunological state and the yeast's virulence, colonization can become an infection, invading the colonized tissues and also disseminating. AIDS is characterized by the host's intensive and progressive immunodepression which manifests as diverse symptoms, mainly lesions in the mouth. Oral candidiasis is the most prevalent opportunistic infection in individuals infected with human immunodeficiency virus (HIV and is an important indicator of the disease progress and the immunosuppression increase. The factors involved in the equilibrium between Candida spp. and HIV-infected subjects are sometimes contradictory and were evaluated in the present study specially for colonization.

  18. [Synchronous Double Cancer Involving Gastric Cancer Resembling a Submucosal Tumor with Stenosis in the Pylorus and Ascending Colon Cancer - A Case Report].

    Science.gov (United States)

    Miyauchi, Tatsuomi; Miyaki, Akira; Ida, Arika; Kishibe, Saki; Yamaguchi, Kentaro; Shiozawa, Shunichi; Usui, Takebumi; Kuhara, Kotaro; Kono, Teppei; Naritaka, Yoshihiko

    2016-11-01

    An 82-year-old woman presented to our hospital with a complaint of frequent vomiting. She was admitted for intensive examination and treatment. Abdominal computed tomography revealed that her stomach was severely expanded, and the wall of the ascending colon was thickened throughout its circumference. Upper gastrointestinal endoscopy uncovered severe stenosis in the pylorus and an elevated lesion resembling a submucosal tumor on the posterior wall of the pylorus. Biopsies of the lesion revealed that it was of Group 1. On colonoscopy, type 2 cancer was found in the ascending colon throughout the circumference, and the biopsies revealed that it was of Group 5. Upper gastrointestinal endoscopy was repeated, and the same result was obtained. The possibility of malignancy could not be excluded; therefore, distal gastrectomy and right colectomy were performed. In terms of histopathology, both resected specimens displayed poorly differentiated adenocarcinoma; however, immunohistochemical studies revealed differences in staining at the two sites. The case was diagnosed as synchronous double cancer involving gastric cancer resembling a submucosal tumor with stenosis in the pylorus and ascending colon cancer. Gastric cancer resembling a submucosal tumor is usually difficult to diagnose on biopsy. If the endoscopic findings reveal an elevated lesion resembling a submucosal tumor with stenosis, then the possibility of carcinoma should be considered, and the most suitable treatment should be selected.

  19. Combined 5-FU and ChoKα inhibitors as a new alternative therapy of colorectal cancer: evidence in human tumor-derived cell lines and mouse xenografts.

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    Ana de la Cueva

    Full Text Available Colorectal cancer (CRC is the third major cause of cancer related deaths in the world. 5-fluorouracil (5-FU is widely used for the treatment of colorectal cancer but as a single-agent renders low response rates. Choline kinase alpha (ChoKα, an enzyme that plays a role in cell proliferation and transformation, has been reported overexpressed in many different tumors, including colorectal tumors. ChoKα inhibitors have recently entered clinical trials as a novel antitumor strategy.ChoKα specific inhibitors, MN58b and TCD-717, have demonstrated a potent antitumoral activity both in vitro and in vivo against several tumor-derived cell line xenografts including CRC-derived cell lines. The effect of ChoKα inhibitors in combination with 5-FU as a new alternative for the treatment of colon tumors has been investigated both in vitro in CRC-tumour derived cell lines, and in vivo in mouse xenografts models. The effects on thymidilate synthase (TS and thymidine kinase (TK1 levels, two enzymes known to play an essential role in the mechanism of action of 5-FU, were analyzed by western blotting and quantitative PCR analysis. The combination of 5-FU with ChoKα inhibitors resulted in a synergistic effect in vitro in three different human colon cancer cell lines, and in vivo against human colon xenografts in nude mice. ChoKα inhibitors modulate the expression levels of TS and TK1 through inhibition of E2F production, providing a rational for its mechanism of action.Our data suggest that both drugs in combination display a synergistic antitumoral effect due to ChoKα inhibitors-driven modulation of the metabolization of 5-FU. The clinical relevance of these findings is strongly supported since TCD-717 has recently entered Phase I clinical trials against solid tumors.

  20. Suppression of Angiogenesis and Therapy of Human Colon Cancer Liver Metastasis by Systemic Administration of Interferon-α

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    Shutaro Ozawa

    2001-01-01

    Full Text Available The purpose of this study was to determine whether systemic administration of interferon-alpha (IFN-α can inhibit liver metastasis produced in nude mice by human colon cancer cells. KM12L4 (IFN-α-sensitive or KM12L4 IFNR (IFN-α-resistant cells were injected into the spleen of nude mice. Seven days later, the mice were treated with subcutaneous (s.c. injections of IFN-α (70,000 units/week at different dosing schedules (1, 2, or 7 times/week. Significant inhibition of tumor growth, vascularization and expression of basic fibroblast growth factor (bFGF or matrix metal loproteinase9 (MMP-9 mRNA and protein occurred in mice given daily injections of IFN-α. Kinetic analysis of therapy showed that daily s.c. administrations of 10,000 units of IFN-α induced apoptosis in liver metastasis-associated endothelial cells, followed by inhibition of tumor cell division and apoptosis of tumor cells. These data suggest that the antiangiogenic activity of IFN-α-2a depends on frequent administration of the optimal biologic dose.

  1. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp transcription factors

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    Pathi Satya

    2011-08-01

    Full Text Available Abstract Background Betulinic acid (BA inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells. Methods The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a and ZBTB10 mRNA expression. Results BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS, ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10. Conclusions These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent.

  2. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors

    International Nuclear Information System (INIS)

    Chintharlapalli, Sudhakar; Papineni, Sabitha; Lei, Ping; Pathi, Satya; Safe, Stephen

    2011-01-01

    Betulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells. The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression. BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10. These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent

  3. Up-regulation of CNDP2 facilitates the proliferation of colon cancer.

    Science.gov (United States)

    Xue, Conglong; Zhang, Zhenwei; Yu, Honglan; Yu, Miao; Yuan, Kaitao; Yang, Ting; Miao, Mingyong; Shi, Hanping

    2014-05-21

    Cytosolic nonspecific dipetidase (CN2) belongs to the family of M20 metallopeptidases. It was stated in previous articles that higher expression levels of CN2 were observed in renal cell carcinoma and breast cancer. Our study explored the correlation between CN2 and colon carcinogenesis. We analysed the relationship between 183 patients clinicopathological characteristics and its CN2 expression. To detect the levels of CN2 in colon cancer cell lines and colon cancer tissues by western blot. To verify cell proliferation in colon cancer cells with knockdown of CNDP2 and explore the causes of these phenomena. The expression levels of CN2 in clinical colon tumors and colon cancer cell lines were significantly higher than that in normal colon mucosa and colon cell lines. The difference in CN2 levels was associated with tumor location (right- and left-sided colon cancer), but there was no significant association with age, gender, tumor size, tumor grade, tumor stage or serum carcinoembryonic antigen (CEA). Knockdown of CNDP2 inhibited cell proliferation, blocked cell cycle progression and retarded carcinogenesis in an animal model. The signaling pathway through which knockdown of CNDP2 inhibited cell proliferation and tumorigenesis involved in EGFR, cyclin B1 and cyclin E. Knockdown of CNDP2 can inhibit the proliferation of colon cancer in vitro and retarded carcinogenesis in vivo.

  4. Advanced colonic cancer associated with radiation colitis, report of a case

    Energy Technology Data Exchange (ETDEWEB)

    Moriyama, Tomohiko; Sato, Tomoo; Iwai, Keiichirou; Yao, Takashi; Mibu, Ryuichi; Iida, Mitsuo [Kyushu Univ., Fukuoka (Japan). Graduate School of Medical Sciences; Matsumoto, Takayuki [Kyushu Univ., Fukuoka (Japan). Hospital

    2002-07-01

    A 68-year-old woman with a history of irradiation for uterine cervical cancer was admitted to our institute, because of abdominal distension. Barium enema examination and total colonoscopy revealed narrowing, irregular mucosa and an ulcerating tumor in the sigmoid colon and a flat elevation in the transverse colon. Biopsy specimens from these tumors contained adenocarcinoma. Histological examination of the resected colon revealed the tumor in the sigmoid colon to be a well-differentiated adenocarcinoma invading the subserosa and that in the transverse colon to be an intramucosal adenocarcinoma. There were also areas of low or high grade dysplasia in the sigmoid colon. Histological findings compatible with radiation colitis were found in the sigmoid colon. These clinicopathologic features suggested a diagnosis of colonic cancer associated with radiation colitis. (author)

  5. Advanced colonic cancer associated with radiation colitis, report of a case

    International Nuclear Information System (INIS)

    Moriyama, Tomohiko; Sato, Tomoo; Iwai, Keiichirou; Yao, Takashi; Mibu, Ryuichi; Iida, Mitsuo; Matsumoto, Takayuki

    2002-01-01

    A 68-year-old woman with a history of irradiation for uterine cervical cancer was admitted to our institute, because of abdominal distension. Barium enema examination and total colonoscopy revealed narrowing, irregular mucosa and an ulcerating tumor in the sigmoid colon and a flat elevation in the transverse colon. Biopsy specimens from these tumors contained adenocarcinoma. Histological examination of the resected colon revealed the tumor in the sigmoid colon to be a well-differentiated adenocarcinoma invading the subserosa and that in the transverse colon to be an intramucosal adenocarcinoma. There were also areas of low or high grade dysplasia in the sigmoid colon. Histological findings compatible with radiation colitis were found in the sigmoid colon. These clinicopathologic features suggested a diagnosis of colonic cancer associated with radiation colitis. (author)

  6. Vasohibin-1 suppresses colon cancer

    Science.gov (United States)

    Liu, Shuai; Han, Bing; Zhang, Qunyuan; Dou, Jie; Wang, Fang; Lin, Wenli; Sun, Yuping; Peng, Guangyong

    2015-01-01

    Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor. However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo. PMID:25797264

  7. Vasohibin-1 suppresses colon cancer.

    Science.gov (United States)

    Liu, Shuai; Han, Bing; Zhang, Qunyuan; Dou, Jie; Wang, Fang; Lin, Wenli; Sun, Yuping; Peng, Guangyong

    2015-04-10

    Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor.However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.

  8. Expanding the Tissue Toolbox : Deriving Colon Tissue from Human Pluripotent Stem Cells

    NARCIS (Netherlands)

    Bruens, Lotte; Snippert, Hugo J.G.

    2017-01-01

    Organoid technology holds great potential for disease modeling and regenerative medicine. In this issue of Cell Stem Cell, Múnera et al. (2017) establish the generation of pluripotent stem cell-derived colon organoids that upon transplantation in mice, resembling human colon to a large extent,

  9. Clinicopathologic factors identify sporadic mismatch repair-defective colon cancers

    DEFF Research Database (Denmark)

    Halvarsson, Britta; Anderson, Harald; Domanska, Katarina

    2008-01-01

    Identification of sporadic mismatch repair (MMR)-defective colon cancers is increasingly demanded for decisions on adjuvant therapies. We evaluated clinicopathologic factors for the identification of these prognostically favorable tumors. Histopathologic features in 238 consecutive colon cancers...... and excluded 61.5% of the tumors from MMR testing. This clinicopathologic index thus successfully selects MMR-defective colon cancers. Udgivelsesdato: 2008-Feb...

  10. Tetranectin, a plasminogen kringle 4-binding protein. Cloning and gene expression pattern in human colon cancer

    DEFF Research Database (Denmark)

    Wewer, U M; Albrechtsen, R

    1992-01-01

    BACKGROUND: Tetranectin is a recently discovered protein that binds to kringle 4 region of plasminogen (Clemmensen I, Petersen LC, Kluft C. Eur J Biochem 1986; 156:327. EXPERIMENTAL DESIGN: The mRNA encoding human tetranectin was cloned by using degenerate primers in a reverse transcriptase...... reaction followed by polymerase chain reaction amplification. The resulting polymerase chain reaction product was examined by DNA sequencing and subsequently used as probe for screening a human placental cDNA library. A full length cDNA clone (TET-1) was isolated, characterized, and used for Northern blot...... prominent in the lungs and spleen. No hybridization signal was detected in three carcinoma cell lines examined in parallel. Northern blot analysis of poly A+ RNA isolated from solid tumors revealed a tetranectin specific mRNA band. In situ hybridizations on tissue sections of colon carcinomas and normal...

  11. Effect of Agaricus blazei Murrill extract on HT-29 human colon cancer cells in SCID mice in vivo.

    Science.gov (United States)

    Wu, Ming-Fang; Chen, Yung-Liang; Lee, Mei-Hui; Shih, Yung-Luen; Hsu, Yu-Ming; Tang, Ming-Chu; Lu, Hsu-Feng; Tang, Nou-Ying; Yang, Su-Tso; Chueh, Fu-Shin; Chung, Jing-Gung

    2011-01-01

    Agaricus blazei Murrill (ABM) popularly known as 'Cogumelo do Sol' in Brazil, or 'Himematsutake' in Japan, is a mushroom native to Brazil and widely cultivated in Japan for its medicinal uses and is now considered one of the most important edible and culinary-medicinal biotechnological species. This study is the first tumor growth model to evaluate the amelioratory effect of ABM extract using HT-29 human colon cancer cells in severe combined immunodeficiency (SCID) mice. Forty SCID mice were inoculated with HT-29 cells to induce tumor formation and were then divided into four groups. All the four groups (control, low, medium and high concentration treatment) of mice were separately orally administered 0 mg, 1.125 mg, 4.5 mg or 45 mg ABM extract daily. After six weeks of treatment, 8 out of the 40 mice had not survived including one mouse which scored +++ (tumor up to 15 mm diameter) and four mice which scored ++++ (tumor over 15 mm diameter) in the control group and three mice which scored ++++ on the low-dose ABM treatment. After high- or medium-dose treatment, all ten mice in each group survived. The oral administration of ABM does not prevent tumor growth, as shown by increased tumor mass, but compared with the control group, the tumor mass seems to grow more slowly depending on the ABM dose.

  12. Comparison of the tumor inhibiting effects of three histamine H2-receptor antagonists.

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1983-01-01

    Three histamine H2-receptor antagonists, Cimetidine, Metiamide and Ranitidine, were tested for their inhibitory effect on two experimental bowel cancer models. In the first model mitotic rates were measured in dimethylhydrazine-induced tumors of rat colon and in the second model volumetric changes in human large bowel cancer xenografts were assessed. In tumors of rat colon all three drugs were able to suppress mitotic activity, but the effects of Metiamide and Ranitidine were more prolonged than that of Cimetidine in each of two lines of human bowel cancer that were used. Metiamide and Ranitidine were also more effective growth inhibitors than was Cimetidine.

  13. Diet-Induced Obesity Is Associated with an Impaired NK Cell Function and an Increased Colon Cancer Incidence

    Directory of Open Access Journals (Sweden)

    Ina Bähr

    2017-01-01

    Full Text Available Obesity is associated with an increased colon cancer incidence, but underlying mechanisms remained unclear. Previous studies showed altered Natural killer (NK cell functions in obese individuals. Therefore, we studied the impact of an impaired NK cell functionality on the increased colon cancer risk in obesity. In vitro investigations demonstrated a decreased IFN-γ secretion and cytotoxicity of human NK cells against colon tumor cells after NK cell preincubation with the adipokine leptin. In addition, leptin incubation decreased the expression of activating NK cell receptors. In animal studies, colon cancer growth was induced by injection of azoxymethane (AOM in normal weight and diet-induced obese rats. Body weight and visceral fat mass were increased in obese animals compared to normal weight rats. AOM-treated obese rats showed an increased quantity, size, and weight of colon tumors compared to the normal weight tumor group. Immunohistochemical analyses demonstrated a decreased number of NK cells in spleen and liver in obesity. Additionally, the expression levels of activating NK cell receptors were lower in spleen and liver of obese rats. The results show for the first time that the decreased number and impaired NK cell function may be one cause for the higher colon cancer risk in obesity.

  14. Radiation-associated colon cancer: A case report.

    Science.gov (United States)

    Sasaki, Kazuhito; Ishihara, Soichiro; Hata, Keisuke; Kiyomatsu, Tomomichi; Nozawa, Hiroaki; Kawai, Kazushige; Tanaka, Toshiaki; Nishikawa, Takeshi; Otani, Kensuke; Yasuda, Koji; Kaneko, Manabu; Murono, Koji; Abe, Hiroyuki; Morikawa, Teppei; Watanabe, Toshiaki

    2017-06-01

    Radiation-associated colon cancer is a rare clinical entity. We herein describe the case of a patient with radiation-associated colon cancer who had undergone low anterior resection for rectal cancer following preoperative radiotherapy. Certain characteristics of radiation-associated colon cancer are highlighted. The patient was a 48-year-old man who had undergone low anterior resection for rectal cancer following preoperative radiotherapy at a total dose of 50 Gy, at the age of 29 years. When the patient presented at the University of Tokyo Hospital, 19 years after the surgery, he complained of severe anal pain and frequent defecation. Colonoscopy revealed two flat tumors in the sigmoid colon, located 10 cm to the oral side of the anastomosis site, which were diagnosed as well-differentiated adenocarcinomas. In addition, colonoscopy identified five flat polyps near the tumors, which were resected endoscopically. Computed tomography and magnetic resonance imaging revealed a mass in the sigmoid colon and no evidence of distant metastasis. Laparoscopic-assisted intersphincteric resection of the rectum and sigmoid colon with diverting ileostomy was performed. There were no specific postoperative complications and the patient was discharged from the hospital on the 20th postoperative day. On pathological examination, the resected rectum and sigmoid colon contained two separate tumors and six flat polyps. The two tumors were diagnosed as well-differentiated adenocarcinomas with invasion of the subserosa and submucosa, respectively. A total of 17 regional lymph nodes without metastasis were resected. The six flat polyps were diagnosed as tubular adenomas. We herein present a case of a radiation-associated colon cancer in a patient who had undergone low anterior resection for rectal cancer following preoperative radiotherapy 19 years prior. Colonoscopic surveillance of radiation-associated colon cancer may be indicated for rectal cancer patients treated with preoperative

  15. Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH genes in multiple human solid tumors: A systematic expression analysis

    Directory of Open Access Journals (Sweden)

    Werbowetski-Ogilvie Tamra

    2008-01-01

    Full Text Available Abstract Background The inter-alpha-trypsin inhibitors (ITI are a family of plasma protease inhibitors, assembled from a light chain – bikunin, encoded by AMBP – and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5, contributing to extracellular matrix stability by covalent linkage to hyaluronan. So far, ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis. Methods We systematically investigated differential gene expression of the ITIH gene family, as well as AMBP and the interacting partner TNFAIP6 in 13 different human tumor entities (of breast, endometrium, ovary, cervix, stomach, small intestine, colon, rectum, lung, thyroid, prostate, kidney, and pancreas using cDNA dot blot analysis (Cancer Profiling Array, CPA, semiquantitative RT-PCR and immunohistochemistry. Results We found that ITIH genes are clearly downregulated in multiple human solid tumors, including breast, colon and lung cancer. Thus, ITIH genes may represent a family of putative tumor suppressor genes that should be analyzed in greater detail in the future. For an initial detailed analysis we chose ITIH2 expression in human breast cancer. Loss of ITIH2 expression in 70% of cases (n = 50, CPA could be confirmed by real-time PCR in an additional set of breast cancers (n = 36. Next we studied ITIH2 expression on the protein level by analyzing a comprehensive tissue micro array including 185 invasive breast cancer specimens. We found a strong correlation (p Conclusion Altogether, this is the first systematic analysis on the differential expression of ITIH genes in human cancer, showing frequent downregulation that may be associated with initiation and/or progression of these malignancies.

  16. γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells.

    Science.gov (United States)

    Song, Lihua; Du, Aiying; Xiong, Ying; Jiang, Jing; Zhang, Yao; Tian, Zhaofeng; Yan, Hongli

    2016-11-01

    γ-Aminobutyric acid (GABA) is a natural non-protein amino acid, which broadly exists in many plant parts and is widely used as an ingredient in the food industry. In mammals, it is widely distributed in central nervous system and non-neural tissues. In addition to a primary inhibitory neurotransmitter in the central nervous system, endogenous GABA content has been found to be elevated in neoplastic tissues in colon cancer. However, the effect of extraneous GABA on colon cancer has rarely been reported. In this study, we found the inhibitory effects of GABA on the proliferation of colon cancer cells (CCCs). The amino acid also suppressed metastasis of SW480 and SW620 cells. To further study the correlated mechanism, we analyzed the changes in cell cycle distribution and found that GABA suppressed cell cycle progression through G2/M or G1/S phase. Furthermore, RNA sequencing analysis revealed GABA-induced changes in the mRNA expression of 30 genes, including EGR1, MAPK4, NR4A1, Fos, and FosB, in all the three types of CCC. Importantly, GABA enhanced the anti-tumor efficacy of oxaliplatin (OXA) in subcutaneous xenograft tumor model in nude mice. The data suggest that GABA inhibits colon cancer cell proliferation perhaps by attenuating EGR1-NR4A1 axis, EGR1-Fos axis, and by disrupting MEK-EGR1 signaling pathway. This work reveals the pharmacological value of GABA derived from food and suggests that exogenous GABA might play an auxiliary role in polychemotherapy of colon cancer.

  17. Characteristics of [18F] fluorodeoxyglucose uptake in human colon cancer cells

    International Nuclear Information System (INIS)

    Kim, Chae Kyun; Chung, June Key; Jeong, Jae Min; Lee, Myung Chul; Koh, Chang Soon

    1997-01-01

    Cancer tissues are characterized by increased glucose uptake. 18 F-fluorodeoxyglucose(FDG), a glucose analogue is used for the diagnosis of cancer in PET studies. This study was aimed to compare the glucose uptake and glucose transporter 1(GLUT1) expression in various human colon cancer cells. We measured FDG uptake by cell retention study and expression of GLUT1 using Western blotting. Human colon cancer cells, SNU-C2A, SNU-C4 and SNU-C5, were used. The cells were incubated with 1μ Ci/ml of FDG in HEPES- buffered saline for one hour. The FDG uptake of SNU-C2A, SNU-C4 and SNU-C5 were 16.8±1.36, 12.3±5.55 and 61.0±2.17 cpm/μg of protein, respectively. Dose-response and time-course studies represent that FDG uptake of cancer cells were dose dependent and time dependent. The rate of FDG uptake of SNU-C2A, SNU-C4 and SNU-C5 were 0.29±0.03, 0.21±0.09 and 1.07±0.07 cpm/min/μg of protein, respectively. Western blot analysis showed that the GLUT1 expression of SNU-C5 was significantly higher than those of SNU-C2A and SNU-C4. These results represent that FDG uptake into human colon cancer cells are different from each other. In addition, FDG uptake and expression of GLUT1 are closely related in human colon cancer cells

  18. Isolation of Human Colon Stem Cells Using Surface Expression of PTK7.

    Science.gov (United States)

    Jung, Peter; Sommer, Christian; Barriga, Francisco M; Buczacki, Simon J; Hernando-Momblona, Xavier; Sevillano, Marta; Duran-Frigola, Miquel; Aloy, Patrick; Selbach, Matthias; Winton, Douglas J; Batlle, Eduard

    2015-12-08

    Insertion of reporter cassettes into the Lgr5 locus has enabled the characterization of mouse intestinal stem cells (ISCs). However, low cell surface abundance of LGR5 protein and lack of high-affinity anti-LGR5 antibodies represent a roadblock to efficiently isolate human colonic stem cells (hCoSCs). We set out to identify stem cell markers that would allow for purification of hCoSCs. In an unbiased approach, membrane-enriched protein fractions derived from in vitro human colonic organoids were analyzed by quantitative mass spectrometry. Protein tyrosine pseudokinase PTK7 specified a cell population within human colonic organoids characterized by highest self-renewal and re-seeding capacity. Antibodies recognizing the extracellular domain of PTK7 allowed us to isolate and expand hCoSCs directly from patient-derived mucosa samples. Human PTK7+ cells display features of canonical Lgr5+ ISCs and include a fraction of cells that undergo differentiation toward enteroendocrine lineage that resemble crypt label retaining cells (LRCs). Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Radioimmunoimaging of human colon and gastric cancers xenografts by NCC-ST-439 and NCC-ST-433 monoclonal antibodies

    International Nuclear Information System (INIS)

    Nakamura, Kayoko; Tsukatani, Yasushi; Nishiguchi, Iku

    1987-01-01

    Both NCC-ST-439 and NCC-ST-433 are monoclonal antibodies raised against human gastric cancer (St-4) xenografts in nude mice. Imaging and localization experiments were performed by injecting I-125 labeled antibodies into nude mice bearing CO-4 (colon carcinoma) and H-111 (gastric carcinoma). There was uptake of NCC-ST-439 (polymer) into the CO-4, though it was not clearly visualized until 5 days post injection. By injecting NCC-ST-439 (monomer), CO-4 was better seen at day 3, while average accumulation into the tumors decreased compared with NCC-ST-439 (polymer). High radioactivities were observed in the liver and spleen, which was probably due to the immunocomplex with the antigen in the blood. NCC-ST-433 was selectively accumulated into the H-111 with tumor to blood ratio 7.8 at day 7, without significant uptake into the liver and spleen. Significant correlation was also found between the tumor uptake level of NCC-ST-433 and size of tumors. Excellent images of H-111 were obtained 3 days after the injection. NCC-ST-433 holds promise for the radioimmunodetection of gastric cancers. (author)

  20. δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages.

    Science.gov (United States)

    Chen, Jayson X; Liu, Anna; Lee, Mao-Jung; Wang, Hong; Yu, Siyuan; Chi, Eric; Reuhl, Kenneth; Suh, Nanjoo; Yang, Chung S

    2017-01-01

    Tocopherols, the major forms of vitamin E, are a family of fat-soluble compounds that exist in alpha (α-T), beta (β-T), gamma (γ-T), and delta (δ-T) variants. A cancer preventive effect of vitamin E is suggested by epidemiological studies. However, past animal studies and human intervention trials with α-T, the most active vitamin E form, have yielded disappointing results. A possible explanation is that the cancer preventive activity of α-T is weak compared to other tocopherol forms. In the present study, we investigated the effects of δ-T, γ-T, and α-T (0.2% in diet) in a novel colon cancer model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS)-induced colitis in CYP1A-humanized (hCYP1A) mice. PhIP/DSS treatments induced multiple polypoid tumors, mainly tubular adenocarcinomas, in the middle to distal colon of the hCYP1A mice after 10 wk. Dietary supplementation with δ-T and γ-T significantly reduced colon tumor formation and suppressed markers of oxidative and nitrosative stress (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory mediators (i.e., NF-κB p65 and p-STAT3) in tumors and adjacent tissues. By administering δ-T at different time periods, we obtained results suggesting that the inhibitory effect of δ-T against colon carcinogenesis is mainly due to protection against early cellular and DNA damages caused by PhIP. α-T was found to be ineffective in inhibiting colon tumors and less effective in attenuating the molecular changes. Altogether, we demonstrated strong cancer preventive effects of δ-T and γ-T in a physiologically relevant model of human colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. CT in colon cancer

    International Nuclear Information System (INIS)

    Fujita, Nobuyuki; Hasegawa, Takashi; Kubo, Kozo; Ogawa, Hajime; Sato, Yukihiko; Tomita, Masayoshi; Hanawa, Makoto; Matsuzawa, Tohru; Nishioka, Ken

    1990-01-01

    CT pictures from 59 lesions of advanced colon cancer including rectal cancer were reviewed to evaluate a role of CT in preoperative staging diagnosis. CT findings were recorded following general rules for clinical and pathological studies on cancer of colon rectum and anus, proposed by Japanese society for cancer of colon and rectum. Tumors were detected in 90% of advanced colon cancers. Sensitivity in local extension (S factor) was 58.0%. Sensitivity in lymphonode involvement (N factor) was 50.0%. Sensitivity in final staging diagnosis, dividing colon cancer into two groups below st II and above st III, was 63.3%. Further study should be necessitated to provide useful information for preoperative staging diagnosis of colon cancer. (author)

  2. Separation of water-soluble metabolites of benzo[a]pyrene formed by cultured human colon

    DEFF Research Database (Denmark)

    Autrup, Herman

    1979-01-01

    A method has been developed to separate conjugated metabolites of benzo[a]pyrene into three major fractions: sulfate esters, glucuronides and glutathione conjugates. In cultured human colon, formation of sulfate esters and glutathione conjugates is the major conjugation pathway, while formation......-hydroxybenzo[a]pyrene were the major substrates for sulfotransferase in cultured human colon....

  3. Oropharyngeal perinatal colonization by human papillomavirus.

    Science.gov (United States)

    Sánchez-Torices, María Soledad; Corrales-Millan, Rocío; Hijona-Elosegui, Jesús J

    2016-01-01

    Human papillomavirus (HPV) infection is the most common human sexually transmitted disease. It is clinically relevant because this condition is necessary for the development of epithelial cervical cancer, and it is also a factor closely associated with the occurrence of diverse tumours and various benign and malignant lesions of the head and neck area. The infective mechanism in most of these cases is associated with sexual intercourse, but there is recent scientific evidence suggesting that HPV infection may also be acquired by other routes of infection not necessarily linked to sexual contact. One of them is vertical transmission from mother to child, either during pregnancy or at the time of delivery. The aim of our research was to study maternal-foetal HPV transmission during childbirth in detail, establishing the rate of oropharyngeal neonatal HPV in vaginal deliveries. The presence and type of HPV viral DNA at the time of delivery in samples of maternal cervical secretions, amniotic fluid, venous cord blood samples and neonatal oropharynx in pregnant women (and their babies) were determined. The rate of oropharyngeal neonatal HPV colonization in vaginal deliveries was 58.24%. The maternal and neonatal HPV colonization mechanism is essentially, but not exclusively, transvaginal. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

  4. Review article: loss of the calcium-sensing receptor in colonic epithelium is a key event in the pathogenesis of colon cancer.

    LENUS (Irish Health Repository)

    Rogers, Ailín C

    2012-03-01

    The calcium-sensing receptor (CaSR) is expressed abundantly in normal colonic epithelium and lost in colon cancer, but its exact role on a molecular level and within the carcinogenesis pathway is yet to be described. Epidemiologic studies show that inadequate dietary calcium predisposes to colon cancer; this may be due to the ability of calcium to bind and upregulate the CaSR. Loss of CaSR expression does not seem to be an early event in carcinogenesis; indeed it is associated with late stage, poorly differentiated, chemo-resistant tumors. Induction of CaSR expression in neoplastic colonocytes arrests tumor progression and deems tumors more sensitive to chemotherapy; hence CaSR may be an important target in colon cancer treatment. The CaSR has a complex role in colon cancer; however, more investigation is required on a molecular level to clarify its exact function in carcinogenesis. This review describes the mechanisms by which the CaSR is currently implicated in colon cancer and identifies areas where further study is needed.

  5. Protein S-glutathionylation induced by hypoxia increases hypoxia-inducible factor-1α in human colon cancer cells.

    Science.gov (United States)

    Jeon, Daun; Park, Heon Joo; Kim, Hong Seok

    2018-01-01

    Hypoxia is a common characteristic of many types of solid tumors. Intratumoral hypoxia selects for tumor cells that survive in a low oxygen environment, undergo epithelial-mesenchymal transition, are more motile and invasive, and show gene expression changes driven by hypoxia-inducible factor-1α (HIF-1α) activation. Therefore, targeting HIF-1α is an attractive strategy for disrupting multiple pathways crucial for tumor growth. In the present study, we demonstrated that hypoxia increases the S-glutathionylation of HIF-1α and its protein levels in colon cancer cells. This effect is significantly prevented by decreasing oxidized glutathione as well as glutathione depletion, indicating that S-glutathionylation and the formation of protein-glutathione mixed disulfides is related to HIF-1α protein levels. Moreover, colon cancer cells expressing glutaredoxin 1 are resistant to inducing HIF-1α and expressing hypoxia-responsive genes under hypoxic conditions. Therefore, S-glutathionylation of HIF-1α induced by tumor hypoxia may be a novel therapeutic target for the development of new drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Colonic macrophage polarization in homeostasis, inflammation, and cancer

    Science.gov (United States)

    Appleyard, Caroline B.

    2016-01-01

    Our review focuses on the colonic macrophage, a monocyte-derived, tissue-resident macrophage, and the role it plays in health and disease, specifically in inflammatory conditions such as inflammatory bowel disease and cancer of the colon and rectum. We give special emphasis to macrophage polarization, or phenotype, in these different states. We focus on macrophages because they are one of the most numerous leukocytes in the colon, and because they normally contribute to homeostasis through an anti-inflammatory phenotype. However, in conditions such as inflammatory bowel disease, proinflammatory macrophages are increased in the colon and have been linked to disease severity and progression. In colorectal cancer, tumor cells may employ anti-inflammatory macrophages to promote tumor growth and dissemination, whereas proinflammatory macrophages may antagonize tumor growth. Given the key roles that this cell type plays in homeostasis, inflammation, and cancer, the colonic macrophage is an intriguing therapeutic target. As such, potential macrophage-targeting strategies are discussed. PMID:27229123

  7. Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation.

    Science.gov (United States)

    Zeng, Huawei; Claycombe, Kate J; Reindl, Katie M

    2015-10-01

    Consumption of a high-fat diet causes an increase in bile acid deoxycholic acid (DCA) in colon lumen and colon cancer risk, while butyrate, an intestinal microbiota metabolite of dietary fiber, has been shown to exhibit colon cancer-preventive effects. To distinguish these opposing effects of DCA and butyrate (two major metabolites in colon lumen), we examined the effects of physiologically relevant doses of butyrate (0.5-2 mmol/l) and DCA (0.05-0.3 mmol/l) on colon cell proliferation. We hypothesize that butyrate and DCA each modulates the cell cycle and apoptosis via common and distinct cellular signaling targets. In this study, we demonstrated that both butyrate and DCA inhibited cell proliferation by up to 89% and 92% and increased cell apoptosis rate by up to 3.1- and 4.5-fold, respectively. Cell cycle analyses revealed that butyrate led to an increase in G1 and G2 fractions with a concomitant drop in the S-phase fraction, but DCA induced an increase in only G1 fraction with a concomitant drop in the S-phase fraction when compared with the untreated cells. The examination of early cellular signaling revealed that DCA but not butyrate increased intracellular reactive oxygen species, genomic DNA breakage, the activation of ERK1/2, caspase-3 and PARP. In contrast, DCA decreased activated Rb protein level, and butyrate but not DCA increased p21 expression. Collectively, although both butyrate and DCA inhibit colonic cell proliferation, butyrate increases tumor suppressor gene expression, whereas DCA decreases tumor suppressor activation in cell cycle and apoptosis pathways. Published by Elsevier Inc.

  8. Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth

    Energy Technology Data Exchange (ETDEWEB)

    Stagg, Brian C., E-mail: briancstagg@gmail.com; Uehara, Hironori; Lambert, Nathan; Rai, Ruju; Gupta, Isha; Radmall, Bryce; Bates, Taylor; Ambati, Balamurali K. [John A Moran Eye Center, University of Utah, Salt Lake City, UT, 65 Mario Capecchi Drive, Salt Lake City, UT 84132 (United States)

    2014-11-26

    Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells.

  9. Influence of the surgical manipulation of the colon in colonic induced carcinogenesis in rats Influencia de la manipulación quirúrgica del colon en la carcinogénesis cólica inducida en ratas

    Directory of Open Access Journals (Sweden)

    J. F. Noguera Aguilar

    2004-05-01

    Full Text Available Aim: to investigate the influence of different experimental manipulations in a model of colonic experimental carcinogenesis with pharmacological induction in the rat. Experimental design: a total of 90 Sprague-Dawley male rats, divided into three groups, were used: non-surgical (n = 30; surgical with colonic trauma (n = 20, and surgical with colo-colonic anastomosis (n = 40. Carcinogenic induction was carried out with 1-2 dimethylhydrazine dihydrochloride. Colonic adenocarcinomas were identified and the number of tumors, as well as tumoral surface and percentage of tumoral surface was established. One-way ANOVA and Chi-square were employed for the statistical analysis. Results: the number of tumors was greater in the surgical group than in the control group, and tumors preferentially develop-ed around the manipulated colon. Surface and tumoral percentage were greater in the surgical group than in the control group, being also greater in the anastomosis group than in the group with colonic trauma. Within anastomosis groups, a greater tumor surface and percentage was found in the group with titanium than in the group with reabsorbable material. Conclusions: the experimental manipulation of the colon in rats enhances drug-induced colon carcingenesis. The creation of an anastomosis further increases the carcinogenic process compared with simulated anastomosis. This process is also enhanced by the quantity of suture material included in the anastomosis, and by the non-reabsorbable nature of the materials used in the anastomotic line.Objetivo: valorar la influencia de las distintas manipulaciones experimentales en un modelo de carcinogénesis cólica experimental con inducción farmacológica en la rata. Diseño experimental: se emplearon 90 ratas Sprague-Dawley macho, divididas en tres grupos: no quirúrgico (n=30; quirúrgico con traumatismo cólico (n=20, y quirúrgico con anastomosis colocólica (n=40. La inducción carcinogénica se realizó con

  10. Inhibitory effect of gene combination in a mouse model of colon cancer with liver metastasis.

    Science.gov (United States)

    DU, Tong; Niu, Hongxin

    2014-09-01

    The aim of the present study was to establish an animal liver metastasis model with human colon cancer and investigate the inhibitory effect of the wild type (WT) p53 gene combined with thymidine kinase/ganciclovir (TK/GCV) and cytosine deaminase/5-fluorocytosine (CD/5-FC) systems on liver metastasis of colon cancer. A nude mouse liver metastasis model with human colon cancer was established via a spleen cultivation method. A total of 32 nude mice were randomly divided into four groups, each group with eight mice. Group 1 mice received splenic injections of SW480 cells (control group), while group 2 mice were injected with SW480/p53 cells in the spleen. Group 3 mice were administered splenic injections of SW480/TK-CD cells, and GCV and 5-FC were injected into the abdominal cavity. Finally, group 4 mice received splenic injections of SW480/p53 cells mixed in equal proportion with SW480/TK-CD cells, as well as GCV and 5-FC injections in the abdominal cavity. These cells described were constructed in our laboratory and other laboratories. The number of liver metastatic tumors, the liver metastasis rate, conventional pathology, electron microscopy and other indicators in the nude mice of each group were compared and observed. The nude mouse liver metastasis model with human colon cancer was successfully established; the liver metastasis rate of the control group was 100%. The results demonstrated that the rate of liver metastasis in the nude mice in each treatment group decreased, as well as the average number of liver metastatic tumors. Furthermore, the effect of the treatment group with genetic combination (group 4) was the most effective, demonstrating that WTp53 had a synergistic effect with TK/GCV and CD/5-FC. Therefore, the present study successfully established a mouse model of liver metastasis with colon cancer by injecting human colon cancer cells in the spleen. Combined gene therapy was shown to have a synergistic effect, which effectively inhibited the

  11. A CASE REPORT OF MULTIPLE PRIMARY SQUAMOUS CELL CARCINOMAS OF THE OVARY AND SIGMOID COLON

    Directory of Open Access Journals (Sweden)

    A. B. Villert

    2016-01-01

    Full Text Available Squamous cell ovarian and sigmoid colon carcinomas are extremely rare malignancies. Because of their rarity, it is difficult to investigate the clinical characteristics and prognosis of patients with theses malignancies, and therefore, the increased interest in each clinical case report is highly relevant. Multiple primary squamous cell ovarian and sigmoid colon carcinomas are the subject of discussion and differential diagnosis of sigmoid colon cancer with secondary ovarian cancer. Histopathological and clinical characteristics of the tumors were present and evidences in favor of the multiple primary malignancies were given. The association of squamous cell ovarian and sigmoid colon carcinomas with human papilloma virus type 16 was shown.

  12. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Directory of Open Access Journals (Sweden)

    Nibedita Chattopadhyay

    Full Text Available In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  13. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Science.gov (United States)

    Chattopadhyay, Nibedita; Berger, Allison J; Koenig, Erik; Bannerman, Bret; Garnsey, James; Bernard, Hugues; Hales, Paul; Maldonado Lopez, Angel; Yang, Yu; Donelan, Jill; Jordan, Kristen; Tirrell, Stephen; Stringer, Bradley; Xia, Cindy; Hather, Greg; Galvin, Katherine; Manfredi, Mark; Rhodes, Nelson; Amidon, Ben

    2015-01-01

    In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  14. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay.

    Science.gov (United States)

    Alley, M C; Scudiero, D A; Monks, A; Hursey, M L; Czerwinski, M J; Fine, D L; Abbott, B J; Mayo, J G; Shoemaker, R H; Boyd, M R

    1988-02-01

    For the past 30 years strategies for the preclinical discovery and development of potential anticancer agents have been based largely upon the testing of agents in mice bearing transplantable leukemias and solid tumors derived from a limited number of murine as well as human sources. The feasibility of implementing an alternate approach, namely combined in vitro/in vivo screening for selective cytotoxicity among panels of human tumor cell lines derived from a broad spectrum of human solid tumors is under investigation. A group of 30 cell lines acquired from a variety of sources and representing 8 lung cancer pathologies as well as 76 cell lines representing 10 other categories of human cancer (carcinomas of colon, breast, kidney, prostate, ovary, head and neck; glioma; leukemia; melanoma; and sarcoma) have exhibited acceptable growth characteristics and suitable colorimetric profiles in a single, standard culture medium. Measurements of in vitro growth in microculture wells by cell-mediated reduction of tetrazolium showed excellent correlation (0.89 less than r2 less than 0.98) with measurements of cellular protein in adherent cell line cultures as well as viable cell count in suspension cell line cultures (0.94 less than r2 less than 0.99). Since the microculture tetrazolium assay provides sensitive and reproducible indices of growth as well as drug sensitivity in individual cell lines over the course of multiple passages and several months' cultivation, it appears suitable for initial-stage in vitro drug screening.

  15. COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

    International Nuclear Information System (INIS)

    Asting, Annika Gustafsson; Carén, Helena; Andersson, Marianne; Lönnroth, Christina; Lagerstedt, Kristina; Lundholm, Kent

    2011-01-01

    Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4) showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3) were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue

  16. COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

    Directory of Open Access Journals (Sweden)

    Lagerstedt Kristina

    2011-06-01

    Full Text Available Abstract Background Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Method Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Results Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4 showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3 were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Conclusions Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue.

  17. Synchronous colon and gastric advanced carcinomas

    International Nuclear Information System (INIS)

    Giuliani, A.; Demoro, M.; Corona, M.; Di Bari, M.; Ricciardulli, T.; Galati, G.; Ciardi, A.

    2005-01-01

    An unusual case of advanced synchronous colon and gastric carcinoma is described. A 36 year old female was admitted to our Department with a stenosing right colon cancer diagnosed at endoscopy which was performed for lower crampy abdominal pain and gross blood in the stool. Multiple colon polyps, distal to the tumor, were also detected. On preoperative abdominal computed tomography, a stenosing right colon cancer, without evidence of abdominal diffusion, was confirmed. At laparotomy, in addition to colon cancer, an antral gastric cancer was incidentally found. En bloc hemi gastrectomy and subtotal colectomy were performed. Digestive continuity was restored by gastrojejunal and ileosigmoid anastomoses. At histology, a poorly differentiated gastric adenocarcinoma with signet ring-cell component (pT2, pN0; stage IB) and a moderately differentiated colon adenocarcinoma with a tubulovillous component (pT3, pN1; stage III, Stage Dukes C) were revealed. Both tumors showed a low expression of p53 and c-erb2 oncoproteins. No genetic defect was identified in the APC and MMR genes. The patient is alive, without recurrence, two years after the operation

  18. Towards the human colorectal cancer microbiome.

    Directory of Open Access Journals (Sweden)

    Julian R Marchesi

    Full Text Available Multiple factors drive the progression from healthy mucosa towards sporadic colorectal carcinomas and accumulating evidence associates intestinal bacteria with disease initiation and progression. Therefore, the aim of this study was to provide a first high-resolution map of colonic dysbiosis that is associated with human colorectal cancer (CRC. To this purpose, the microbiomes colonizing colon tumor tissue and adjacent non-malignant mucosa were compared by deep rRNA sequencing. The results revealed striking differences in microbial colonization patterns between these two sites. Although inter-individual colonization in CRC patients was variable, tumors consistently formed a niche for Coriobacteria and other proposed probiotic bacterial species, while potentially pathogenic Enterobacteria were underrepresented in tumor tissue. As the intestinal microbiota is generally stable during adult life, these findings suggest that CRC-associated physiological and metabolic changes recruit tumor-foraging commensal-like bacteria. These microbes thus have an apparent competitive advantage in the tumor microenvironment and thereby seem to replace pathogenic bacteria that may be implicated in CRC etiology. This first glimpse of the CRC microbiome provides an important step towards full understanding of the dynamic interplay between intestinal microbial ecology and sporadic CRC, which may provide important leads towards novel microbiome-related diagnostic tools and therapeutic interventions.

  19. Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: A systematic expression analysis

    International Nuclear Information System (INIS)

    Hamm, Alexander; Knuechel, Ruth; Dahl, Edgar; Veeck, Juergen; Bektas, Nuran; Wild, Peter J; Hartmann, Arndt; Heindrichs, Uwe; Kristiansen, Glen; Werbowetski-Ogilvie, Tamra; Del Maestro, Rolando

    2008-01-01

    The inter-alpha-trypsin inhibitors (ITI) are a family of plasma protease inhibitors, assembled from a light chain – bikunin, encoded by AMBP – and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), contributing to extracellular matrix stability by covalent linkage to hyaluronan. So far, ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis. We systematically investigated differential gene expression of the ITIH gene family, as well as AMBP and the interacting partner TNFAIP6 in 13 different human tumor entities (of breast, endometrium, ovary, cervix, stomach, small intestine, colon, rectum, lung, thyroid, prostate, kidney, and pancreas) using cDNA dot blot analysis (Cancer Profiling Array, CPA), semiquantitative RT-PCR and immunohistochemistry. We found that ITIH genes are clearly downregulated in multiple human solid tumors, including breast, colon and lung cancer. Thus, ITIH genes may represent a family of putative tumor suppressor genes that should be analyzed in greater detail in the future. For an initial detailed analysis we chose ITIH2 expression in human breast cancer. Loss of ITIH2 expression in 70% of cases (n = 50, CPA) could be confirmed by real-time PCR in an additional set of breast cancers (n = 36). Next we studied ITIH2 expression on the protein level by analyzing a comprehensive tissue micro array including 185 invasive breast cancer specimens. We found a strong correlation (p < 0.001) between ITIH2 expression and estrogen receptor (ER) expression indicating that ER may be involved in the regulation of this ECM molecule. Altogether, this is the first systematic analysis on the differential expression of ITIH genes in human cancer, showing frequent downregulation that may be associated with initiation and/or progression of these malignancies

  20. A cross sectional study of animal and human colonization with Methicillin-Resistant Staphylococcus aureus (MRSA in an Aboriginal community

    Directory of Open Access Journals (Sweden)

    Peter Daley

    2016-07-01

    Full Text Available Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA infections are common among humans in Aboriginal communities in Canada, for unknown reasons. Methods Cross sectional study of humans and dogs in an Aboriginal community of approximately 1200 persons. Our objectives were to measure community-based prevalence of nasal MRSA colonization among humans, use multivariable logistic regression to analyze risk factors for MRSA colonization, and perform molecular typing of Staphylococci isolated to investigate interspecies transmission. Results 461 humans were approached for consent and 442 provided complete data. 109/442 (24.7 %, 95 % C.I. = 20.7–28.7 % of humans were colonized with MRSA. 169/442 (38.2 % of humans had received antibiotics in the last 12 months. Only number of rooms in the house (OR 0.86, p = 0.023 and recreational dog use (OR 7.7, p = 0.002 were significant risk factors for MRSA colonization. 95/109 (87.1 % of MRSA strains from humans were of the same spa type (CMRSA10/USA300. 8/157 (5.1 %, 95 % C.I. = 1.7–8.5 % of dogs were colonized with methicillin-susceptible S. aureus, and no dogs were colonized with MRSA. Conclusions Human MRSA colonization in this community is very common, and a single clone is predominant, suggesting local transmission. Antibiotic use is also very common. Crowding may partially explain high colonization, but most considered risk factors including animal exposure were not predictive. Very few dogs carried human Staphylococcal strains.

  1. Assessing the potential for raw meat to influence human colonization with Staphylococcus aureus

    OpenAIRE

    Carrel, Margaret; Zhao, Chang; Thapaliya, Dipendra; Bitterman, Patrick; Kates, Ashley E.; Hanson, Blake M.; Smith, Tara C.

    2017-01-01

    The role of household meat handling and consumption in the transfer of Staphylococcus aureus (S. aureus) from livestock to consumers is not well understood. Examining the similarity of S. aureus colonizing humans and S. aureus in meat from the stores in which those individuals shop can provide insight into the role of meat in human S. aureus colonization. S. aureus isolates were collected from individuals in rural and urban communities in Iowa (n?=?3347) and contemporaneously from meat produc...

  2. Chemo prevention of Tea Polyphenols against Tumor Growth of Hepato-Colon Cancer Induced by Azoxy methane in Rats

    International Nuclear Information System (INIS)

    Heibashy, M.I.A.; Mazen, G.M.A.

    2008-01-01

    This investigation was conducted to evaluate the chemo prevention of tea polyphenols as anticancer agent in rats which were injected with azoxy methane (AOM) which is a potent hepato-colon carcinogen agents in rodents. The obtained data revealed a significant elevation in serum tumor markers, carcino-embryonic antigen (CEA), alpha-fetoprotein (AFP) and cancer antigen (CA 1 9.9) in carcinogenic rats in comparison to their corresponding normal control ones. Also, there was a significant increase in the content of cytochrome P 4 50 and the activity of alcohol dehydrogenase (ADH) in both liver and colon as well as a significant elevation in the activities of methoxyresorufin-O-dealkylase (MRD), ethoxyresorutin-O-dealkylase (ERD) and pentoxyresorufin-O- dealkylase (PRD) in liver microsomes. While, glutathione content (GSH) and glutathione peroxidase (Gp x ) activity were decreased significantly in liver and colon as a result of cancer induction. On the other hand, the supplementation of black or green tea before induction of cancer in rats led to a considerable correction in all previous parameters studied. These amelioration effects dependent on magic biochemical properties of flavanols (catechins) and type of tea. In conclusion, tea polyphenols have appreciable anti-cancer efficacy on hepato colon cancer in rats. The underlying mechanisms of through which tea counteracted hepato-colon cancer were discussed

  3. Computer-assisted stereology and automated image analysis for quantification of tumor infiltrating lymphocytes in colon cancer.

    Science.gov (United States)

    Eriksen, Ann C; Andersen, Johnnie B; Kristensson, Martin; dePont Christensen, René; Hansen, Torben F; Kjær-Frifeldt, Sanne; Sørensen, Flemming B

    2017-08-29

    Precise prognostic and predictive variables allowing improved post-operative treatment stratification are missing in patients treated for stage II colon cancer (CC). Investigation of tumor infiltrating lymphocytes (TILs) may be rewarding, but the lack of a standardized analytic technique is a major concern. Manual stereological counting is considered the gold standard, but digital pathology with image analysis is preferred due to time efficiency. The purpose of this study was to compare manual stereological estimates of TILs with automatic counts obtained by image analysis, and at the same time investigate the heterogeneity of TILs. From 43 patients treated for stage II CC in 2002 three paraffin embedded, tumor containing tissue blocks were selected one of them representing the deepest invasive tumor front. Serial sections from each of the 129 blocks were immunohistochemically stained for CD3 and CD8, and the slides were scanned. Stereological estimates of the numerical density and area fraction of TILs were obtained using the computer-assisted newCAST stereology system. For the image analysis approach an app-based algorithm was developed using Visiopharm Integrator System software. For both methods the tumor areas of interest (invasive front and central area) were manually delineated by the observer. Based on all sections, the Spearman's correlation coefficients for density estimates varied from 0.9457 to 0.9638 (p heterogeneity, intra-class correlation coefficients (ICC) for CD3+ TILs varied from 0.615 to 0.746 in the central area, and from 0.686 to 0.746 in the invasive area. ICC for CD8+ TILs varied from 0.724 to 0.775 in the central area, and from 0.746 to 0.765 in the invasive area. Exact objective and time efficient estimates of numerical densities and area fractions of CD3+ and CD8+ TILs in stage II colon cancer can be obtained by image analysis and are highly correlated to the corresponding estimates obtained by the gold standard based on stereology

  4. Tumor sincrónico: cáncer de colon y liposarcoma

    Directory of Open Access Journals (Sweden)

    Himerón Limaylla

    2013-04-01

    Full Text Available Se presenta el caso clínico de un paciente varón de 58 años, natural de Junín, que ingresó por Emergencia, referido de un hospital provincial por un cuadro de obstrucción intestinal, con un tiempo de enfermedad de 7 días, caracterizado por dolor abdominal tipo cólico difuso, náuseas y vómitos y distensión abdominal. Por dos meses presentaba dolor abdominal intermitente intenso, 3 a 4 episodios por mes, que cedía en forma espontánea, pero progresivamente aumentó su frecuencia y se asoció con ingesta de alimentos, disminuyó el apetito y perdió peso aproximadamente 6 a 7 kilos; no presentaba antecedentes patológicos ni quirúrgicos de importancia. Durante su hospitalización en nuestro nosocomio se obtuvo una tomografía (TAC abdominal que mostró la presencia de dos tumoraciones, una en colon ascendente y otra en región retroperitoneal, que fueron extraídas en cirugía electiva. El resultado de la anatomía patológica fue adenocarcinoma bien diferenciado de colon y liposarcoma dediferenciado del tumor retroperitoneal; ambos presentaron bordes quirúrgicos libres de neoplasia. La coincidencia de ambas patologías no ha sido descrita en la literatura médica.

  5. Protein expression profile of HT-29 human colon cancer cells after treatment with a cytotoxic daunorubicin-GnRH-III derivative bioconjugate.

    Directory of Open Access Journals (Sweden)

    Verena Natalie Schreier

    Full Text Available Targeted delivery of chemotherapeutic agents is a new approach for the treatment of cancer, which provides increased selectivity and decreased systemic toxicity. We have recently developed a promising drug delivery system, in which the anticancer drug daunorubicin (Dau was attached via oxime bond to a gonadotropin-releasing hormone-III (GnRH-III derivative used as a targeting moiety (Glp-His-Trp-Lys(Ac-His-Asp-Trp-Lys(Da  = Aoa-Pro-Gly-NH2; Glp = pyroglutamic acid, Ac = acetyl; Aoa = aminooxyacetyl. This bioconjugate exerted in vitro cytostatic/cytotoxic effect on human breast, prostate and colon cancer cells, as well as significant in vivo tumor growth inhibitory effect on colon carcinoma bearing mice. In our previous studies, H-Lys(Dau = Aoa-OH was identified as the smallest metabolite produced in the presence of rat liver lysosomal homogenate, which was able to bind to DNA in vitro. To get a deeper insight into the mechanism of action of the bioconjugate, changes in the protein expression profile of HT-29 human colon cancer cells after treatment with the bioconjugate or free daunorubicin were investigated by mass spectrometry-based proteomics. Our results indicate that several metabolism-related proteins, molecular chaperons and proteins involved in signaling are differently expressed after targeted chemotherapeutic treatment, leading to the conclusion that the bioconjugate exerts its cytotoxic action by interfering with multiple intracellular processes.

  6. Secreted Human Adipose Leptin Decreases Mitochondrial Respiration in HCT116 Colon Cancer Cells

    Science.gov (United States)

    Yehuda-Shnaidman, Einav; Nimri, Lili; Tarnovscki, Tanya; Kirshtein, Boris; Rudich, Assaf; Schwartz, Betty

    2013-01-01

    Obesity is a key risk factor for the development of colon cancer; however, the endocrine/paracrine/metabolic networks mediating this connection are poorly understood. Here we hypothesize that obesity results in secreted products from adipose tissue that induce malignancy-related metabolic alterations in colon cancer cells. Human HCT116 colon cancer cells, were exposed to conditioned media from cultured human adipose tissue fragments of obese vs. non-obese subjects. Oxygen consumption rate (OCR, mostly mitochondrial respiration) and extracellular acidification rate (ECAR, mostly lactate production via glycolysis) were examined vis-à-vis cell viability and expression of related genes and proteins. Our results show that conditioned media from obese (vs. non-obese) subjects decreased basal (40%, prespiration and function in HCT116 colon cancer cells, an effect that is at least partly mediated by leptin. These results highlight a putative novel mechanism for obesity-associated risk of gastrointestinal malignancies, and suggest potential new therapeutic avenues. PMID:24073224

  7. MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL

    DEFF Research Database (Denmark)

    Baraniskin, Alexander; Birkenkamp-Demtröder, Karin; Maghnouj, Abdelouahid

    2012-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that are involved in different biological processes by suppressing target gene expression. Altered expression of miR-30a-5p has been reported in colon carcinoma. To elucidate its potential biological role in colon cancer, miR-30a-5p was overexpressed via...... with in silico miRNA target prediction, we identified the denticleless protein homolog (DTL) as a potential miRNA-30a-5p target. Subsequent reporter gene assays confirmed the predicted miR-30a-5p binding site in the 3'untranslated region of DTL. Importantly, overexpression of DTL in HCT116 cells partially...... is frequently overexpressed in colorectal cancer. Thus, our data suggest that restoring miR-30a-5p function may prove useful as therapeutic strategy for tumors with reduced miR-30a-5p expression....

  8. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis.

    Science.gov (United States)

    Jung, Cho-Rok; Hwang, Kyung-Sun; Yoo, Jinsang; Cho, Won-Kyung; Kim, Jin-Man; Kim, Woo Ho; Im, Dong-Soo

    2006-07-01

    The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including hypoxia-inducible factor-1alpha (HIF-1alpha), which is involved in tumor progression and angiogenesis. It remains unclear, however, how pVHL is destabilized. Here we show that E2-EPF ubiquitin carrier protein (UCP) associates with and targets pVHL for ubiquitin-mediated proteolysis in cells, thereby stabilizing HIF-1alpha. UCP is detected coincidently with HIF-1alpha in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells. UCP level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway. Our results suggest that UCP helps stabilize HIF-1alpha and may be a new molecular target for therapeutic intervention in human cancers.

  9. Colon cancer modulation by a diabetic environment: A single institutional experience.

    Science.gov (United States)

    Prieto, Isabel; Del Puerto-Nevado, Laura; Gonzalez, Nieves; Portal-Nuñez, Sergio; Zazo, Sandra; Corton, Marta; Minguez, Pablo; Gomez-Guerrero, Carmen; Arce, Jose Miguel; Sanz, Ana Belen; Mas, Sebastian; Aguilera, Oscar; Alvarez-Llamas, Gloria; Esbrit, Pedro; Ortiz, Alberto; Ayuso, Carmen; Egido, Jesus; Rojo, Federico; Garcia-Foncillas, Jesus

    2017-01-01

    Multiple observational studies suggest an increased risk of colon cancer in patients with diabetes mellitus (DM). This can theoretically be the result of an influence of the diabetic environment on carcinogenesis or the tumor biologic behavior. To gain insight into the influence of a diabetic environment on colon cancer characteristics and outcomes. Retrospective analysis of clinical records in an academic tertiary care hospital with detailed analysis of 81 diabetic patients diagnosed of colon cancer matched with 79 non-diabetic colon cancer patients. The impact of streptozotocin-induced diabetes on the growth of colon cancer xenografts was studied in mice. The incidence of DM in 1,137 patients with colorectal cancer was 16%. The diabetic colon cancer cases and non-diabetic colon cancer controls were well matched for demographic and clinical variables. The ECOG Scale Performance Status was higher (worse) in diabetics (ECOG ≥1, 29.1% of controls vs 46.9% of diabetics, p = 0.02), but no significant differences were observed in tumor grade, adjuvant therapy, tumor site, lymphovascular invasion, stage, recurrence, death or cancer-related death. Moreover, no differences in tumor variables were observed between patients treated or not with metformin. In the xenograft model, tumor growth and histopathological characteristics did not differ between diabetic and nondiabetic animals. Our findings point towards a mild or negligible effect of the diabetes environment on colon cancer behavior, once cancer has already developed.

  10. Effect of administration route and dose of streptavidin or biotin on the tumor uptake of radioactivity in intraperitoneal tumor with multistep targeting

    International Nuclear Information System (INIS)

    Zhang Meili; Yao Zhengsheng; Sakahara, Harumi; Saga, Tsuneo; Nakamoto, Yuji; Sato, Noriko; Zhao Songji; Nakada, Hiroshi; Yamashina, Ikuo; Konishi, Junji

    1998-01-01

    The effect of the administration route and dose of streptavidin or biotin on the biodistribution of radioactivity in multistep targeting was studied in nude mice bearing intraperitoneal (IP) colon cancer xenograft. The multistep targeting included a two-step method using biotinylated antibody and radiolabeled streptavidin and a three-step method with radiolabeled biotin based on the two-step method. A monoclonal antibody, MLS128, which recognizes Tn antigen on mucin, was biotinylated and injected intravenously (IV) or IP in nude mice bearing human colon cancer LS180 IP xenografts for pretargeting. In the two-step method, IP-injected streptavidin showed a higher tumor uptake and tumor-to-nontumor ratios than IV-injected streptavidin regardless of administration route of pretargeting. The tumor uptake of radiolabeled streptavidin was increased with a high dose of biotinylated antibody pretargeting, but decreased with an increasing dose of streptavidin. In the three-step targeting, IP injection also gave a higher tumor uptake of radiolabeled biotin than IV injection. In conclusion, IP administration of radiolabeled streptavidin or biotin resulted in more efficient IP tumor targeting with the multistep methods

  11. Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae.

    Science.gov (United States)

    Qiu, J; Hendrixson, D R; Baker, E N; Murphy, T F; St Geme, J W; Plaut, A G

    1998-10-13

    Haemophilus influenzae is a major cause of otitis media and other respiratory tract disease in children. The pathogenesis of disease begins with colonization of the upper respiratory mucosa, a process that involves evasion of local immune mechanisms and adherence to epithelial cells. Several studies have demonstrated that human milk is protective against H. influenzae colonization and disease. In the present study, we examined the effect of human milk on the H. influenzae IgA1 protease and Hap adhesin, two autotransported proteins that are presumed to facilitate colonization. Our results demonstrated that human milk lactoferrin efficiently extracted the IgA1 protease preprotein from the bacterial outer membrane. In addition, lactoferrin specifically degraded the Hap adhesin and abolished Hap-mediated adherence. Extraction of IgA1 protease and degradation of Hap were localized to the N-lobe of the bilobed lactoferrin molecule and were inhibited by serine protease inhibitors, suggesting that the lactoferrin N-lobe may contain serine protease activity. Additional experiments revealed no effect of lactoferrin on the H. influenzae P2, P5, and P6 outer-membrane proteins, which are distinguished from IgA1 protease and Hap by the lack of an N-terminal passenger domain or an extracellular linker region. These results suggest that human milk lactoferrin may attenuate the pathogenic potential of H. influenzae by selectively inactivating IgA1 protease and Hap, thereby interfering with colonization. Future studies should examine the therapeutic potential of lactoferrin, perhaps as a supplement in infant formulas.

  12. In vitro and in vivo characteristics of a human colon cancer cell line, SNU-C5N, expressing sodium-iodide symporter

    International Nuclear Information System (INIS)

    Min, Jung-Jun; Chung, June-Key; Jin Lee, Yong; Hoon Shin, Jae; Seok Yeo, Jeong; Min Jeong, Jae; Bom, Dong Soo Leea Hee-Seung; Chul Lee, Myung

    2002-01-01

    Rat NIS (rNIS) genes were transfected into a human colon cancer cell line (SNU-C5) by lipofection. The transfected cells (SNU-C5N) exhibited an increase 125 I uptake to a level 10 times higher than the untransfected SNU-C5 cells. The addition of 300 μM DIDS, an anion channel blocker, to the culture media led to a 2.35 times increase of 125 I uptake in the cells. For the first 10 minutes, up to 70% of the cellular radioactivity was released into the medium. In the biodistribution study using SNU-C5N-xenografted mice, the %ID/g of the SNU-C5N tumors at 1, 3, 6, and 12 h after the 125 I injection were 4.43%, 1.09%, 1.05%, and 0.05%, respectively, which were significantly higher than those for the SNU-C5 tumors (P<0.05). In tumor imaging, the SNU-C5N-xenografted tumor was clearly visible. In this study, NIS lipofection is efficient for triggering significant iodide uptake by a nonthyroidal tumor. However, for an increased therapeutic effect, the key issue is iodide retention in the target tissue

  13. In vitro and in vivo characteristics of a human colon cancer cell line, SNU-C5N, expressing sodium-iodide symporter

    Energy Technology Data Exchange (ETDEWEB)

    Min, Jung-Jun; Chung, June-Key E-mail: jkchung@plaza.snu.ac.kr; Jin Lee, Yong; Hoon Shin, Jae; Seok Yeo, Jeong; Min Jeong, Jae; Bom, Dong Soo Leea Hee-Seung; Chul Lee, Myung

    2002-07-01

    Rat NIS (rNIS) genes were transfected into a human colon cancer cell line (SNU-C5) by lipofection. The transfected cells (SNU-C5N) exhibited an increase {sup 125}I uptake to a level 10 times higher than the untransfected SNU-C5 cells. The addition of 300 {mu}M DIDS, an anion channel blocker, to the culture media led to a 2.35 times increase of {sup 125}I uptake in the cells. For the first 10 minutes, up to 70% of the cellular radioactivity was released into the medium. In the biodistribution study using SNU-C5N-xenografted mice, the %ID/g of the SNU-C5N tumors at 1, 3, 6, and 12 h after the {sup 125}I injection were 4.43%, 1.09%, 1.05%, and 0.05%, respectively, which were significantly higher than those for the SNU-C5 tumors (P<0.05). In tumor imaging, the SNU-C5N-xenografted tumor was clearly visible. In this study, NIS lipofection is efficient for triggering significant iodide uptake by a nonthyroidal tumor. However, for an increased therapeutic effect, the key issue is iodide retention in the target tissue.

  14. mTOR inhibition elicits a dramatic response in PI3K-dependent colon cancers.

    Directory of Open Access Journals (Sweden)

    Dustin A Deming

    Full Text Available The phosphatidylinositide-3-kinase (PI3K signaling pathway is critical for multiple cellular functions including metabolism, proliferation, angiogenesis, and apoptosis, and is the most commonly altered pathway in human cancers. Recently, we developed a novel mouse model of colon cancer in which tumors are initiated by a dominant active PI3K (FC PIK3ca. The cancers in these mice are moderately differentiated invasive mucinous adenocarcinomas of the proximal colon that develop by 50 days of age. Interestingly, these cancers form without a benign intermediary or aberrant WNT signaling, indicating a non-canonical mechanism of tumorigenesis. Since these tumors are dependent upon the PI3K pathway, we investigated the potential for tumor response by the targeting of this pathway with rapamycin, an mTOR inhibitor. A cohort of FC PIK3ca mice were treated with rapamycin at a dose of 6 mg/kg/day or placebo for 14 days. FDG dual hybrid PET/CT imaging demonstrated a dramatic tumor response in the rapamycin arm and this was confirmed on necropsy. The tumor tissue remaining after treatment with rapamycin demonstrated increased pERK1/2 or persistent phosphorylated ribosomal protein S6 (pS6, indicating potential resistance mechanisms. This unique model will further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification.

  15. REDOX IMAGING OF THE p53-DEPENDENT MITOCHONDRIAL REDOX STATE IN COLON CANCER EX VIVO

    Science.gov (United States)

    XU, HE N.; FENG, MIN; MOON, LILY; DOLLOFF, NATHAN; EL-DEIRY, WAFIK; LI, LIN Z.

    2015-01-01

    The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported. Nor has how p53 regulates mitochondrial respiration been measured at (deep) tissue level, presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration depth. Our prior work demonstrated that the mitochondrial redox state and its intratumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models, with the more metastatic tumors exhibiting localized regions of more oxidized redox state. Using the Chance redox scanner with an in-plane spatial resolution of 200 μm, we imaged the mitochondrial redox state of the wild-type p53 colon tumors (HCT116 p53 wt) and the p53-deleted colon tumors (HCT116 p53−/−) by collecting the fluorescence signals of nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins [Fp, including flavin adenine dinucleotide (FAD)] from the mouse xenografts snap-frozen at low temperature. Our results show that: (1) both tumor lines have significant degree of intratumor heterogeneity of the redox state, typically exhibiting a distinct bi-modal distribution that either correlates with the spatial core–rim pattern or the “hot/cold” oxidation-reduction patches; (2) the p53−/− group is significantly more heterogeneous in the mitochondrial redox state and has a more oxidized tumor core compared to the p53 wt group when the tumor sizes of the two groups are matched; (3) the tumor size dependence of the redox indices (such as Fp and Fp redox ratio) is significant in the p53−/− group with the larger ones being more oxidized and more heterogeneous in their redox state, particularly more oxidized in the tumor central regions; (4) the H&E staining images of tumor sections grossly correlate with the redox images. The present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattern

  16. Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche.

    Science.gov (United States)

    Templeton, Zach S; Lie, Wen-Rong; Wang, Weiqi; Rosenberg-Hasson, Yael; Alluri, Rajiv V; Tamaresis, John S; Bachmann, Michael H; Lee, Kitty; Maloney, William J; Contag, Christopher H; King, Bonnie L

    2015-12-01

    Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Trypanosomiasis-induced megacolon illustrates how myenteric neurons modulate the risk for colon cancer in rats and humans.

    Directory of Open Access Journals (Sweden)

    Vinicius Kannen

    2015-04-01

    Full Text Available Trypanosomiasis induces a remarkable myenteric neuronal degeneration leading to megacolon. Very little is known about the risk for colon cancer in chagasic megacolon patients. To clarify whether chagasic megacolon impacts on colon carcinogenesis, we investigated the risk for colon cancer in Trypanosoma cruzi (T. cruzi infected patients and rats.Colon samples from T. cruzi-infected and uninfected patients and rats were histopathologically investigated with colon cancer biomarkers. An experimental model for chemical myenteric denervation was also performed to verify the myenteric neuronal effects on colon carcinogenesis. All experiments complied the guidelines and approval of ethical institutional review boards.No colon tumors were found in chagasic megacolon samples. A significant myenteric neuronal denervation was observed. Epithelial cell proliferation and hyperplasia were found increased in chagasic megacolon. Analyzing the argyrophilic nucleolar organiser regions within the cryptal bottom revealed reduced risk for colon cancer in Chagas' megacolon patients. T. cruzi-infected rats showed a significant myenteric neuronal denervation and decreased numbers of colon preneoplastic lesions. In chemical myenteric denervated rats preneoplastic lesions were reduced from the 2nd wk onward, which ensued having the colon myenteric denervation significantly induced.Our data suggest that the trypanosomiasis-related myenteric neuronal degeneration protects the colon tissue from carcinogenic events. Current findings highlight potential mechanisms in tropical diseases and cancer research.

  18. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

    Science.gov (United States)

    Ritter, G; Cohen, L S; Williams, C; Richards, E C; Old, L J; Welt, S

    2001-09-15

    Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

  19. Effects of liquid versus solid diet on colonic transit in humans. Evaluation by standard colonic transit scintigraphy

    International Nuclear Information System (INIS)

    Kaufman, P.N.; Richter, J.E.; Chilton, H.M.; Kerr, R.M.; Cowan, R.C.; Gelfand, D.W.; Ott, D.J.

    1990-01-01

    The effects of liquid versus solid diet on human colonic transit were investigated, and transit following cecal instillation of tracer was compared with transit following instillation in the proximal jejunum. In a randomized cross-over, single-blind fashion, 6 normal volunteers ingesting either normal solid foods or a liquid diet were studied using colonic transit scintigraphy. 111In-DTPA was instilled either into the cecum via a long intestinal tube or into the proximal jejunum via a feeding tube. Compared with the liquid diet, the solid diet slowed transit in the cecum and ascending colon (p less than 0.025) and delayed progression of the geometric center (p less than 0.05) during the first 4 h of the study. Transit from 18 to 48 h was similar on the 2 diets. On the solid diet, transit was similar whether 111In-DTPA was instilled into the proximal jejunum or into the cecum. Transit from the terminal ileum to the cecum was assessed in an additional 5 volunteers following jejunal instillation of 99mTc-DTPA. Cecal filling was rapid (T1/2 = 0.49 h) and complete in all subjects before the onset of cecal emptying. These results suggest that colonic transit is slower on a solid than a liquid diet and that jejunal instillation of radiopharmaceuticals should be suitable for colonic transit studies in most subjects

  20. Effect of soy saponin on the growth of human colon cancer cells

    Science.gov (United States)

    Tsai, Cheng-Yu; Chen, Yue-Hwa; Chien, Yi-Wen; Huang, Wen-Hsuan; Lin, Shyh-Hsiang

    2010-01-01

    AIM: To investigate the effect of extracted soybean saponins on the growth of human colon cancer cells. METHODS: WiDr human colon cancer cells were treated with 150, 300, 600 or 1200 ppm of soy saponin to determine the effect on cell growth, cell morphology, alkaline phosphatase (AP) and protein kinase C (PKC) activities, and P53 protein, c-Fos and c-Jun gene expression. RESULTS: Soy saponin decreased the number of viable cells in a dose-dependent manner and suppressed 12-O-tetradecanol-phorbol-13-acetate-stimulated PKC activity (P saponins developed cytoplasmic vesicles and the cell membrane became rougher and more irregular in a dose-dependent manner, and eventually disassembled. At 600 and 1200 ppm, the activity of AP was increased (P saponin. CONCLUSION: Soy saponin may be effective in preventing colon cancer by affecting cell morphology, cell proliferation enzymes, and cell growth. PMID:20632438

  1. Vasohibin-1 suppresses colon cancer

    OpenAIRE

    Liu, Shuai; Han, Bing; Zhang, Qunyuan; Dou, Jie; Wang, Fang; Lin, Wenli; Sun, Yuping; Peng, Guangyong

    2015-01-01

    Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor. However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and co...

  2. Recombinant human erythropoietin alpha improves the efficacy of radiotherapy of a human tumor xenograft, affecting tumor cells and microvessels

    International Nuclear Information System (INIS)

    Loevey, J.; Bereczky, B.; Gilly, R.; Kenessey, I.; Raso, E.; Simon, E.; Timar, J.; Dobos, J.; Vago, A.; Kasler, M.; Doeme, B.; Tovari, J.

    2008-01-01

    Background and purpose: tumor-induced anemia often occurs in cancer patients, and is corrected by recombinant human erythropoietins (rHuEPOs). Recent studies indicated that, besides erythroid progenitor cells, tumor and endothelial cells express erythropoietin receptor (EPOR) as well; therefore, rHuEPO may affect their functions. Here, the effect of rHuEPOα on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested. Material and methods: A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPOα at human-equivalent dose. Xenografts were irradiated (5 Gy) on day 14, and the final tumor mass was measured on day 22. The systemic effects of rHuEPOα on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1α expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPOα and irradiation were also tested in vitro. Results: in vitro, rHuEPOα treatment alone did not modify the proliferation of EPOR-positive A431 tumor cells but enhanced the effect of irradiation on proliferation, apoptosis and clonogenic capacity. In vivo, rHuEPOα administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1α expression but had no effect on tumor growth. At the same time rHuEPOα treatment significantly increased the efficacy of radiotherapy in vivo (tumor weight of 23.9 ± 4.7 mg and 34.9 ± 4.6 mg, respectively), mediated by increased tumoral blood vessel destruction. Conclusion: rHuEPOα treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1α expression, but also by destroying tumoral vessels. (orig.)

  3. Comparison of radioimmunotherapy and external beam radiotherapy in colon cancer xenografts

    International Nuclear Information System (INIS)

    Buras, R.R.; Wong, J.F.C.; Kuhn, J.A.; Beatty, B.G.; Williams, L.E.; Beatty, J.D.; Wanek, P.M.

    1993-01-01

    Radioimmunotherapy and external beam radiotherapy were compared in a nude mouse human colon cancer model. Radioimmunotherapy was delivered by intraperitoneal injection of 90 Y-labeled anticarcinoembryonic antigen monoclonal antibody (anti-CEA MAB). Single fraction external beam radiotherapy was delivered using a 60 Co teletherapy unit. Control groups received saline, unlabeled anit-CEA monoclonal antibody and labeled nonspecific monoclonal antibody. Tumor growth suppression was expressed as delay to reach 2g compared to saline controls. Unlabeled anti-CEA monoclonal antibody and labeled nonspecific monoclonal antibody had no effect. External beam radiotherapy of 300, 600, 1000 and 2000 cGy produced growth delays of 3, 12, 17, and 22 days, respectively. Radioimmunotherapy with 120 μCi, 175 μCi, and 225 μCi resulted in growth delays of 20, 34, and 36 days. Estimated absorbed tumor dose was 1750 cGy in the 120 μCi group. Similar comparisons were done with the more radioresistant WiDr human colon carcinoma cell line. External beam radiotherapy doses of 400, 800, 1200, and 1600 cGy resulted in growth delays of 6, 21, 36 and 48 days, respectively. Radioimmunotherapy of 120 μCi and 175 μCi resulted in growth delays of 9 and 19 days, respectively. The 120 μCi dose delivered an estimated absorbed tumor dose of 1080 cGy to WiDr tumors. In summary, for the radiosensitive LS174T line, radioimmunotherapy produced biologic effects that were comparable to a similar dose of single fraction external beam radiotherapy. For the more radioresistant WiDr tumor, radioimmunotherapy produced a biologic effect which was less than a similar dose of single fraction external beam radiotherapy. These studies suggest that a tumor's response to radioimmunotherapy relative to that of external beam radiotherapy is, in part, dependent on tumor radiosensitivity and repair capacity. 23 refs., 5 figs. 4 tabs

  4. Subepithelial myofibroblasts are novel nonprofessional APCs in the human colonic mucosa.

    Science.gov (United States)

    Saada, Jamal I; Pinchuk, Irina V; Barrera, Carlos A; Adegboyega, Patrick A; Suarez, Giovanni; Mifflin, Randy C; Di Mari, John F; Reyes, Victor E; Powell, Don W

    2006-11-01

    The human gastrointestinal mucosa is exposed to a diverse normal microflora and dietary Ags and is a common site of entry for pathogens. The mucosal immune system must respond to these diverse signals with either the initiation of immunity or tolerance. APCs are important accessory cells that modulate T cell responses which initiate and maintain adaptive immunity. The ability of APCs to communicate with CD4+ T cells is largely dependent on the expression of class II MHC molecules by the APCs. Using immunohistochemistry, confocal microscopy, and flow cytometry, we demonstrate that alpha-smooth muscle actin(+), CD90+ subepithelial myofibroblasts (stromal cells) constitutively express class II MHC molecules in normal colonic mucosa and that they are distinct from professional APCs such as macrophages and dendritic cells. Primary isolates of human colonic myofibroblasts (CMFs) cultured in vitro were able to stimulate allogeneic CD4+ T cell proliferation. This process was dependent on class II MHC and CD80/86 costimulatory molecule expression by the myofibroblasts. We also demonstrate that CMFs, engineered to express a specific DR4 allele, can process and present human serum albumin to a human serum albumin-specific and DR4 allele-restricted T cell hybridoma. These studies characterize a novel cell phenotype which, due to its strategic location and class II MHC expression, may be involved in capture of Ags that cross the epithelial barrier and present them to lamina propria CD4+ T cells. Thus, human CMFs may be important in regulating local immunity in the colon.

  5. Factors that mediate colonization of the human stomach by Helicobacter pylori.

    Science.gov (United States)

    Dunne, Ciara; Dolan, Brendan; Clyne, Marguerite

    2014-05-21

    Helicobacter pylori (H. pylori) colonizes the stomach of humans and causes chronic infection. The majority of bacteria live in the mucus layer overlying the gastric epithelial cells and only a small proportion of bacteria are found interacting with the epithelial cells. The bacteria living in the gastric mucus may act as a reservoir of infection for the underlying cells which is essential for the development of disease. Colonization of gastric mucus is likely to be key to the establishment of chronic infection. How H. pylori manages to colonise and survive in the hostile environment of the human stomach and avoid removal by mucus flow and killing by gastric acid is the subject of this review. We also discuss how bacterial and host factors may together go some way to explaining the susceptibility to colonization and the outcome of infection in different individuals. H. pylori infection of the gastric mucosa has become a paradigm for chronic infection. Understanding of why H. pylori is such a successful pathogen may help us understand how other bacterial species colonise mucosal surfaces and cause disease.

  6. The lifetime of hypoxic human tumor cells

    International Nuclear Information System (INIS)

    Durand, Ralph E.; Sham, Edward

    1998-01-01

    Purpose: For hypoxic and anoxic cells in solid tumors to be a therapeutic problem, they must live long enough to be therapeutically relevant, or else be rapidly recruited into the proliferating compartment during therapy. We have, therefore, estimated lifetime and recruitment rate of hypoxic human tumor cells in multicell spheroids in vitro, or in xenografted tumors in SCID mice. Materials and Methods: Cell turnover was followed by flow cytometry techniques, using antibodies directed at incorporated halogenated pyrimidines. The disappearance of labeled cells was quantified, and verified to be cell loss rather than label dilution. Repopulation was studied in SiHa tumor xenografts during twice-daily 2.5-Gy radiation exposures. Results: The longevity of hypoxic human tumor cells in spheroids or xenografts exceeded that of rodent cell lines, and cell turnover was slower in xenografts than under static growth as spheroids. Human tumor cells remained viable in the hypoxic regions of xenografts for 4-10 days, compared to 3-5 days in spheroids, and 1-3 days for most rodent cells in spheroids. Repopulation was observed within the first few radiation treatments for the SiHa xenografts and, with accumulated doses of more than 10 Gy, virtually all recovered cells had progressed through at least one S-phase. Conclusion: Our results suggest an important difference in the ability of human vs. rodent tumor cells to withstand hypoxia, and raise questions concerning the increased longevity seen in vivo relative to the steady-state spheroid system

  7. Colonization and infection by Helicobacter pylori in humans.

    Science.gov (United States)

    Andersen, Leif Percival

    2007-11-01

    When Helicobacter pylori arrives in the human stomach, it may penetrate the mucin layer and adhere to the gastric epithelial cells or it may pass through the stomach without colonizing the mucosa. In this paper, the colonization process and the ensuing immunological response will be briefly described. Urease production is necessary for H. pylori to establish a pH-neutral microenvironment around the bacteria. The flagella enable the bacteria to move and the shape of H. pylori makes it possible to penetrate the mucin layer where it comes into contact with the gastric epithelial cells. H. pylori contains several adhesins that enable it to adhere to the epithelial cells. This adherence activates IL-8 which, together with bacterial antigens, attracts polymorphs and monocytes and causes acute gastritis. Antigen-presenting cells activate lymphocytes and other mononuclear cells that are attracted to the inflamed mucosa, causing chronic superficial gastritis and initiating a cytotoxic or an antigen-producing Th response. The infection is established within a few weeks after the primary exposure to H. pylori. After this initial colonization, many chemical, biochemical, and immunologic reactions take place that are of importance in the progress of the infection and the development of disease.

  8. Accuracy of colonoscopy in localizing colonic cancer.

    Science.gov (United States)

    Stanciu, C; Trifan, Anca; Khder, Saad Alla

    2007-01-01

    It is important to establish the precise localization of colonic cancer preoperatively; while colonoscopy is regarded as the diagnostic gold standard for colorectal cancer, its ability to localize the tumor is less reliable. To define the accuracy of colonoscopy in identifying the location of colonic cancer. All of the patients who had a colorectal cancer diagnosed by colonoscopy at the Institute of Gastroenterology and Hepatology, Iaşi and subsequently received a surgical intervention at three teaching hospitals in Iaşi, between January 2001 and December 2005, were included in this study. Endoscopic records and operative notes were carefully reviewed, and tumor localization was recorded. There were 161 patients (89 men, 72 women, aged 61.3 +/- 12.8 years) who underwent conventional surgery for colon cancer detected by colonoscopy during the study period. Twenty-two patients (13.66%) had erroneous colonoscopic localization of the tumors. The overall accuracy of preoperative colonoscopic localization was 87.58%. Colonoscopy is an accurate, reliable method for locating colon cancer, although additional techniques (i.e., endoscopic tattooing) should be performed at least for small lesions.

  9. Imaging Nuclear-Cytoplasmic Dynamics in Primary and Metastatic Colon Cancer in Nude Mice.

    Science.gov (United States)

    Hasegawa, Kosuke; Suetsugu, Atsushi; Nakamura, Miki; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Bouvet, Michael; Shimizu, Masahito; Hoffman, Robert M

    2016-05-01

    Colon cancer frequently results in metastasis to the liver, where it becomes the main cause of death. However, the cell cycle in primary tumors and metastases is poorly understood. We developed a mouse model of liver metastasis using the human colon cancer cell line HCT-116, which expresses green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm (HCT-116-GFP-RFP). HCT-116 GFP-RFP cells were injected into the spleen of nu/nu nude mice. HCT-116-GFP-RFP cells subsequently formed primary tumors in the spleen, as well as metastatic colonies in the liver and retroperitoneum by 28 days after cell transplantation. Using an Olympus FV1000 confocal microscope, it was possible to clearly image mitosis of the dual-colored colon cancer cells in the primary tumor as well as liver and other metastases. Multi-nucleate cancer cells, in addition to mono-nucleate cancer cells and their mitosis, were observed in the primary tumor and metastasis. Multi-nucleate HCT-116-GFP-RFP cells were also observed after culture of the primary and metastatic tumors. A similar ratio of mono-nucleate, multi-nucleate, and mitotic cells grew from the primary and metastatic tumors in culture, suggesting similarity of the nuclear-cytoplasmic dynamics of primary and metastatic cancer cells, further emphasizing the stochastic nature of metastasis. Our results demonstrate a similar heterogeneity of nuclear-cytoplasmic dynamics within primary tumors and metastases, which may be an important factor in the stochastic nature of metastasis. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. Transit of solids through the human colon: Regional quantification in the unprepared bowel

    International Nuclear Information System (INIS)

    Proano, M.; Camilleri, M.; Phillips, S.F.; Brown, M.L.; Thomforde, G.M.

    1990-01-01

    We used a noninvasive method to label the solid phase of contents in the unprepared human colon. 111 In-labeled Amberlite pellets (0.5-1.8 mm diam) were placed in a gelatin capsule that was then coated with a pH-sensitive polymer (methacrylate). In vitro, the capsules disintegrated in simulated small bowel contents within 1-2 h; when ingested by healthy subjects, capsules released radiolabel in the distal ileum or proximal colon in 13 of 15 subjects. Transit of 111 In-pellets through the unprepared colon could then be quantitated radioscintigraphically. Segmental transit was defined in the ascending (AC), transverse (TC), descending (DC), and rectosigmoid (RS) colon. Radioactivity was also quantitated in stools. At 12 h, radioactivity was most obvious in the AC (59 +/- 11%, mean +/- SE) and the TC (21 +/- 6%); at 24 h, counts were distributed equally between AC, TC, and stools (P greater than 0.05); by 48 h, 56 +/- 11% counts had been excreted, although 30 +/- 10% remained in the TC. At 24 and 48 h, the amount in DC or RS was lower (P less than 0.05) than in the TC or in stools. Emptying of the AC was characterized by an initial lag period, when no counts emptied into the TC, followed by a period of emptying that was approximately linear. Thus this simple approach is able to label contents in the healthy human colon. The ascending and transverse colon appear to be sites of storage of solid residue, whereas the left colon and rectosigmoid function mainly as conduits

  11. Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models

    Directory of Open Access Journals (Sweden)

    Yingjen Jeffrey Wu

    2009-02-01

    Full Text Available The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally 24 hours before human ovarian carcinoma (SKOV3, small cell lung carcinoma (LX-1 SCLC, and glioma (UW28, U87MG, and U251 tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0% of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

  12. Tissue distribution of aryl hydrocarbon receptor in the intestine: Implication of putative roles in tumor suppression

    International Nuclear Information System (INIS)

    Ikuta, Togo; Kurosumi, Masafumi; Yatsuoka, Toshimasa; Nishimura, Yoji

    2016-01-01

    Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc"M"i"n"/"+mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression. - Highlights: • In the normal intestine, AhR was mainly localized in stroma containing immune cells. • In the tumor tissue, AhR expression was found in both stromal and tumor cells. • AhR knockdown promoted cell growth in colon cancer cell lines.

  13. Tissue distribution of aryl hydrocarbon receptor in the intestine: Implication of putative roles in tumor suppression

    Energy Technology Data Exchange (ETDEWEB)

    Ikuta, Togo, E-mail: togo@cancer-c.pref.saitama.jp [Department of Cancer Prevention, Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Kurosumi, Masafumi, E-mail: mkurosumi@cancer-c.pref.saitama.jp [Division of Pathology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Yatsuoka, Toshimasa, E-mail: yatsuoka-gi@umin.ac.jp [Division of Gastroenterological Surgery, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Nishimura, Yoji, E-mail: yojinish@cancr-c.pref.saitama.jp [Division of Gastroenterological Surgery, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan)

    2016-05-01

    Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc{sup Min/+}mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression. - Highlights: • In the normal intestine, AhR was mainly localized in stroma containing immune cells. • In the tumor tissue, AhR expression was found in both stromal and tumor cells. • AhR knockdown promoted cell growth in colon cancer cell lines.

  14. Calcium antagonist radioprotectors do not reduce radiotherapeutic efficacy in three human tumor xenografts

    International Nuclear Information System (INIS)

    Floersheim, G.L.; Racine, C.

    1995-01-01

    One Ewing's sarcoma and 2 colon carcinomas were grown as xenografts in immunosuppressed mice. The mice were treated with diltiazem, nifedipine, nimodipine and nitrendipine. The effect of whole body γ-radiation on the growth of the subcutaneously implanted tumors was assessed. Growth delay or regression of the tumors in mice treated with the calcium antagonists prior to irradiation was not reduced as compared to only irradiated controls. (orig.) [de

  15. Human neutrophils facilitate tumor cell transendothelial migration.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

  16. [Isolation and identification of brain tumor stem cells from human brain neuroepithelial tumors].

    Science.gov (United States)

    Fang, Jia-sheng; Deng, Yong-wen; Li, Ming-chu; Chen, Feng-Hua; Wang, Yan-jin; Lu, Ming; Fang, Fang; Wu, Jun; Yang, Zhuan-yi; Zhou, Xang-yang; Wang, Fei; Chen, Cheng

    2007-01-30

    To establish a simplified culture system for the isolation of brain tumor stem cells (BTSCs) from the tumors of human neuroepithelial tissue, to observe the growth and differentiation pattern of BTSCs, and to investigate their expression of the specific markers. Twenty-six patients with brain neuroepithelial tumors underwent tumor resection. Two pieces of tumor tissues were taken from each tumor to be dissociated, triturated into single cells in sterile DMEM-F12 medium, and then filtered. The tumor cells were seeded at a concentration of 200,000 viable cells per mL into serum-free DMEM-F12 medium simply supplemented with B27, human basic fibroblast growth factor (20 microg/L), human epidermal growth factor (20 microg /L), insulin (4 U/L), L-glutamine, penicillin and streptomycin. After the primary brain tumor spheres (BTSs) were generated, they were triturated again and passed in fresh medium. Limiting dilution assay was performed to observe the monoclone formation. 5-bromodeoxyuridine (BrdU) incorporation test was performed to observe the proliferation of the BTS. The BTSCs were cultured in mitogen-free DMEM-F12 medium supplemented with 10% fetal bovine serum to observe their differentiation. Immunocytochemistry was used to examine the expression of CD133 and nestin, specific markers of BTSC, and the rate of CD133 positive cells. Only a minority of subsets of cells from the tumors of neuroepithelial tissue had the capacity to survive, proliferate, and generate free-floating neurosphere-like BTSs in the simplified serum-free medium. These cells attached to the poly-L-lysine coated coverslips in the serum-supplemented medium and differentiated. The BTSCs were CD133 and nestin positive. The rate of CD133 positive cells in the tumor specimens was (21 +/- 6.2)% - (38 +/- 7.0)%. A new simplified culture system for the isolation of BTSCs is established. The tumors of human neuroepithelial tissue contain CD133 and nestin positive tumor stem cells which can be isolated

  17. Tumor-Associated Neutrophils in Human Lung Cancer

    Science.gov (United States)

    2017-10-01

    markers in humans. The logistical, ethical , and regulatory difficulties in obtaining human tumor tissue for research also act to discourage such...Mouse models of cancer. Annu. Rev. Pathol 6, 95–119 52. Merlo, L.M. et al. (2006) Cancer as an evolutionary and ecological process. Nat. Rev. Cancer...some effect on the phenotype and function of TANs. The logistical, ethical , and regulatory difficulties in obtaining human tumor tissue for research

  18. Tuft (caveolated) cells in two human colon carcinoma cell lines.

    Science.gov (United States)

    Barkla, D H; Whitehead, R H; Foster, H; Tutton, P J

    1988-09-01

    The presence of an unusual cell type in two human colon carcinoma cell lines is reported. The cells show the same morphology as "tuft" (caveolated) cells present in normal gastrointestinal epithelium. Tuft cells were seen in cell line LIM 1863 growing in vitro and in human colon carcinoma cell line LIM 2210 growing as subcutaneous solid tumour xenografts in nude mice. Characteristic morphologic features of tuft cells included a wide base, narrow apex and a tuft of long microvilli projecting from the apical surface. The microvilli are attached by a core of long microfilaments passing deep into the apical cytoplasm. Between the microvilli are parallel arrays of vesicles (caveoli) containing flocculent material. Two different but not mutually exclusive explanations for the presence of tuft cells are proposed. The first explanation is that tuft cells came from the resected tumour and have survived by mitotic division during subsequent passages. The second explanation suggests that tuft cells are the progeny of undifferentiated tumour cells. Descriptions of tuft cells in colon carcinomas are uncommon and possible reasons for this are presented. The morphology of tuft cells is consistent with that of a highly differentiated cell specialised for absorption, and these new models provide an opportunity to further investigate the structure and function of tuft cells.

  19. Cáncer de colon recurrente: diagnóstico y tratamiento Recurrent colon cancer: diagnosis and treatment

    Directory of Open Access Journals (Sweden)

    Roswell Enrique GonzálezRodiles Heredia

    2009-03-01

    Full Text Available INTRODUCCIÓN. El cáncer recurrente es aquel que reaparece luego de un período de tiempo durante el cual no podía ser detectado. El objetivo del presente estudio fue identificar los elementos diagnósticos más relevantes del cáncer de colon recurrente, así como las opciones más adecuadas de tratamiento. MÉTODOS. Se realizó un estudio observacional, descriptivo, longitudinal y retrospectivo sobre el diagnóstico y los resultados del tratamiento de la recurrencia tumoral en 68 pacientes operados por cáncer de colon en un período de 16 años. RESULTADOS. Predominaron los pacientes mayores de 60 años, del sexo femenino; entre las localizaciones, el tumor primario en el colon sigmoides y ascendente, con estadificación en etapa II después de la operación inicial. Las recurrencias más frecuentes fueron la locorregional y la hepática, y su forma de presentación predominante, el tumor palpable. El método clínico y la ecografía abdominal fueron determinantes para el diagnóstico. El tratamiento quirúrgico con quimioterapia adyuvante fue el más efectivo en general, y en particular en la localización locorregional. La supervivencia alcanzó 2 años en el 30,9 % de los pacientes, con predominio de los que habían recibido tratamiento quirúrgico. A los 5 años había fallecido el 85,3 % de la serie. CONCLUSIONES. El diagnóstico precoz y el tratamiento adecuado de la recurrencia tumoral requieren la actuación de un equipo médico multidisciplinario pues es la causa de muerte preponderante en los operados de cáncer de colon con intención curativa. Los 2 primeros años de seguimiento posoperatorio constituyen el período de mayor riesgo de recurrencias.INTRODUCTION. Recurrent cancer is that that reappears after a period of time during which it could not be detected. The objective of this study was to identify the most important diagnostic elements of recurrent colon cancer, as well as the most adequate treatment options. METHODS. An

  20. The action of sennosides and related compounds on human colon and rectum 1

    Science.gov (United States)

    Hardcastle, J. D.; Wilkins, J. L.

    1970-01-01

    The direct action of intraluminal senna and related compounds on the human colon and rectum has been investigated. Motility was recorded by balloon kymography with recording units inserted into well established transverse colostomies or into the rectum. The motility of the colon was not changed by intraluminal senna glycosides but the introduction of senna previously incubated with faeces or Esch. coli stimulated the colon to peristalt. The peristalsis was similar to that stimulated by rheinanthrone, an oxanthrone produced by chemical hydrolysis and reduction of senna. Both activated senna and rheinanthrone appeared to act in the colon by contact stimulation. No peristaltic response was stimulated in the rectum, either with activated senna or with rheinanthrone. PMID:4929273

  1. pH distribution in human tumors

    International Nuclear Information System (INIS)

    Thistlethwaite, A.J.; Leeper, D.B.; Moylan, D.J.; Nerlinger, R.E.

    1984-01-01

    pH distribution in human tumors is being determined to evaluate this parameter as a prognostic indicator of hyperthermia response. pH is measured by a modified glass pH electrode (21g, model MI 408, Microelectrodes, Inc., Londonderry, NH) inserted through an 18g open-ended Angiocath. Eight tumors have been evaluated to date; and of those, 3 were also assayed after the first heat treatment coincident with determination of blood flow. Tumors were between 2-5 cm, of various histologies, and of primary, recurrent, or metastatic origin. 2-4 measurements were made per tumor. Pretreatment readings were between 6.4 and 7.2 pH units. As tumor blood flow increased after 1 hr heating (41.5 - 43 0 ) pH rose 0.1 - 0.3 units. Normal rat muscle yields pH readings of 7.35 - 7.45. Although there was considerable heterogeneity of pH within tumors, accuracy and drift were not a problem. 5-15 min were required for pH stabilization after catheter insertion and <5 min after electrode insertion. A saline wheal was used for anesthesia to preclude modification of pH by anesthetics. Patient tolerance has not been a problems. This study suggests that human tumor tissue has a preponderance of areas more acidic than normal tissue. This may serve to sensitize tumor cells to hyperthermia and provide a prognostic indicator of tumor response

  2. Rapid effects of phytoestrogens on human colonic smooth muscle are mediated by oestrogen receptor beta.

    LENUS (Irish Health Repository)

    Hogan, A M

    2012-02-01

    Epidemiological studies have correlated consumption of dietary phytoestrogens with beneficial effects on colon, breast and prostate cancers. Genomic and non-genomic mechanisms are responsible for anti-carcinogenic effects but, until now, the effect on human colon was assumed to be passive and remote. No direct effect on human colonic smooth muscle has previously been described. Institutional research board approval was granted. Histologically normal colon was obtained from the proximal resection margin of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended under 1g of tension in organ baths containing oxygenated Krebs solution at 37 degrees C. After an equilibration period, tissues were exposed to diarylpropionitrile (DPN) (ER beta agonist) and 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) (ER alpha agonist) or to the synthetic phytoestrogen compounds genistein (n=8), daidzein (n=8), fisetin (n=8) and quercetin (n=8) in the presence or absence of fulvestrant (oestrogen receptor antagonist). Mechanism of action was investigated by inhibition of downstream pathways. The cholinergic agonist carbachol was used to induce contractile activity. Tension was recorded isometrically. Phytoestrogens inhibit carbachol-induced colonic contractility. In keeping with a non-genomic, rapid onset direct action, the effect was within minutes, reversible and similar to previously described actions of 17 beta oestradiol. No effect was seen in the presence of fulvestrant indicating receptor modulation. While the DPN exerted inhibitory effects, PPT did not. The effect appears to be reliant on a p38\\/mitogen activated protein kinase mediated induction of nitric oxide production in colonic smooth muscle. The present data set provides the first description of a direct effect of genistein, daidzein, fisetin and quercetin on human colonic smooth muscle. The presence of ER in colonic smooth muscle has been functionally proven and the beta

  3. CacyBP/SIP promotes the proliferation of colon cancer cells.

    Directory of Open Access Journals (Sweden)

    Huihong Zhai

    Full Text Available CacyBP/SIP is a component of the ubiquitin pathway and is overexpressed in several transformed tumor tissues, including colon cancer, which is one of the most common cancers worldwide. It is unknown whether CacyBP/SIP promotes the proliferation of colon cancer cells. This study examined the expression level, subcellular localization, and binding activity of CacyBP/SIP in human colon cancer cells in the presence and absence of the hormone gastrin. We found that CacyBP/SIP was expressed in a high percentage of colon cancer cells, but not in normal colonic surface epithelium. CacyBP/SIP promoted the cell proliferation of colon cancer cells under both basal and gastrin stimulated conditions as shown by knockdown studies. Gastrin stimulation triggered the translocation of CacyBP/SIP to the nucleus, and enhanced interaction between CacyBP/SIP and SKP1, a key component of ubiquitination pathway which further mediated the proteasome-dependent degradation of p27kip1 protein. The gastrin induced reduction in p27kip1 was prevented when cells were treated with the proteasome inhibitor MG132. These results suggest that CacyBP/SIP may be promoting growth of colon cancer cells by enhancing ubiquitin-mediated degradation of p27kip1.

  4. Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

    NARCIS (Netherlands)

    Tetteh, Paul W.; Kretzschmar, Kai; Begthel, Harry; Van Den Born, Maaike; Korving, Jeroen; Morsink, Folkert; Farin, Henner; Van Es, Johan H.; Offerhaus, G. Johan A; Clevers, Hans

    2016-01-01

    Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic

  5. [Comparison of clinicopathological features and prognosis between left-sided colon cancer and right-sided colon cancer].

    Science.gov (United States)

    Gao, Xianhua; Yu, Guanyu; Liu, Peng; Hao, Liqiang; Liu, Lianjie; Zhang, Wei

    2017-06-25

    To compare the clinicopathological features and prognosis between left-sided colon cancer (LC) and right-sided colon cancer (RC). Clinicopathological and follow-up data of 2 174 colon carcinoma cases undergoing resection at Shanghai Changhai Hospital of The Second Military Medical University from January 2000 to December 2010 were retrospectively analyzed. Patients with transverse colon cancer, overlapping position, unknown location, recurrent cancer, multiple primary cancer, concomitant malignant tumors, preoperative chemotherapy, local resection, incomplete clinical data and missed follow up were excluded. Finally, a total of 1 036 patients, whose primary tumors were radically removed, were enrolled, with 563 patients in LC group (including carcinoma in cecum, ascending colon and hepatic flexure) and 473 in RC group (including carcinoma in splenic flexure, descending colon and sigmoid colon). The clinicopathological features and survival, including median overall survival, 5-year overall survival rate, tumor specific median overall survival, cancer specific 5-year overall survival rate, were compared between LC and RC groups. Tumor specific overall survival was defined as the period between operation date to the date of death caused by cancer progression. Multivariate Cox regression analysis was used to analyze the influencing factors of survival. Propensity score matching was carried out to balance the clinicopathological factors between the two groups with the SAS 9.3, taking the following parameters into consideration (age, gender, gross appearance, tumor diameter, invasion depth, lymph node metastasis, distant metastasis, TNM stages, differentiation, CEA and CA199-9). Patients in RC group and LC group were matched according to the propensity scores and the clinicopathological characteristics and prognosis of two groups were compared again. No significant differences were identified between the two groups in age, distant metastasis and serum CEA level

  6. CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype

    Science.gov (United States)

    Paschall, Amy V.; Yang, Dafeng; Lu, Chunwan; Redd, Priscilla S.; Choi, Jeong-Hyeon; Heaton, Christopher M.; Lee, Jeffrey R.; Nayak-Kapoor, Asha; Liu, Kebin

    2016-01-01

    The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment selectively enriches a subset of CD133+ colon cancer cells in vitro. 5-FU chemotherapy also increases CD133+ tumor cells in human colon cancer patients. However, sorted CD133+ colon cancer cells exhibit no increased resistance to 5-FU, and CD133 levels exhibit no correlation with colon cancer patient survival or cancer recurrence. Genome-wide analysis of gene expression between sorted CD133+ colon cancer cells and 5-FU-selected colon cancer cells identifies 207 differentially expressed genes. CD24 is one of the genes whose expression level is lower in the CD133+ and 5-FU-resistant colon cancer cells as compared to CD133+ and 5-FU-sensitive colon cancer cells. Consequently, CD133+CD24lo cells exhibit decreased sensitivity to 5-FU. Therefore, we determine that CD133+CD24lo phenotype defines 5-FU-resistant human colon cancer stem cell-like cells. PMID:27659530

  7. Laminarin Induces Apoptosis of Human Colon Cancer LOVO Cells through a Mitochondrial Pathway

    Directory of Open Access Journals (Sweden)

    He Zhang

    2012-08-01

    Full Text Available Many scientific studies have shown that laminarin has anti-tumor effects, but the anti-tumor mechanism was unclear. The purpose of this study was to investigate the effect of laminarin on the induction of apoptosis in human colon cancer LOVO cells and the molecular mechanism involved. LOVO cells were treated with different concentrations of laminarin at different times. Morphology observations were performed to determine the effects of laminarin on apoptosis of LOVO cells. Flow cytometry (FCM was used to detect the level of intracellular reactive oxygen species (ROS and pH. Laser scanning confocal microscope (LSCM was used to analyze intracellular calcium ion concentration, mitochondrion permeability transition pore (MPTP and mitochondrial membrane potential (MMP. Western blotd were performed to analyze the expressions of Cyt-C, Caspase-9 and -3. The results showed the apoptosis morphology, which showed cell protuberance, concentrated cytoplasm and apoptotic bodies, was obvious after 72 h treatment. Laminarin treatment for 24 h increased the intracellular level of ROS and Ca2+; decreased pH value; activated intracellular MPTP and decreased MMP in dose-dependent manners. It also induced the release of Cyt-C and the activation of Caspase-9 and -3. In conclusion, laminarin induces LOVO cell apoptosis through a mitochondrial pathway, suggesting that it could be a potent agent for cancer prevention and treatment.

  8. Clinical significance of MCM-2 and MCM-5 expression in colon cancer: association with clinicopathological parameters and tumor proliferative capacity.

    Science.gov (United States)

    Giaginis, Constantinos; Georgiadou, Maria; Dimakopoulou, Konstantina; Tsourouflis, Gerasimos; Gatzidou, Elisavet; Kouraklis, Gregorios; Theocharis, Stamatios

    2009-02-01

    Minichromosome maintenance (MCM) proteins are essential components of DNA replication, being related to cell proliferation, and serve as useful markers for cancer screening, surveillance, and prognosis. Our aim was to examine the clinical significance of MCM-2 and MCM-5 protein expression in colon cancer and to evaluate the association with various clinicopathological characteristics and tumor proliferative capacity. Immunohistochemical expression of MCM-2 and MCM-5 was performed on paraffin-embedded malignant tissue sections obtained from 96 patients with colon cancer. MCM-2 and MCM-5 expression was correlated with different clinicopathological characteristics, proliferative capacity (Ki-67 labeling index), and p53 cell-cycle regulator expression. MCM-2 and Ki-67 expression was significantly associated with the tumors' histological grade (P = 0.003), existence of nodular metastases (N) (P = 0.003 and P = 0.030, respectively), malignancy on adenoma (P = 0.029 and P = 0.024, respectively), and vascular invasion (P = 0.010 and P = 0.011, respectively). MCM-2 expression was additionally associated with Dukes' stage (P = 0.005). Significant positive relationships were found between the expression of MCM-2 or MCM-5 proteins and that of Ki-67 protein (r = 0.963, P-value characteristics examined. The current data suggest that MCM-2 protein expression is significantly associated with important clinicopathological characteristics for patients' management, being correlated with the cell proliferation state in colon cancer.

  9. Comparative effectiveness of primary tumor resection in patients with stage IV colon cancer.

    Science.gov (United States)

    Alawadi, Zeinab; Phatak, Uma R; Hu, Chung-Yuan; Bailey, Christina E; You, Y Nancy; Kao, Lillian S; Massarweh, Nader N; Feig, Barry W; Rodriguez-Bigas, Miguel A; Skibber, John M; Chang, George J

    2017-04-01

    Although the safety of combination chemotherapy without primary tumor resection (PTR) in patients with stage IV colon cancer has been established, questions remain regarding a potential survival benefit with PTR. The objective of this study was to compare mortality rates in patients who had colon cancer with unresectable metastases who did and did not undergo PTR. An observational cohort study was conducted among patients with unresectable metastatic colon cancer identified from the National Cancer Data Base (2003-2005). Multivariate Cox regression analyses with and without propensity score weighting (PSW) were performed to compare survival outcomes. Instrumental variable analysis, using the annual hospital-level PTR rate as the instrument, was used to account for treatment selection bias. To account for survivor treatment bias, in situations in which patients might die soon after diagnosis from different reasons, a landmark method was used. In the total cohort, 8641 of 15,154 patients (57%) underwent PTR, and 73.8% of those procedures (4972 of 6735) were at landmark. PTR was associated with a significant reduction in mortality using Cox regression (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.44-0.47) or PSW (HR, 0.46; 95% CI, 0. 44-0.49). However, instrumental variable analysis revealed a much smaller effect (relative mortality rate, 0.91; 95% CI, 0.87-0.96). Although a smaller benefit was observed with the landmark method using Cox regression (HR, 0.6; 95% CI, 0.55-0.64) and PSW (HR, 0.59; 95% CI, 0.54-0.64), instrumental variable analysis revealed no survival benefit (relative mortality rate, 0.97; 95% CI, 0.87-1.06). Among patients with unresectable metastatic colon cancer, after adjustment for confounder effects, PTR was not associated with improved survival compared with systemic chemotherapy; therefore, routine noncurative PTR is not recommended. Cancer 2017;123:1124-1133. © 2016 American Cancer Society. © 2016 American Cancer Society.

  10. Real-time detection system for tumor localization during minimally invasive surgery for gastric and colon cancer removal: In vivo feasibility study in a swine model.

    Science.gov (United States)

    Choi, Won Jung; Moon, Jin-Hee; Min, Jae Seok; Song, Yong Keun; Lee, Seung A; Ahn, Jin Woo; Lee, Sang Hun; Jung, Ha Chul

    2018-03-01

    During minimally invasive surgery (MIS), it is impossible to directly detect marked clips around tumors via palpation. Therefore, we developed a novel method and device using Radio Frequency IDentification (RFID) technology to detect the position of clips during minimally invasive gastrectomy or colectomy. The feasibility of the RFID-based detection system was evaluated in an animal experiment consisting of seven swine. The primary outcome was to successfully detect the location of RFID clips in the stomach and colon. The secondary outcome measures were to detect time (time during the intracorporeal detection of the RFID clip), and accuracy (distance between the RFID clip and the detected site). A total of 25 detection attempts (14 in the stomach and 11 in the colon) using the RFID antenna had a 100% success rate. The median detection time was 32.5 s (range, 15-119 s) for the stomach and 28.0 s (range, 8-87 s) for the colon. The median detection distance was 6.5 mm (range, 4-18 mm) for the stomach and 6.0 mm (range, 3-13 mm) for the colon. We demonstrated favorable results for a RFID system that detects the position of gastric and colon tumors in real-time during MIS. © 2017 Wiley Periodicals, Inc.

  11. Protective effects of the ethanolic extract of Melia toosendan fruit against colon cancer

    International Nuclear Information System (INIS)

    Tang, Xue-Lian; Yang, Xin-Ying; Park, Hyun; Kim, Youn-Chul; Kim, Sung-Yeon; Kang, Baek-Dong; Park, Won-Cheol; Choi, Du-Young; Kjm, Ok-jin

    2012-01-01

    Colorectal cancer is one of the leading causes of death in the world. Plant-derived products have proven to be valuable sources for discovery and development of unique anticancer drugs. In this study, the inhibitory effects of ethanolic extract of Melia toosendan fruit (EMTF), a traditional medicine in the Chinese Pharmacopoeia were evaluated in vitro and in vivo against colon cancer. Human colon cancer cells SW480 and murine colorectal adenocarcinoma cells CT26 were used to investigate cell proliferation. The results showed that EMTF inhibited cell proliferation of SW480 and CT26 by promoting apoptosis as indicated by nuclear chromatin condensation and DNA fragmentation. Through increasing mitochondrial membrane permeability and cytochrome c release from mitochondria, EMTF induced caspase-9 activity which further activated caspase-3 and poly(ADP-ribose) polymerase cleavage, leading the tumor cells to apoptosis. The in vivo results confirmed reduction of tumor volume and apoptotic effects and the side effects were not induced by EMTF. Therefore, EMTF may be an effective chemotherapeutic agent for colon cancer treatment. (author)

  12. Echoendoscopic characterization of the human colon

    Directory of Open Access Journals (Sweden)

    Fernando M. Castro-Poças

    Full Text Available Purpose: To characterize colon and rectum walls, pericolic and perirectal spaces, using endoscopic ultrasonography miniprobes. Methods: Sixty individuals (50% males, aged 18-80, were included. Using 12 and 20 MHz endoscopic ultrasonography miniprobes, all different colon segments (ascending, transverse, descending, sigmoid and rectum were evaluated according to the number and thickness of the different layers in intestinal wall, to the presence and (largest diameter of vessels in the submucosa and of peri-intestinal nodes. Results: The 20 MHz miniprobe identified a higher number of layers than the 12 MHz miniprobe, with medians of 7 and 5 respectively (p < 0.001. The rectal wall (p = 0.001, its muscularis propria (p < 0.001 and mucosa (p = 0.01 were significantly thicker than the different segments of the colon, which had no significant differences between them. Patients aged 41-60 presented thicker colonic wall and muscularis propria in descending (p = 0.001 and p = 0.004 and rectum (p=0.01 and p=0.01. Submucosal vessels were identified in 30% of individuals in descending and rectum, and in 12% in ascending. Adenopathies were observed in 9% of the colon segments and 5% in rectum. Conclusions: A higher frequency enabled the identification of a higher number of layers. Rectal wall is thicker than the one from all the segments of the colon and there are no differences between these, namely in the ascending colon. Moreover, peri-intestinal adenopathies were rarely identified but present in asymptomatic individuals. All together, these results describe for the first time features which are relevant during staging and therapeutic management of colonic lesions.

  13. PPARδ deficiency disrupts hypoxia-mediated tumorigenic potential of colon cancer cells.

    Science.gov (United States)

    Jeong, Eunshil; Koo, Jung Eun; Yeon, Sang Hyeon; Kwak, Mi-Kyoung; Hwang, Daniel H; Lee, Joo Young

    2014-11-01

    Peroxisome proliferator-activated receptor (PPAR) δ is highly expressed in colon epithelial cells and closely linked to colon carcinogenesis. However, the role of PPARδ in colon cancer cells in a hypoxic tumor microenvironment is not fully understood. We found that expression of the tumor-promoting cytokines, IL-8 and VEGF, induced by hypoxia (colon cancer cells. Consequently, PPARδ-knockout colon cancer cells exposed to hypoxia and deferoxamine failed to stimulate endothelial cell vascularization and macrophage migration/proliferation, whereas wild-type cells were able to induce angiogenesis and macrophage activation in response to hypoxic stress. Hypoxic stress induced transcriptional activation of PPARδ, but not its protein expression, in HCT116 cells. Exogenous expression of p300 potentiated deferoxamine-induced PPARδ transactivation, while siRNA knockdown of p300 abolished hypoxia- and deferoxamine-induced PPARδ transactivation. PPARδ associated with p300 upon hypoxic stress as demonstrated by coimmunoprecipitation studies. PI3K inhibitors or siRNA knockdown of Akt suppressed the PPARδ transactivation induced by hypoxia and deferoxamine in HCT116 cells, leading to decreased expression of IL-8 and VEGF. Collectively, these results reveal that PPARδ is required for hypoxic stress-mediated cytokine expression in colon cancer cells, resulting in promotion of angiogenesis, macrophage recruitment, and macrophage proliferation in the tumor microenvironment. p300 and the PI3K/Akt pathway play a role in the regulation of PPARδ transactivation induced by hypoxic stress. Our results demonstrate the positive crosstalk between PPARδ in tumor cells and the hypoxic tumor microenvironment and provide potential therapeutic targets for colon cancer. © 2014 Wiley Periodicals, Inc.

  14. Analysis of beta-catenin, Ki-ras, and microsatellite stability in azoxymethane-induced colon tumors of BDIX/Orl Ico rats

    DEFF Research Database (Denmark)

    Sørensen, Nanna Møller; Kobaek-Larsen, Morten; Bonne, Anita

    2003-01-01

    The aim of the study reported here was to investigate whether the azoxymethane (AOM)-induced colon cancer rat model mimics the human situation with regard to microsatellite stability, changes in expression of beta-catenin, and/or changes in the sequence of the proto-oncogene Ki-ras. Colon cancer ...

  15. CPP2-p16MIS treatment–induced colon carcinoma cell death in vitro and prolonged lifespan of tumor-bearing mice

    International Nuclear Information System (INIS)

    Wang, Lifeng; Chen, Haijin; Yu, Jinlong; Lin, Xiaohua; Qi, Jia; Cui, Chunhui; Xie, Lang; Huang, Shuxin

    2016-01-01

    Cell-penetrating peptides (CPPs) are a research hotspot due to their noninvasive delivery ability. Among the identified CPPs, the TAT and R8 peptides have been preferentially applied to transduction into different cells. However, this process is nonselective among various cells. Recent research suggested that CPP2 could selectively penetrate human colorectal cancer (CRC) cells. Using in vitro experiments, the mean fluorescence intensity of fluorescein isothiocyanate–labeled CPPs (CPPs-FITC) incubated with different cell lines was compared to corroborate the colon tumor targeting ability of CPP2. The targeting ability of CPP2 was determined in the same way in tumor-bearing mice. We synthesized antitumor peptides by fusing CPP2 to the minimal inhibitory sequence of p16 (p16MIS), which had the ability to restore the function of lost p16, the expression of which was absent in tumor cell lines of various origins. The antitumor effect of the combined peptide was tested in both CRC cell lines and tumor-bearing mice. In each CRC cell line, the mean fluorescence intensity of CPP2-FITC was higher than that of the TAT-FITC (p < 0.001) and R8-FITC (p < 0.001) groups. CPP2-p16MIS, the targeting carrier, showed a higher antitumor response in the in vitro cell research. CPP2-p16MIS showed a prolonged mean lifespan of tumor-bearing mice, further characterizing its role in specific tumor-targeting ability in vivo. Survival analysis showed that the mice treated with CPP2-p16MIS had significantly longer survival than the mice treated with phosphate-buffered saline (p < 0.05) or those treated with control peptides, including the CPP2 (p < 0.05) and p16MIS (p < 0.05) groups. CPP2 could more selectively penetrate CRC cells than TAT or R8 as well as effectively deliver the p16MIS to the tumor

  16. Pigmentation, Melanocyte Colonization, and p53 Status in Basal Cell Carcinoma

    International Nuclear Information System (INIS)

    Frey, L. M.; Houben, R.; Brocker, E. B.

    2011-01-01

    Basal cell carcinoma (BCC) is the most common neoplasm in the Caucasian population. Only a fraction of BCC exhibits pigmentation. Lack of melanocyte colonization has been suggested to be due to p53-inactivating mutations in the BCC cells interfering with the p53-proopiomelanocortin pathway and the production of alpha melanocyte-stimulating hormone in the tumor. To evaluate this, we determined tumor pigmentation as well as expression of melan-A and of p53 in 49 BCC tissues by means of immunohistochemistry. As expected, we observed a positive relation between tumor pigmentation and melan-A positive intra-tumoral melanocytes. Melanocyte colonization and, to a lesser extent, p53 overexpression showed intraindividual heterogeneity in larger tumors. p53 overexpression, which is indicative of p53 mutations, was not correlated to melanocyte colonization of BCC. Sequencing of exon 5-8 of the p53 gene in selected BCC cases revealed that colonization by melanocytes and BCC pigmentation is neither ablated by p53 mutations nor generally present in BCCs with wild-type p53.

  17. Innovations that influence the pharmacology of monoclonal antibody guided tumor targeting

    International Nuclear Information System (INIS)

    Schlom, J.; Hand, P.H.; Greiner, J.W.; Colcher, D.; Shrivastav, S.; Carrasquillo, J.A.; Reynolds, J.C.; Larson, S.M.; Raubitschek, A.

    1990-01-01

    Tumor targeting by monoclonal antibodies (MAbs) can be enhanced by (a) increasing the percentage of injected dose taken up by the tumor and/or (b) increasing the tumor:nontumor ratios. Several groups have demonstrated that one can increase tumor to nontumor ratios by the use of antibody fragments or the administration of second antibodies. Several other modalities are also possible: (a) the use of recombinant interferons to up-regulate the expression of specific tumor associated antigens such as carcinoembryonic antigen or TAG-72 on the surface of carcinoma cells and thus increase MAb tumor binding has proved successful in both in vitro and in vivo studies; (b) the intracavitary administration of MAbs. Recent studies have demonstrated that when radiolabeled B72.3 is administered i.p. to patients with carcinoma of the peritoneal cavity, it localizes tumor masses with greater efficiency than does concurrent i.v. administered antibody. Studies involving the comparative pharmacology of intracavitary administration of radiolabeled MAb in patients and several animal models will be discussed; (c) it has been reported that prior exposure of hepatoma to external beam radiation will increase radiolabeled MAb tumor targeting. We and others have not been able to duplicate this phenomenon with a human colon cancer xenograft model and radiolabeled MAbs to two different colon carcinoma associated antigens. The possible reasons for these differences will be discussed; (d) the cloning and expression of recombinant MAbs with human constant regions and subsequent size modification constructs will also undoubtedly alter the pharmacology of MAb tumor binding in both diagnostic and therapeutic applications. 66 references

  18. CD44 regulates cell migration in human colon cancer cells via Lyn kinase and AKT phosphorylation.

    Science.gov (United States)

    Subramaniam, Venkateswaran; Vincent, Isabella R; Gardner, Helena; Chan, Emily; Dhamko, Helena; Jothy, Serge

    2007-10-01

    Colon cancer is among the leading causes of cancer death in North America. CD44, an adhesion and antiapoptotic molecule is overexpressed in colon cancer. Cofilin is involved in the directional motility of cells. In the present study, we looked at how CD44 might modulate cell migration in human colon cancer via cofilin. We used a human colon cancer cell line, HT29, which expresses CD44, HT29 where CD44 expression was knocked down by siRNA, SW620, a human colon cancer cell line which does not express CD44, stably transfected exons of CD44 in SW620 cells and the colon from CD44 knockout and wild-type mouse. Western blot analysis of siRNA CD44 lysates showed increased level of AKT phosphorylation and decreased level of cofilin expression. Similar results were also observed with SW620 cells and CD44 knockout mouse colon lysates. Experiments using the AKT phosphorylation inhibitor LY294002 indicate that AKT phosphorylation downregulates cofilin. Immunoprecipitation studies showed CD44 complex formation with Lyn, providing an essential link between CD44 and AKT phosphorylation. LY294002 also stabilized Lyn from phosphorylated AKT, suggesting an interaction between Lyn and AKT phosphorylation. Immunocytochemistry showed that cofilin and Lyn expression were downregulated in siRNA CD44 cells and CD44 knockout mouse colon. siRNA CD44 cells had significantly less migration compared to HT29 vector. Given the well-defined roles of CD44, phosphorylated AKT in apoptosis and cancer, these results indicate that CD44-induced cell migration is dependent on its complex formation with Lyn and its consequent regulation of AKT phosphorylation and cofilin expression.

  19. Staphylococcus aureus MnhF mediates cholate efflux and facilitates survival under human colonic conditions

    OpenAIRE

    Sannasiddappa, Thippeswamy; Hood, Graham; Hanson, Kevan; Costabile, Adele; Gibson, Glenn; Clarke, Simon

    2015-01-01

    Resistance to the innate defenses of the intestine is crucial for the survival and carriage of Staphylococcus aureus, a common colonizer of the human gut. Bile salts produced by the liver and secreted into the intestines are one such group of molecules with potent antimicrobial activity. The mechanisms by which S. aureus is able to resist such defenses in order to colonize and survive in the human gut are unknown. Here we show that mnhF confers resistance to bile salts, which can be abrogated...

  20. Cytotoxicity of Portuguese Propolis: The Proximity of the In Vitro Doses for Tumor and Normal Cell Lines

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    Ricardo C. Calhelha

    2014-01-01

    Full Text Available With a complex chemical composition rich in phenolic compounds, propolis (resinous substance collected by Apis mellifera from various tree buds exhibits a broad spectrum of biological activities. Recently, in vitro and in vivo data suggest that propolis has anticancer properties, but is the cytoxicity of propolis specific for tumor cells? To answer this question, the cytotoxicity of phenolic extracts from Portuguese propolis of different origins was evaluated using human tumor cell lines (MCF7—breast adenocarcinoma, NCI-H460—non-small cell lung carcinoma, HCT15—colon carcinoma, HeLa—cervical carcinoma, and HepG2—hepatocellular carcinoma, and non-tumor primary cells (PLP2. The studied propolis presented high cytotoxic potential for human tumor cell lines, mostly for HCT15. Nevertheless, excluding HCT15 cell line, the extracts at the GI50 obtained for tumor cell lines showed, in general, cytotoxicity for normal cells (PLP2. Propolis phenolic extracts comprise phytochemicals that should be further studied for their bioactive properties against human colon carcinoma. In the other cases, the proximity of the in vitro cytotoxic doses for tumor and normal cell lines should be confirmed by in vivo tests and may highlight the need for selection of specific compounds within the propolis extract.

  1. Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

    Science.gov (United States)

    Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

    2016-03-31

    The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis.

  2. Different molecular organization of two carotenoids, lutein and zeaxanthin, in human colon epithelial cells and colon adenocarcinoma cells

    Science.gov (United States)

    Grudzinski, Wojciech; Piet, Mateusz; Luchowski, Rafal; Reszczynska, Emilia; Welc, Renata; Paduch, Roman; Gruszecki, Wieslaw I.

    2018-01-01

    Two cell lines, human normal colon epithelial cells (CCD 841 CoTr) and human colon adenocarcinoma cells (HT-29) were cultured in the presence of exogenous carotenoids, either zeaxanthin or lutein. Both carotenoids demonstrated cytotoxicity with respect to cancer cells but not to normal cells. Cells from both the cell lines were analyzed with application of fluorescence lifetime imaging microscopy and Raman scattering microscopy. Both imaging techniques show effective incorporation of carotenoid molecules into growing cells. Comparison of the Raman scattering and fluorescence lifetime characteristics reveals different molecular organization of carotenoids in the carcinoma and normal cells. The main difference consists in a carotenoid aggregation level which is substantially lower in the carcinoma cells as compared to the normal cells. Different molecular organization of carotenoids was interpreted in terms of a different metabolism of normal and carcinoma cells and has been concluded to provide a possibility of cancer diagnosis based on spectroscopic analyses.

  3. Induction of cancer stem cell properties in colon cancer cells by defined factors.

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    Nobu Oshima

    Full Text Available Cancer stem cells (CSCs are considered to be responsible for the dismal prognosis of cancer patients. However, little is known about the molecular mechanisms underlying the acquisition and maintenance of CSC properties in cancer cells because of their rarity in clinical samples. We herein induced CSC properties in cancer cells using defined factors. We retrovirally introduced a set of defined factors (OCT3/4, SOX2 and KLF4 into human colon cancer cells, followed by culture with conventional serum-containing medium, not human embryonic stem cell medium. We then evaluated the CSC properties in the cells. The colon cancer cells transduced with the three factors showed significantly enhanced CSC properties in terms of the marker gene expression, sphere formation, chemoresistance and tumorigenicity. We designated the cells with CSC properties induced by the factors, a subset of the transduced cells, as induced CSCs (iCSCs. Moreover, we established a novel technology to isolate and collect the iCSCs based on the differences in the degree of the dye-effluxing activity enhancement. The xenografts derived from our iCSCs were not teratomas. Notably, in contrast to the tumors from the parental cancer cells, the iCSC-based tumors mimicked actual human colon cancer tissues in terms of their immunohistological findings, which showed colonic lineage differentiation. In addition, we confirmed that the phenotypes of our iCSCs were reproducible in serial transplantation experiments. By introducing defined factors, we generated iCSCs with lineage specificity directly from cancer cells, not via an induced pluripotent stem cell state. The novel method enables us to obtain abundant materials of CSCs that not only have enhanced tumorigenicity, but also the ability to differentiate to recapitulate a specific type of cancer tissues. Our method can be of great value to fully understand CSCs and develop new therapies targeting CSCs.

  4. miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy.

    Science.gov (United States)

    Tan, Shifan; Shi, Huijuan; Ba, Mingchen; Lin, Shengqv; Tang, Hongsheng; Zeng, Xiaoqi; Zhang, Xiangliang

    2016-04-01

    The chemoresistance of colon cancer cells limits the efficacy of chemotherapy. miR-409-3p has been shown to be downregulated in various types of cancer. In the present study, we examined the role of miR-409-3p in colon cancer as well as the effects of miR‑409-3p on the sensitivity of colon cancer cells to oxaliplatin. The expression of miR-409 was significantly downregulated in the human colon cancer cell lines compared with the normal colon epithelial cells. Importantly, the miR-409-3p expression levels were lower in human colon cancer patient samples than in normal colon tissues. Moreover, we observed a negative correlation between the miR‑409-3p levels and resistance to oxaliplatin: the oxaliplatin-resistant colon cancer cells exhibited significantly downregulated miR‑409-3p levels, but higher autophagic activity than the oxaliplatin-sensitive cells. Using bioinformatics analysis, we predicted that miR‑409-3p miRNA binds to the key autophagy gene encoding Beclin-1. Our findings indicated that the overexpression of miR‑409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR‑409-3p enhanced the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR‑409-3p. In a xenograft model using nude mice, we examined the effects of miR‑409-3p on tumor growth during chemotherapy. miR‑409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1. The findings of our study suggest that miR-409-3p is capable of enhancing the chemosensitivity of colon cancer cells by inhibiting Beclin-1-mediated autophagy.

  5. Enhancement of anticancer effect of interferon-γ gene transfer against interferon-γ-resistant tumor by depletion of tumor-associated macrophages.

    Science.gov (United States)

    Kiyota, Tsuyoshi; Takahashi, Yuki; Watcharanurak, Kanitta; Nishikawa, Makiya; Ohara, Saori; Ando, Mitsuru; Watanabe, Yoshihiko; Takakura, Yoshinobu

    2014-05-05

    Tumor-associated macrophages (TAMs) negatively affect the therapeutic effects of anticancer agents. To examine the role of TAMs in interferon (IFN)-γ gene therapy, we selected two types of solid tumors, which varied in the number of TAMs, and investigated the effects of IFN-γ gene transfer on tumor growth. Many TAMs were detected in the solid tumors of murine adenocarcinoma colon-26 cells, whereas few TAMs were detected in murine melanoma B16-BL6 cells. IFN-γ gene transfer hardly suppressed the growth of colon-26 tumors, whereas it was effective in suppressing the growth of B16-BL6 tumors. The antiproliferative effects of IFN-γ on cultured colon-26 cells were similar to those on cultured B16-BL6 cells. To evaluate the role of TAMs, we injected clodronate liposomes (CLs) modified with poly(ethylene glycol) (PEG) to functionally deplete TAMs in tumor-bearing mice. Repeated injections of PEG-CLs significantly retarded the growth of colon-26 tumors and combination with IFN-γ gene transfer further inhibited the growth. In contrast, PEG-CLs hardly retarded the growth of B16-BL6 tumors. These results clearly indicate that TAM depletion is effective in enhancing the therapeutic effect of IFN-γ in TAM-repleted and IFN-γ-resistant tumors.

  6. Boletus edulis ribonucleic acid - a potent apoptosis inducer in human colon adenocarcinoma cells.

    Science.gov (United States)

    Lemieszek, Marta Kinga; Ribeiro, Miguel; Guichard Alves, Helena; Marques, Guilhermina; Nunes, Fernando Milheiro; Rzeski, Wojciech

    2016-07-13

    Despite the large popularity of the Boletus edulis mushroom, little is known about its influence on human health and the possibilities of its therapeutic use. Nevertheless, several reports revealed the usefulness of biopolymers isolated from it in cancer treatment. Our previous studies have shown that B. edulis water soluble biopolymers are not toxic against normal colon epithelial cells (CCD841 CoTr) and at the same concentration range elicited a very prominent antiproliferative effect in colon cancer cells (LS180) which was accompanied with cell cycle arrest in the G0/G1 phase. The purpose of the present study was to verify the proapoptotic properties of a selected fraction from B. edulis - BE3, as well as determine its chemical nature. The BE3 fraction was extracted with hot water and purified by anion-exchange chromatography. Further chemical examinations revealed that BE3 consists mainly of ribonucleic acid (59.1%). The ability of BE3 to induce programmed cell death was examined in human colon cancer cell lines LS180 and HT-29 by measuring caspase activation, DNA fragmentation and expression of BAX, BCL2, TP53 and CDKN1A genes. The sensitivity of colon cancer cells with silenced BAX, TP53 and CDKN1A expression to BE3 treatment was also evaluated. We have demonstrated for the first time that the BE3 fraction is a potent apoptosis inducer in human colon cancer cells. The revealed mechanism of apoptosis triggering was dependent on the presence of functional p53 and consequently was a little different in investigated cell lines. Our results indicated that BE3 stimulated proapoptotic genes BAX (LS180, HT-29), TP53 (LS180) and CDKN1A (HT-29) while at the same time silenced the expression of the key prosurvival gene BCL2 (LS180, HT-29). The obtained results indicate the high therapeutic potential of the BE3 fraction against colon cancer, yet it is necessary to further confirm fraction efficacy and safety in animal and clinical studies.

  7. Radiogenic stenosis of the colon following hypernephroma irradiation

    International Nuclear Information System (INIS)

    Razzaghipour, A.I.

    1973-01-01

    Refering to extensive home and foreign literature and to the number of 200 patients who were treated during the last 12 years, this paper reports about the radiogenic damage of the colon after irradiating renal tumors. Although no side dispositions of these types of radiation damage were mentioned in the literature, it was noticed in the group of the patients asked as well as in an Anglo-Saxon publication that both after conventional and after cobalt treatment exclusively the upper descending colon resp. the left half of the transverse colon showed alterations in the sense of a stenosing radiation colitis. The possible causes like differing topography of the colon as well as an individual disposition for increased radiation sensibility are discussed. The results of the clinical examination and the radiological symptoms colon stenosis in the number of the patients examined are shown casuistically, the successful surgical treatment of the colon stenosis is put briefly. This should help to contradict the reservations against a combined therapy for renal tumors and make the prognoses of malignant growth more pleasant. (orig.) [de

  8. Fluorescent diagnostics of epithelial neoplasms of different colon parts.

    Science.gov (United States)

    Korneva, Yulia S; Dorosevich, Alexander E; Maryakhina, Valeriya S

    2017-10-01

    Changes in the biochemical composition of the tissue during colon cancer progression usually precede morphological changes registered by light microscopy. These changes are very sensitive and may be used for diagnostics in difficult cases, when it is impossible to obtain sufficient amount of material during colonoscopy. The aim of the study is analysis of spectral characteristics of sporadic adenomas and tumors in different parts of colon for improving tumors diagnostics in disputable cases. The spectra of fluorescence excitation of histological sections from 78 patients with colon cancer (adenocarcinoma) and colonic adenomas of different localizations were measured. The spectra of fluorescence excitation of all types of adenomas as well as adenocarcinoma have two maxima at 260/270 nm and at 330/340 nm. The first maximum is primarily defined by tryptophan and phenylalanin containing peptides, one of them is glucagon. The second maximum is mainly defined by collagen in stroma. Progression of precancer lesions to advanced cancer leads to increase of NADH concentration impacting on the second maximum of spectra. However, spectra of all types of the investigated lesions have peculiarities depending on localization. At odds to the previous data about similarities between distal colon and rectum, our results demonstrate similar spectra for proximal colon and rectum due to some similarities in morphological and, as a consequence, biochemical composition. Tumor can be detected by spectral techniques on histological slides even if the specimen contains very few tumorous cells in stroma. Biochemical changes and their similarities for precancer lesions and advanced colon cancer have described. Peculiarities of spectral data for different parts of colon may change the previous opinion about similar mechanisms of cancerogenesis for distal colon and rectum. Moreover, investigation of tissue specimen obtained for histological examination and containing lack of malignant

  9. Boletus edulis biologically active biopolymers induce cell cycle arrest in human colon adenocarcinoma cells.

    Science.gov (United States)

    Lemieszek, Marta Kinga; Cardoso, Claudia; Ferreira Milheiro Nunes, Fernando Hermínio; Ramos Novo Amorim de Barros, Ana Isabel; Marques, Guilhermina; Pożarowski, Piotr; Rzeski, Wojciech

    2013-04-25

    The use of biologically active compounds isolated from edible mushrooms against cancer raises global interest. Anticancer properties are mainly attributed to biopolymers including mainly polysaccharides, polysaccharopeptides, polysaccharide proteins, glycoproteins and proteins. In spite of the fact that Boletus edulis is one of the widely occurring and most consumed edible mushrooms, antitumor biopolymers isolated from it have not been exactly defined and studied so far. The present study is an attempt to extend this knowledge on molecular mechanisms of their anticancer action. The mushroom biopolymers (polysaccharides and glycoproteins) were extracted with hot water and purified by anion-exchange chromatography. The antiproliferative activity in human colon adenocarcinoma cells (LS180) was screened by means of MTT and BrdU assays. At the same time fractions' cytotoxicity was examined on the human colon epithelial cells (CCD 841 CoTr) by means of the LDH assay. Flow cytometry and Western blotting were applied to cell cycle analysis and protein expression involved in anticancer activity of the selected biopolymer fraction. In vitro studies have shown that fractions isolated from Boletus edulis were not toxic against normal colon epithelial cells and in the same concentration range elicited a very prominent antiproliferative effect in colon cancer cells. The best results were obtained in the case of the fraction designated as BE3. The tested compound inhibited cancer cell proliferation which was accompanied by cell cycle arrest in the G0/G1-phase. Growth inhibition was associated with modulation of the p16/cyclin D1/CDK4-6/pRb pathway, an aberration of which is a critical step in the development of many human cancers including colon cancer. Our results indicate that a biopolymer BE3 from Boletus edulis possesses anticancer potential and may provide a new therapeutic/preventive option in colon cancer chemoprevention.

  10. Endoscopic Localization of Colon Cancer Is Frequently Inaccurate.

    Science.gov (United States)

    Nayor, Jennifer; Rotman, Stephen R; Chan, Walter W; Goldberg, Joel E; Saltzman, John R

    2017-08-01

    Colonoscopic location of a tumor can influence both the surgical procedure choice and overall treatment strategy. To determine the accuracy of colonoscopy in determining the location of colon cancer compared to surgical localization and to elucidate factors that predict discordant colon cancer localization. We conducted a retrospective cross-sectional study of colon cancers diagnosed on colonoscopy at two academic tertiary-care hospitals and two affiliated community hospitals from 2012 to 2014. Colon cancer location was obtained from the endoscopic and surgical pathology reports and characterized by colon segment. We collected data on patient demographics, tumor characteristics, endoscopic procedure characteristics, surgery planned, and surgery performed. Univariate analyses using Chi-squared test and multivariate analysis using forward stepwise logistic regression were performed to determine factors that predict discordant colon cancer localization. There were 110 colon cancer cases identified during the study period. Inaccurate endoscopic colon cancer localization was found in 29% (32/110) of cases. These included 14 cases (12.7%) that were discordant by more than one colonic segment and three cases where the presurgical planned procedure was significantly changed at the time of surgery. On univariate analyses, right-sided colon lesions were associated with increased inaccuracy (43.8 vs 24.4%, p = 0.04). On multivariate analysis, right-sided colon lesions remained independently associated with inaccuracy (OR 1.74, 95% CI 1.03-2.93, p = 0.04). Colon cancer location as determined by colonoscopy is often inaccurate, which can result in intraoperative changes to surgical management, particularly in the right colon.

  11. Malignant transformation of colonic epithelial cells by a colon-derived long noncoding RNA

    International Nuclear Information System (INIS)

    Franklin, Jeffrey L.; Rankin, Carl R.; Levy, Shawn; Snoddy, Jay R.; Zhang, Bing; Washington, Mary Kay; Thomson, J. Michael; Whitehead, Robert H.; Coffey, Robert J.

    2013-01-01

    Highlights: •Non-coding RNAs are found in the colonic crypt progenitor compartment. •Colonocytes transformed by ncNRFR are highly invasive and metastatic. •ncNRFR has a region similar to the miRNA, let-7 family. •ncNRFR expression alters let-7 activity as measured by reporter construct. •ncNRFR expression upregulates let-7b targets. -- Abstract: Recent progress has been made in the identification of protein-coding genes and miRNAs that are expressed in and alter the behavior of colonic epithelia. However, the role of long non-coding RNAs (lncRNAs) in colonic homeostasis is just beginning to be explored. By gene expression profiling of post-mitotic, differentiated tops and proliferative, progenitor-compartment bottoms of microdissected adult mouse colonic crypts, we identified several lncRNAs more highly expressed in crypt bottoms. One identified lncRNA, designated non-coding Nras functional RNA (ncNRFR), resides within the Nras locus but appears to be independent of the Nras coding transcript. Stable overexpression of ncNRFR in non-transformed, conditionally immortalized mouse colonocytes results in malignant transformation, as determined by growth in soft agar and formation of highly invasive tumors in nude mice. Moreover, ncNRFR appears to inhibit the function of the tumor suppressor let-7. These results suggest precise regulation of ncNRFR is necessary for proper cell growth in the colonic crypt, and its misregulation results in neoplastic transformation

  12. Evaluation of selected features of Staphylococcus cohnii enabling colonization of humans.

    Science.gov (United States)

    Waldon, E; Sobiś-Glinkowska, M; Szewczyk, E M

    2002-01-01

    Based on iron utilization, sensitivity to skin fatty acids, lipolytic and proteolytic activity the potential abilities of Staphylococcus cohnii strains to colonize humans were evaluated. The investigation included 60 strains that belong to both subspecies, viz. S. cohnii ssp. cohnii and S. cohnii ssp. urealyticus. Strains were isolated from different sources of the Intensive Care Unit and from non-hospital environment. Most of the strains were multiple antibiotic-resistant. Strains of both subspecies revealed a relatively low iron requirement. These strains were capable of utilizing iron bound in oxo acids and from host iron-binding proteins. S. cohnii ssp. urealyticus were more effective in iron uptake than S. cohnii ssp. cohnii. All investigated strains revealed sensitivity to skin fatty acids, but S. cohnii ssp. urealyticus strains were more resistant. Special features of strains of this subspecies promote colonization of humans.

  13. Prognostic and predictive potential molecular biomarkers in colon cancer.

    Science.gov (United States)

    Nastase, A; Pâslaru, L; Niculescu, A M; Ionescu, M; Dumitraşcu, T; Herlea, V; Dima, S; Gheorghe, C; Lazar, V; Popescu, I

    2011-01-01

    An important objective in nowadays research is the discovery of new biomarkers that can detect colon tumours in early stages and indicate with accuracy the status of the disease. The aim of our study was to identify potential biomarkers for colon cancer onset and progression. We assessed gene expression profiles of a list of 10 candidate genes (MMP-1, MMP-3, MMP-7, DEFA 1, DEFA-5, DEFA-6, IL-8, CXCL-1, SPP-1, CTHRC-1) by quantitative real time PCR in triplets of colonic mucosa (normal, adenoma, tumoral tissue) collected from the same patient during surgery for a group of 20 patients. Additionally we performed immunohistochemistry for DEFA1-3 and SPP1. We remarked that DEFA5 and DEFA6 are key factors in adenoma formation (p<0.05). MMP7 is important in the transition from a benign to a malignant status (p <0.01) and further in metastasis being a prognostic indicator for tumor transformation and for the metastatic potential of cancer cells. IL8, irrespective of tumor stage, has a high mRNA level in adenocarcinoma (p< 0.05). The level of expression for SPP1 is correlated with tumor level. We suggest that high levels of DEFAS, DEFA6 (key elements in adenoma formation), MMP7 (marker of colon cancer onset and progression to metastasis), SPP1 (marker of progression) and IL8 could be used to diagnose an early stage colon cancer and to evaluate the prognostic of progression for colon tumors. Further, if DEFA5 and DEFA6 level of expression are low but MMP7, SPP1 and IL8 level are high we could point out that the transition from adenoma to adenocarcinoma had already occurred. Thus, DEFA5, DEFA6, MMP7, IL8 and SPP1 consist in a valuable panel of biomarkers, whose detection can be used in early detection and progressive disease and also in prognostic of colon cancer.

  14. Indoors forensic entomology: colonization of human remains in closed environments by specific species of sarcosaprophagous flies.

    Science.gov (United States)

    Pohjoismäki, Jaakko L O; Karhunen, Pekka J; Goebeler, Sirkka; Saukko, Pekka; Sääksjärvi, Ilari E

    2010-06-15

    Fly species that are commonly recovered on human corpses concealed in houses or other dwellings are often dependent on human created environments and might have special features in their biology that allow them to colonize indoor cadavers. In this study we describe nine typical cases involving forensically relevant flies on human remains found indoors in southern Finland. Eggs, larvae and puparia were reared to adult stage and determined to species. Of the five species found the most common were Lucilia sericata Meigen, Calliphora vicina Robineau-Desvoidy and Protophormia terraenovae Robineau-Desvoidy. The flesh fly Sarcophaga caerulescens Zetterstedt is reported for the first time to colonize human cadavers inside houses and a COI gene sequence based DNA barcode is provided for it to help facilitate identification in the future. Fly biology, colonization speed and the significance of indoors forensic entomological evidence are discussed. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  15. Comparative study of intact A7 MoAc and F(ab')2 fragments for radioimmunoimaging of human colon cancer in nude mice

    International Nuclear Information System (INIS)

    Kojima, Shuji; Suzuki, Naomi; Shimura, Noriko; Kubodera, Akiko; Kubota, Kazuhiko; Yamaguchi, Toshiharu; Takahashi, Toshio; Oyamada, Hiyoshimaru

    1993-01-01

    Differences of pharmacokinetics and tumor imaging ability between intact monoclonal antibody A7 (A7 MoAb) and F(ab) 2 fragments were studied in human colon cancer (LS-174T)-bearing nude mice. The authors examined the yield and the immunoreactivity of F(ab) 2 fragments after treatment with ficin as a function of time. The yield of F(ab) 2 fragments reached about 50% after ficin treatment for 8 h, and the F(ab) 2 retained about 80% of the immunoreactivity of the corresponding MoAb. Longer digestion with ficin produced smaller fragments (less than 92 kDa) with a lower yield and most of the immunoreactivity was lost. In pharmacokinetics studies, the F(ab') 2 was preferentially taken up by the tumor, cleared more rapidly from the blood circulation and seemed to have less non-specific tissue binding than intact A7 MoAb. The tumor image obtained at an early time using 131 I-F(ab') 2 was much superior in quality to that with intact 131 I-A7 MoAb. The use of F(ab') 2 fragments may be effective for tumor diagnosis and therapy. (author)

  16. Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8

    Directory of Open Access Journals (Sweden)

    Abdulamir Ahmed S

    2010-09-01

    Full Text Available Abstract Background Colorectal cancer (CRC has long been associated with bacteremia and/or endocarditis by Streptococcus gallolyticus member bacteria (SGMB but the direct colonization of SGMB along with its molecular carcinogenic role, if any, has not been investigated. We assessed the colonization of SGMB in CRC patients with history of bacteremia (CRC-w/bac and without history of bacteremia (CRC-wo/bac by isolating SGMB from feces, mucosal surfaces of colorectum, and colorectal tissues and detecting SGMB DNA, via PCR and in situ hybridization (ISH assays targeting SodA gene in colorectal tissues. Moreover, mRNA of IL1, IL-8, COX-2, IFN-γ, c-Myc, and Bcl-2 in colorectal tissues of studied groups was assessed via ISH and RT-PCR. Results SGMB were found to be remarkably isolated in tumorous (TU and non-tumorous (NTU tissues of CRC-w/bac, 20.5% and 17.3%, and CRC-wo/bac, 12.8% and 11.5%, respectively while only 2% of control tissues revealed SGMB (P 10 CN/g respectively, showed higher colonization in TU than in NTU and in CRC-w/bac than in CRC-wo/bac (P Conclusions The current study indicated that colorectal cancer is remarkably associated with SGMB; moreover, molecular detection of SGMB in CRC was superior to link SGMB with CRC tumors highlighting a possible direct and active role of SGMB in CRC development through most probably inflammation-based sequel of tumor development or propagation via, but not limited to, IL-1, COX-2, and IL-8.

  17. The role of tumor markers (CEA, TPA, CA 19-9) in colon and rectum carcinomas

    International Nuclear Information System (INIS)

    Cangemi, V.; Volpino, P.; Fiori, E.; Giammarco, A.; Piat, G.

    1987-01-01

    We have evaluated the diagnostic efficacy (sensitivity, specificity, accuracy, predictive malignancy index) of CEA, TPA, CA 19-9 in colon and rectum tumors (56 cases), the difference in behaviour of these markers in relation to the stage and grading of the cancer, their reliability regarding postsurgical relapses and/or metastases. The sensitivity of CEA (>10 ng/ml), TPA (>130 U/L), CA 19-9 (>37 u/ml) for diagnostic purpose was rather limited (28.6% - 30% - 18.5%) with a malignancy prediction value of 100% - 81.8% - 62.5%. With regard to relapses and/or metastases, the diagnostic efficacy of the marker proved to be evident only for CEA, TPA, CA 19-9 value greater than 25 ng/ml, 250 U/L and 100 u/ml. The use of thethree markers together was certainly an advantage both for primitive tumors (sensitivity: 52.8%) and relapses and/or metastases after surgery (sensitivity: 66.7%)

  18. STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH+/CD133+ stem cell-like human colon cancer cells

    International Nuclear Information System (INIS)

    Lin, Li; Fuchs, James; Li, Chenglong; Olson, Veronica; Bekaii-Saab, Tanios; Lin, Jiayuh

    2011-01-01

    Highlights: ► The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. ► STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. ► Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. ► STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. ► Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH + /CD133 + ). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower IC50 in colon cancer stem-like cells. In summary, our results indicate that STAT3 is a novel therapeutic target in colon cancer stem

  19. Human gastric emptying and colonic filling of solids characterized by a new method

    Energy Technology Data Exchange (ETDEWEB)

    Camilleri, M.; Colemont, L.J.; Phillips, S.F.; Brown, M.L.; Thomforde, G.M.; Chapman, N.; Zinsmeister, A.R. (Mayo Clinic and Foundation, Rochester, MN (USA))

    1989-08-01

    Our first aim was to compare {sup 111}In-labeled Amberlite IR-12OP resin pellets and {sup 131}I-labeled fiber in the assessment of gastric and small bowel transit and colonic filling in healthy humans. Both radiolabels were highly stable for 3 h in an in vitro stomach model and remained predominantly bound to solid phase of stools collected over 5 days (90.5 +/- 2.1 (SE)% for {sup 131}I and 87.4 +/- 1.4% for {sup 111}In). The lag phase of gastric emptying was shorter for {sup 111}In-pellets (30 +/- 11 min compared with 58 +/- 12 min for {sup 131}I-fiber, P less than 0.05). However, the slope of the postlag phase of gastric emptying and the half time of small bowel transit were not significantly different for {sup 111}In-pellets and {sup 131}I-fiber. Filling of the colon was characterized by bolus movements of the radiolabel (10-80% range, 26% mean) followed by plateaus (periods of no movement of isotope into colon lasting 15-120 min, range; 51 min, mean). Half of the bolus movements occurred within 1 h of the intake of a second meal. Thus {sup 111}In-labeled Amberlite pellets provide an excellent marker for the study of gastric and small bowel transit and colonic filling in humans. The ileum acts as a reservoir and transfers boluses of variable sizes into the colon, often soon after the intake of a subsequent meal.

  20. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

    Science.gov (United States)

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-12-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

  1. Tenascin-W is a better cancer biomarker than tenascin-C for most human solid tumors

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    Brellier Florence

    2012-09-01

    Full Text Available Abstract Background Tenascins are large glycoproteins found in the extracellular matrix of many embryonic and adult tissues. Tenascin-C is a well-studied biomarker known for its high overexpression in the stroma of most solid cancers. Tenascin-W, the least studied member of the family, is highly expressed in the stroma of colon and breast tumors and in gliomas, but not in the corresponding normal tissues. Other solid tumors have not been analyzed. The present study was undertaken to determine whether tenascin-W could serve as a cancer-specific extracellular matrix protein in a broad range of solid tumors. Methods We analyzed the expression of tenascin-W and tenascin-C by immunoblotting and by immunohistochemistry on multiple frozen tissue microarrays of carcinomas of the pancreas, kidney and lung as well as melanomas and compared them to healthy tissues. Results From all healthy adult organs tested, only liver and spleen showed detectable levels of tenascin-W, suggesting that tenascin-W is absent from most human adult organs under normal, non-pathological conditions. In contrast, tenascin-W was detectable in the majority of melanomas and their metastases, as well as in pancreas, kidney, and lung carcinomas. Comparing lung tumor samples and matching control tissues for each patient revealed a clear overexpression of tenascin-W in tumor tissues. Although the number of samples examined is too small to draw statistically significant conclusions, there seems to be a tendency for increased tenascin-W expression in higher grade tumors. Interestingly, in most tumor types, tenascin-W is also expressed in close proximity to blood vessels, as shown by CD31 co-staining of the samples. Conclusions The present study extends the tumor biomarker potential of tenascin-W to a broad range of solid tumors and shows its accessibility from the blood stream for potential therapeutic strategies.

  2. cis-4-[{sup 18}F]-Fluoro-L-proline fails to detect peripheral tumors in humans

    Energy Technology Data Exchange (ETDEWEB)

    Stoffels, Gabriele; Pauleit, Dirk [Institute of Neuroscience and Biophysics-Medicine, Research Centre Juelich, D-52425 Juelich, FRG (Germany); Haas, Rainer; Kobbe, Guido [Department of Oncology, Hematology, and Clinical Immunology, Heinrich-Heine-University Duesseldorf, FRG (Germany); Salber, Dagmar [C. and O. Vogt Institute of Brain Research, Heinrich-Heine-University Duesseldorf, FRG (Germany); Hamacher, Kurt; Coenen, Heinz H. [Institute of Neuroscience and Biophysics - Nuclear Chemistry, Research Centre Juelich, Juelich, FRG (Germany); Langen, Karl-Josef [Institute of Neuroscience and Biophysics-Medicine, Research Centre Juelich, D-52425 Juelich, FRG (Germany)], E-mail: k.j.langen@fz-juelich.de

    2008-11-15

    System A amino acid transport is increased in transformed and malignant cells. The amino acid 4-cis[{sup 18}F]fluoro-L-proline (cis-[{sup 18}F]FPro) has been shown to be a substrate of the System A amino acid carrier. In this pilot study, we investigated the diagnostic potential of cis-[{sup 18}F]FPro in patients with various tumors in comparison with [{sup 18}F]fluorodeoxyglucose-positron emission tomography (FDG-PET). Methods: Eight patients (seven females, one male, age range 43-77 years) with large primary, recurrent or metastatic tumors of different histologies were included in this study. One patient had a recurrent non-Hodgkin lymphoma; two patients, metastatic colon or rectal cancer; one, a metastatic endometrial cancer; one, a multiple myeloma; one, an Ewing sarcoma; one, a metastatic breast cancer and one, a gastrointestinal stromal tumor. PET scans of the trunk were acquired at 1 h after intravenous injection of 400 MBq cis-[{sup 18}F]FPro and compared to PET scans with [{sup 18}F]FDG. Results: None of the tumors or metastatic lesions in this series of patients demonstrated relevant uptake of cis-[{sup 18}F]FPro. In contrast, all tumors with exception of the multiple myeloma showed an intensive uptake of [{sup 18}F]FDG. The mean standardized uptake value of cis-[{sup 18}F]FPro in the tumor or metastases was significantly lower than that of [{sup 18}F]FDG uptake (1.7{+-}0.6 vs. 5.7{+-}3.0; n=8; P<.01). Conclusion: Although other System A-specific tracers have shown relevant tumor uptake, cis-[{sup 18}F]FPro fails to detect most types of human tumors. Based on these results, we cannot recommend a further evaluation of this tracer as a tumor-seeking agent.

  3. Prognostic significance of unintentional body weight loss in colon cancer patients.

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    Kuo, Yi-Hung; Shi, Chung-Sheng; Huang, Cheng Yi; Huang, Yun-Ching; Chin, Chih-Chien

    2018-04-01

    The aim of the present study was to investigate whether unintentional body weight loss (BWL) provides additional clinical information in terms of tumor progression and prognosis in non-metastatic colon cancer. In the present study, a total of 2,406 consecutive colon cancer patients without metastasis were retrospectively enrolled. Unintentional BWL was defined as loss of >5% of body weight within the last 6-12 months, or defined subjectively upon fulfillment of at least two of the following: Evidence of change in clothing size and corroboration of the reported weight loss by family or friend. This category was recorded as present ('with') or absent ('without'). Logistic regression analysis was performed to determine the correlation between BWL and the tumor characteristics and post-operative outcomes of patients with colon cancer. The Cox regression model was used to determine the association of BWL with long-term survival of colon cancer patients. A significant association between BWL and tumor location [right vs. left: Odds ratio (OR)=1.62; Pcolon cancer is not just a symptom, but it is also correlated with tumor location, size and depth, and is a prognostic factor for poor outcomes including overall survival and tumor relapse.

  4. Sigmoid colon cancer arising in a diverticulum of the colon with involvement of the urinary bladder: a case report and review of the literature.

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    Yagi, Yasumichi; Shoji, Yasuhiro; Sasaki, Shozo; Yoshikawa, Akemi; Tsukioka, Yuji; Fukushima, Wataru; Hirosawa, Hisashi; Izumi, Ryohei; Saito, Katsuhiko

    2014-05-13

    Colon cancer can arise from the mucosa in a colonic diverticulum. Although colon diverticulum is a common disease, few cases have been previously reported on colon cancer associated with a diverticulum. We report a rare case of sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder, which presented characteristic radiographic images. A 73-year-old man was admitted to our hospital for macroscopic hematuria. Computed tomography and magnetic resonance imaging revealed a sigmoid colon tumor that protruded into the urinary bladder lumen. The radiographs showed a tumor with a characteristic dumbbell-shaped appearance. Colonoscopy showed a type 1 cancer and multiple diverticula in the sigmoid colon. A diagnosis of sigmoid colon cancer with involvement of the urinary bladder was made based on the pathological findings of the biopsied specimens. We performed sigmoidectomy and total resection of the urinary bladder with colostomy and urinary tract diversion. Histopathological findings showed the presence of a colovesical fistula due to extramurally growing colon cancer. Around the colon cancer, the normal colon mucosa was depressed sharply with lack of the muscular layer, suggesting that the colon cancer was arising from a colon diverticulum. The present case is the first report of sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder. Due to an accurate preoperative radiological diagnosis, we were able to successfully perform a curative resection for sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder.

  5. The Role of Bcl-xL in Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia on Human Colon Cancer

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    Song, Xinxin; Kim, Seog-Young; Lee, Yong J.

    2012-01-01

    Colorectal cancer is the third leading cause of cancer-related mortality in the world. The main cause of death of colorectal cancer is hepatic metastases which can be treated using isolated hepatic perfusion (IHP), allowing treatment of colorectal metastasis with various methods. In this study we present a novel potent multimodality strategy comprising humanized death receptor 4 (DR4) antibody mapatumumab (Mapa) in combination with oxaliplatin and hyperthermia to treat human colon cancer cells. Oxaliplatin and hyperthermia sensitized colon cancer cells to Mapa in the mitochondrial dependent apoptotic pathway and increased reactive oxygen species production, leading to Bcl-xL phosphorylation at Serine 62 in a c-Jun N-terminal kinase (JNK)-dependent manner. Overexpression of Bcl-xL reduced the efficacy of the multimodality treatment, while phosphorylation of Bcl-xL decreased its anti-apoptotic activity. The multimodality treatment dissociated Bcl-xL from Bax, allowing Bax oligomerization to induce cytochrome c release from mitochondria. In addition, the multimodality treatment significantly inhibited colorectal cancer xenografts’ tumor growth. The successful outcome of this study will support the application of multimodality strategy to colorectal hepatic metastases. PMID:23051936

  6. Aberrant crypt foci and colon cancer: comparison between a short- and medium-term bioassay for colon carcinogenesis using dimethylhydrazine in Wistar rats

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    Rodrigues M.A.M.

    2002-01-01

    Full Text Available Aberrant crypt foci (ACF in the colon of carcinogen-treated rodents are considered to be the earliest hallmark of colon carcinogenesis. In the present study the relationship between a short-term (4 weeks and medium-term (30 weeks assay was assessed in a model of colon carcinogenesis induced by dimethylhydrazine (DMH in the rat. Six-week-old male Wistar rats were given subcutaneous injections of DMH (40 mg/kg twice a week for 2 weeks and killed at the end of the 4th or 30th week. ACF were scored for number, distribution pattern along the colon and crypt multiplicity in 0.1% methylene-blue whole-mount preparations. ACF were distinguished from normal crypts by their larger size and elliptical shape. The incidence, distribution and morphology of colon tumors were recorded. The majority of ACF were present in the middle and distal colon of DMH-treated rats and their number increased with time. By the 4th week, 91.5% ACF were composed of one or two crypts and 8.5% had three or more crypts, while by the 30th week 46.9% ACF had three or more crypts. Thus, a progression of ACF consisting of multiple crypts was observed from the 4th to the 30th week. Nine well-differentiated adenocarcinomas were found in 10 rats by the 30th week. Seven tumors were located in the distal colon and two in the middle colon. No tumor was found in the proximal colon. The present data indicate that induction of ACF by DMH in the short-term (4 weeks assay was correlated with development of well-differentiated adenocarcinomas in the medium-term (30 weeks assay.

  7. Efficient and reproducible identification of mismatch repair deficient colon cancer

    DEFF Research Database (Denmark)

    Joost, Patrick; Bendahl, Pär-Ola; Halvarsson, Britta

    2013-01-01

    BACKGROUND: The identification of mismatch-repair (MMR) defective colon cancer is clinically relevant for diagnostic, prognostic and potentially also for treatment predictive purposes. Preselection of tumors for MMR analysis can be obtained with predictive models, which need to demonstrate ease...... of application and favorable reproducibility. METHODS: We validated the MMR index for the identification of prognostically favorable MMR deficient colon cancers and compared performance to 5 other prediction models. In total, 474 colon cancers diagnosed ≥ age 50 were evaluated with correlation between...... clinicopathologic variables and immunohistochemical MMR protein expression. RESULTS: Female sex, age ≥60 years, proximal tumor location, expanding growth pattern, lack of dirty necrosis, mucinous differentiation and presence of tumor-infiltrating lymphocytes significantly correlated with MMR deficiency. Presence...

  8. Role of neutral ceramidase in colon cancer.

    Science.gov (United States)

    García-Barros, Mónica; Coant, Nicolas; Kawamori, Toshihiko; Wada, Masayuki; Snider, Ashley J; Truman, Jean-Philip; Wu, Bill X; Furuya, Hideki; Clarke, Christopher J; Bialkowska, Agnieszka B; Ghaleb, Amr; Yang, Vincent W; Obeid, Lina M; Hannun, Yusuf A

    2016-12-01

    Alterations in sphingolipid metabolism, especially ceramide and sphingosine 1-phosphate, have been linked to colon cancer, suggesting that enzymes of sphingolipid metabolism may emerge as novel regulators and targets in colon cancer. Neutral ceramidase (nCDase), a key enzyme in sphingolipid metabolism that hydrolyzes ceramide into sphingosine, is highly expressed in the intestine; however, its role in colon cancer has not been defined. Here we show that molecular and pharmacological inhibition of nCDase in colon cancer cells increases ceramide, and this is accompanied by decreased cell survival and increased apoptosis and autophagy, with minimal effects on noncancerous cells. Inhibition of nCDase resulted in loss of β-catenin and inhibition of ERK, components of pathways relevant for colon cancer development. Furthermore, inhibition of nCDase in a xenograft model delayed tumor growth and increased ceramide while decreasing proliferation. It is noteworthy that mice lacking nCDase treated with azoxymethane were protected from tumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and these data suggest that this enzyme is a suitable and novel target for colon cancer therapy.-García-Barros, M., Coant, N., Kawamori, T., Wada, M., Snider, A. J., Truman, J.-P., Wu, B. X., Furuya, H., Clarke, C. J., Bialkowska, A. B., Ghaleb, A., Yang, V. W., Obeid, L. M., Hannun, Y. A. Role of neutral ceramidase in colon cancer. © FASEB.

  9. Effect of sulindac sulfide on metallohydrolases in the human colon cancer cell line HT-29.

    Directory of Open Access Journals (Sweden)

    Hector Guillen-Ahlers

    Full Text Available Matrix metalloproteinase 7 (MMP7, a metallohydrolase involved in the development of several cancers, is downregulated in the Apc(Min/+ colon cancer mouse model following sulindac treatment. To determine whether this effect is relevant to the human condition, HT-29 human colon cancer cells were treated with sulindac and its metabolites, and compared to results obtained from in vivo mouse studies. The expression of MMP7 was monitored. The results demonstrated that sulindac sulfide effectively downregulated both MMP7 expression and activity. Furthermore, activity-based proteomics demonstrated that sulindac sulfide dramatically decreased the activity of leukotriene A4 hydrolase in HT-29 cells as reflected by a decrease in the level of its product, leukotriene B4. This study demonstrates that the effect of sulindac treatment in a mouse model of colon cancer may be relevant to the human counterpart and highlights the effect of sulindac treatment on metallohydrolases.

  10. Molecular pathways undergoing dramatic transcriptomic changes during tumor development in the human colon

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    Maglietta Rosalia

    2012-12-01

    Full Text Available Abstract Background The malignant transformation of precancerous colorectal lesions involves progressive alterations at both the molecular and morphologic levels, the latter consisting of increases in size and in the degree of cellular atypia. Analyzing preinvasive tumors of different sizes can therefore shed light on the sequence of these alterations. Methods We used a molecular pathway-based approach to analyze transcriptomic profiles of 59 colorectal tumors representing early and late preinvasive stages and the invasive stage of tumorigenesis. Random set analysis was used to identify biological pathways enriched for genes differentially regulated in tumors (compared with 59 samples of normal mucosa. Results Of the 880 canonical pathways we investigated, 112 displayed significant tumor-related upregulation or downregulation at one or more stages of tumorigenesis. This allowed us to distinguish between pathways whose dysregulation is probably necessary throughout tumorigenesis and those whose involvement specifically drives progression from one stage to the next. We were also able to pinpoint specific changes within each gene set that seem to play key roles at each transition. The early preinvasive stage was characterized by cell-cycle checkpoint activation triggered by DNA replication stress and dramatic downregulation of basic transmembrane signaling processes that maintain epithelial/stromal homeostasis in the normal mucosa. In late preinvasive lesions, there was also downregulation of signal transduction pathways (e.g., those mediated by G proteins and nuclear hormone receptors involved in cell differentiation and upregulation of pathways governing nuclear envelope dynamics and the G2>M transition in the cell cycle. The main features of the invasive stage were activation of the G1>S transition in the cell cycle, upregulated expression of tumor-promoting microenvironmental factors, and profound dysregulation of metabolic pathways (e

  11. A novel model of distal colon cancer in athymic mice Novo modelo de câncer de cólon distal em camundongos atímicos

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    Denise Gonçalves Priolli

    2012-06-01

    Full Text Available PURPOSE: The present a novel adenocarcinoma model in athymic mice. METHODS: Seven athymic mice were used. Colon diversion and distal fistula were made. Adenocarcinoma cells were inoculated in the submucosa of fistula. Tumor growth was monitored daily. Scintigraphy with 99mTc-MIBI was performed to identify the tumor. RESULTS: The model of distal colon cancer is feasible. Tumor detection was possible by both, macroscopically and molecular imaging. All resections demonstrated poorly differentiated tumors. Colon obstruction occurred in one case, similarly to evolution in human tumors of distal colon. CONCLUSION: The proposed model of distal colon cancer is feasible, allows for easy monitoring of tumoral growth by both, macroscopically and molecular imaging, and is suitable for studying the evolution of tumor with implementation of cytotoxic therapy in vivo.OBJETIVO: Apresentar novo modelo de adenocarcinoma distal em camundongos atímicos. MÉTODOS: Foram utilizados sete camundongos atímicos. Desvio do cólon distal e fístula foram feitas. Células de adenocarcinoma foram inoculadas na submucosa da fístula. O crescimento do tumor foi monitorado diariamente. Cintilografia com 99mTc-MIBI foi realizada para identificar o tumor. RESULTADOS: O modelo de câncer de cólon distal é viável. Detecção do tumor foi possível macroscopicamente e por imagem molecular. Todas as ressecções demonstraram tumores pouco diferenciados. Obstrução do cólon ocorreu em um caso, de forma semelhante à evolução em tumores humanos do cólon distal. CONCLUSÃO: O modelo de câncer do cólon distal proposto é viável, permite a monitorização fácil do crescimento tumoral macroscopicamente e por imagem molecular, sendo adequado para o estudo da evolução de tumor com aplicação de terapia citotóxica in vivo.

  12. γδ T cells as a potential tool in colon cancer immunotherapy.

    Science.gov (United States)

    Ramutton, Thiranut; Buccheri, Simona; Dieli, Francesco; Todaro, Matilde; Stassi, Giorgio; Meraviglia, Serena

    2014-01-01

    γδ T cells are capable of recognizing tumor cells and exert potent cellular cytotoxicity against a large range of tumors, including colon cancer. However, tumors utilize numerous strategies to escape recognition or killing by patrolling γδ T cells, such a downregulation of NKG2D ligands, MICA/B and ULBPs. Therefore, the combined upregulation of T-cell receptorand NKG2D ligands on tumor cells and induction of NKG2D expression on γδ T cells may greatly enhance tumor killing and unlock the functions of γδ T cells. Here, we briefly review current data on the mechanisms of γδ T-cell recognition and killing of colon cancer cells and propose that γδ T cells may represent a promising target for the design of novel and highly innovative immunotherapy in patients with colon cancer.

  13. Schwannoma of the Colon

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    Ronaldo Nonose

    2009-09-01

    Full Text Available Schwannomas are neoplasms originating from Schwann cells, which are the cells forming nerve sheaths. These neoplasms generally involve peripheral nerves. They rarely affect the gastrointestinal tract and primary colon involvement is extremely rare. The objective of the present paper was to present a case of primary schwannoma of the sigmoid colon, unassociated with von Recklinghausen disease, that was histopathologically confirmed by means of an immunohistochemical panel. The patient was a 71-year-old woman who had had rectal bleeding when evacuating, with pain and tenesmus, for 4 months. She underwent colonoscopy, which identified a raised submucous lesion of 2.8 cm in diameter, located in the sigmoid colon, 30 cm from the anal margin. During examination, loop polypectomy with lesion excision was performed. Histopathological evaluation showed that this was a tumor of stromal origin. Its resection margins were compromised by neoplasia, and colon resection by means of videolaparoscopy was indicated. Conventional histopathological examination using the hematoxylin-eosin technique suggested that the neoplasm was of mesenchymal origin. An immunohistochemical panel was run for etiological confirmation, using anti-CD34 antibodies, desmin, cytokeratins (AE1/AE3, cKit, chromogranin and S-100 protein. The panel showed intense immunoexpression of S-100 protein. Investigation of the proliferative activity rate using Ki-67 antibodies showed that there was a low rate of mitotic activity, thus confirming the diagnosis of primary benign schwannoma of the colon. The patient’s postoperative evolution was uneventful and she remains in good health, without signs of tumor recurrence, 15 months after surgical excision.

  14. Gadolinium-Loaded Solid Lipid Nanoparticles as a Tumor-Absorbable Contrast Agent for Early Diagnosis of Colorectal Tumors Using Magnetic Resonance Colonography.

    Science.gov (United States)

    Sun, Jihong; Zhang, Shizheng; Jiang, Shaojie; Bai, Weixian; Liu, Fei; Yuan, Hong; Ji, Jiansong; Luo, Jingfeng; Han, Guocan; Chen, Lumin; Jin, Yin; Hu, Peng; Yu, Lei; Yang, Xiaoming

    2016-09-01

    Magnetic resonance (MR) contrast agents focusing on special functions are required to improve cancer diagnosis, particularly in the early stages. Here, we designed multifunctional solid lipid nanoparticles (SLNs) with simultaneous loading of gadolinium (Gd) diethylenetriaminepentaacetic acid (Gd-DTPA) and octadecylamine fluorescein isothiocyanate (FITC) to obtain Gd-FITC-SLNs as a tumor-absorbable nanoparticle contrast agent for the histological confirmation of MR imaging (MRI) findings. Colorectal tumors were evaluated in vitro and in vivo via direct uptake of this contrast agent, which displayed reasonable T1 relaxivity and no significant cytotoxicity at the experimental concentrations in human colon carcinoma cells (HT29) and mouse colon carcinoma cells (CT26). In vitro cell uptake experiments demonstrated that contrast agent absorption by the two types of cancer cells was concentration-dependent in the safe concentration range. During in vivo MRI, transrectal infusion of Gd-FITC-SLNs showed more significant enhancement at the tumor site compared with the infusion of Gd-DTPA in female C57/BL mice with azoxymethane/dextran sulfate sodium-induced colorectal highgrade intraepithelial neoplasia. Subsequent confocal fluorescence microscopy demonstrated Gd-FITC-SLNs as highly concentrated green fluorescent spots distributed from the tumor capsule into the tumor. This study establishes the "proof-of-principle" of a new MRI technique wherein colorectal tumors are enhanced via direct absorption or uptake of the nanoparticle contrast agent.

  15. NK-cell-dependent killing of colon carcinoma cells is mediated by natural cytotoxicity receptors (NCRs) and stimulated by parvovirus infection of target cells

    International Nuclear Information System (INIS)

    Bhat, Rauf; Rommelaere, Jean

    2013-01-01

    Investigating how the immune system functions during malignancies is crucial to developing novel therapeutic strategies. Natural killer (NK) cells, an important component of the innate immune system, play a vital role in immune defense against tumors and virus-infected cells. The poor survival rate in colon cancer makes it particularly important to develop novel therapeutic strategies. Oncolytic viruses, in addition to lysing tumor cells, may have the potential to augment antitumor immune responses. In the present study, we investigate the role of NK cells and how parvovirus H-1PV can modulate NK-cell mediated immune responses against colon carcinoma. Human NK cells were isolated from the blood of healthy donors. The cytotoxicity and antibody-mediated inhibition of NK cells were measured in chromium release assays. Phenotypic assessment of colon cancer and dendritic cells was done by FACS. The statistical significance of the results was calculated with Student’s t test (*p <0.05; **, p < 0.01; ***, p < 0.001). We show that IL-2-activated human NK cells can effectively kill colon carcinoma cells. Killing of colon carcinoma cells by NK cells was further enhanced upon infection of the former cells with parvovirus H-1PV. H-1PV has potent oncolytic activity against various tumors, yet its direct killing effect on colon carcinoma cells is limited. The cytotoxicity of NK cells towards colon carcinoma cells, both mock- and H-1PV-infected, was found to be mostly mediated by a combination of natural cytotoxicity receptors (NCRs), namely NKp30, 44, and 46. Colon carcinoma cells displayed low to moderate expression of NK cell ligands, and this expression was modulated upon H-1PV infection. Lysates of H-1PV-infected colon carcinoma cells were found to increase MHC class II expression on dendritic cells. Altogether, these data suggest that IL-2-activated NK cells actively kill colon carcinoma cells and that this killing is mediated by several natural cytotoxicity receptors

  16. Curcumin-Free Turmeric Exhibits Activity against Human HCT-116 Colon Tumor Xenograft: Comparison with Curcumin and Whole Turmeric

    Science.gov (United States)

    Prasad, Sahdeo; Tyagi, Amit K.; Siddik, Zahid H.; Aggarwal, Bharat B.

    2017-01-01

    Extensive research within last two decades has indicated that curcumin extracted from turmeric (Curcuma longa), exhibits anticancer potential, in part through the modulation of inflammatory pathways. However, the residual antitumor activity of curcumin-free turmeric (CFT) relative to curcumin or turmeric is not well-understood. In the present study, therefore, we determined activities of these agents in both in vitro and in vivo models of human HCT-116 colorectal cancer (CRC). When examined in an in vitro antiproliferative, clonogenic or anti-inflammatory assay system, we found that curcumin was highly active whereas turmeric and CFT had relatively poor activity against CRC cells. However, when examined in vivo at an oral dose of either 100 or 500 mg/kg given to nude mice bearing CRC xenografts, all three preparations of curcumin, turmeric, and CFT similarly suppressed the growth of the xenograft. The effect of CFT on suppression of tumor growth was dose-dependent, with 500 mg/kg tending to be more effective than 100 mg/kg. Interestingly, 100 mg/kg curcumin or turmeric was found to be more effective than 500 mg/kg. When examined in vivo for the expression of biomarkers associated with cell survival (cIAP-1, Bcl-2, and survivin), proliferation (Ki-67 and cyclin D1) and metastasis (ICAM-1 and VEGF), all were down-modulated. These agents also suppressed inflammatory transcription factors (NF-κB and STAT3) in tumor cells. Overall, our results with CFT provide evidence that turmeric must contain additional bioactive compounds other than curcumin that, in contrast to curcumin, exhibit greater anticancer potential in vivo than in vitro against human CRC. Moreover, our study highlights the fact that the beneficial effects of turmeric and curcumin in humans may be more effectively realized at lower doses, whereas CFT could be given at higher doses without loss in favorable activity. PMID:29311914

  17. Curcumin-Free Turmeric Exhibits Activity against Human HCT-116 Colon Tumor Xenograft: Comparison with Curcumin and Whole Turmeric

    Directory of Open Access Journals (Sweden)

    Sahdeo Prasad

    2017-12-01

    Full Text Available Extensive research within last two decades has indicated that curcumin extracted from turmeric (Curcuma longa, exhibits anticancer potential, in part through the modulation of inflammatory pathways. However, the residual antitumor activity of curcumin-free turmeric (CFT relative to curcumin or turmeric is not well-understood. In the present study, therefore, we determined activities of these agents in both in vitro and in vivo models of human HCT-116 colorectal cancer (CRC. When examined in an in vitro antiproliferative, clonogenic or anti-inflammatory assay system, we found that curcumin was highly active whereas turmeric and CFT had relatively poor activity against CRC cells. However, when examined in vivo at an oral dose of either 100 or 500 mg/kg given to nude mice bearing CRC xenografts, all three preparations of curcumin, turmeric, and CFT similarly suppressed the growth of the xenograft. The effect of CFT on suppression of tumor growth was dose-dependent, with 500 mg/kg tending to be more effective than 100 mg/kg. Interestingly, 100 mg/kg curcumin or turmeric was found to be more effective than 500 mg/kg. When examined in vivo for the expression of biomarkers associated with cell survival (cIAP-1, Bcl-2, and survivin, proliferation (Ki-67 and cyclin D1 and metastasis (ICAM-1 and VEGF, all were down-modulated. These agents also suppressed inflammatory transcription factors (NF-κB and STAT3 in tumor cells. Overall, our results with CFT provide evidence that turmeric must contain additional bioactive compounds other than curcumin that, in contrast to curcumin, exhibit greater anticancer potential in vivo than in vitro against human CRC. Moreover, our study highlights the fact that the beneficial effects of turmeric and curcumin in humans may be more effectively realized at lower doses, whereas CFT could be given at higher doses without loss in favorable activity.

  18. Gastrointestinal leiomyosarcoma - unusual sites: Esophagus, colon and porta hepatis

    International Nuclear Information System (INIS)

    Balthazar, E.J.

    1981-01-01

    This paper is based on a retrospective analysis of the radiologic findings of 6 newly proven cases of primary gastrointestinal leiomyosarcomas located in unusual sites. The radiographic and angiographic features of esophageal, colonic, and porta hepatis leiomyosarcomas are described and illustrated. General background information together with a brief review of the literature regarding these lesions are provided. The difficulties encountered in the preoperative diagnosis are explained by the protean and nonspecific clinical and radiographic features of many of these tumors. In addition, although myomatous tumors of the liver and porta hepatis are angiogaphically hypervascular, similar tumors of the colon are slight to moderately vascular, and tumors of the esophagus are avascular. (orig.)

  19. Flux analysis of the human proximal colon using anaerobic digestion model 1.

    Science.gov (United States)

    Motelica-Wagenaar, Anne Marieke; Nauta, Arjen; van den Heuvel, Ellen G H M; Kleerebezem, Robbert

    2014-08-01

    The colon can be regarded as an anaerobic digestive compartment within the gastro intestinal tract (GIT). An in silico model simulating the fluxes in the human proximal colon was developed on basis of the anaerobic digestion model 1 (ADM1), which is traditionally used to model waste conversion to biogas. Model calibration was conducted using data from in vitro fermentation of the proximal colon (TIM-2), and, amongst others, supplemented with the bio kinetics of prebiotic galactooligosaccharides (GOS) fermentation. The impact of water and solutes absorption by the host was also included. Hydrolysis constants of carbohydrates and proteins were estimated based on total short chain fatty acids (SCFA) and ammonia production in vitro. Model validation was established using an independent dataset of a different in vitro model: an in vitro three-stage continuous culture system. The in silico model was shown to provide quantitative insight in the microbial community structure in terms of functional groups, and the substrate and product fluxes between these groups as well as the host, as a function of the substrate composition, pH and the solids residence time (SRT). The model confirms the experimental observation that methanogens are washed out at low pH or low SRT-values. The in silico model is proposed as useful tool in the design of experimental setups for in vitro experiments by giving insight in fermentation processes in the proximal human colon. Copyright © 2014. Published by Elsevier Ltd.

  20. Metabolism of acyclic and cyclic N-nitroamines by cultured human colon

    DEFF Research Database (Denmark)

    Autrup, Herman; Harris, Curtis C.; Trump, Benjamin F.

    1978-01-01

    Cultured human colon mucosa was found to metabolize both acyclic and cyclic N-nitrosamines as measured by 14C-CO2 formation and reaction of the activated moieties with cellular macromolecules. Dimethylnitrosamine and N-nitrosopyrrolidine were metabolized by explants from all patients studied. A p...

  1. Red meat and colon cancer : a possible role for heme

    NARCIS (Netherlands)

    Sesink, Aloysius Lambertus Antonia

    2000-01-01

    Sporadic colon cancer is a multifactorial aging disease affected by long-term exposure to environmental risk factors. Epidemiological studies have shown that risk for colon cancer is associated with diets high in red meat and/or animal fat. The mechanisms by which colonic tumors arise are, however,

  2. [A case of transverse colon cancer mimicking urachal cancer].

    Science.gov (United States)

    Nishimura, Taku; Inoue, Ryo; Kondo, Junya; Nagashima, Yukiko; Okada, Toshimasa; Nakamura, Mitsuo; Sakata, Koichiro; Yamaguchi, Shiro; Setoguchi, Mihoko

    2013-11-01

    A 55-year-old man was admitted to our hospital because of abdominal distension. Computed tomography revealed an abscess in the anterior abdominal wall and invasion of the large intestine. Biopsy of the large intestine revealed adenocarcinoma. Immunohistochemically, the antigen expression profile of the tumor was positive for cytokeratin 7, cytokeratin 903 (34βE12), and cytokeratin 20. We diagnosed the tumor as urachal cancer and performed surgery. Examination of the resected specimen showed that the tumor was located in the transverse colon. Finally, the patient was diagnosed as having transverse colon cancer with urachal abscess.

  3. Local staging of sigmoid colon cancer using MRI

    DEFF Research Database (Denmark)

    Dam, Claus; Lindebjerg, Jan; Jakobsen, Anders

    2017-01-01

    BACKGROUND: An accurate radiological staging of colon cancer is crucial to select patients who may benefit from neoadjuvant chemotherapy. PURPOSE: To evaluate the diagnostic accuracy of preoperative magnetic resonance imaging (MRI) in identifying locally advanced sigmoid colon cancer, poor...... prognostic factors, and the inter-observer variation of the tumor apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI). MATERIAL AND METHODS: Using 1.5 T MRI with high resolution T2-weighted (T2W) imaging, DWI, and no contrast enhancement, 35 patients with sigmoid colon cancer were...... the measured mean ADC values were below 1.0 × 10(-3) mm(2)/s with an intra-class correlation coefficient in T3cd-T4 tumors of 0.85. CONCLUSION: Preoperative MRI can identify locally advanced sigmoid colon cancer and has potential as the imaging of choice to select patients for neoadjuvant chemotherapy. Initial...

  4. The humanized anti-human AMHRII mAb 3C23K exerts an anti-tumor activity against human ovarian cancer through tumor-associated macrophages.

    Science.gov (United States)

    Bougherara, Houcine; Némati, Fariba; Nicolas, André; Massonnet, Gérald; Pugnière, Martine; Ngô, Charlotte; Le Frère-Belda, Marie-Aude; Leary, Alexandra; Alexandre, Jérôme; Meseure, Didier; Barret, Jean-Marc; Navarro-Teulon, Isabelle; Pèlegrin, André; Roman-Roman, Sergio; Prost, Jean-François; Donnadieu, Emmanuel; Decaudin, Didier

    2017-11-21

    Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient's tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic efficacy of 3C23K alone and in combination with a carboplatin-paclitaxel chemotherapy in a panel of OC Patient-Derived Xenografts. In those experiments, we showed that 3C23K significantly increased the proportion and the quality of chemotherapy-based in vivo responses. Altogether, our data support the potential interest of AMHRII targeting in human ovarian cancers and the evaluation of 3C23K in further clinical trials.

  5. Assessing the potential for raw meat to influence human colonization with Staphylococcus aureus.

    Science.gov (United States)

    Carrel, Margaret; Zhao, Chang; Thapaliya, Dipendra; Bitterman, Patrick; Kates, Ashley E; Hanson, Blake M; Smith, Tara C

    2017-09-07

    The role of household meat handling and consumption in the transfer of Staphylococcus aureus (S. aureus) from livestock to consumers is not well understood. Examining the similarity of S. aureus colonizing humans and S. aureus in meat from the stores in which those individuals shop can provide insight into the role of meat in human S. aureus colonization. S. aureus isolates were collected from individuals in rural and urban communities in Iowa (n = 3347) and contemporaneously from meat products in stores where participants report purchasing meat (n = 913). The staphylococcal protein A (spa) gene was sequenced for all isolates to determine a spa type. Morisita indices and Permutational Multivariate Analysis of Variance Using Distance Matrices (PERMANOVA) were used to determine the relationship between spa type composition among human samples and meat samples. spa type composition was significantly different between households and meat sampled from their associated grocery stores. spa types found in meat were not significantly different regardless of the store or county in which they were sampled. spa types in people also exhibit high similarity regardless of residential location in urban or rural counties. Such findings suggest meat is not an important source of S. aureus colonization in shoppers.

  6. [Colorectal cancer the importance of primary tumor location].

    Science.gov (United States)

    Ryska, M; Bauer, J

    2017-01-01

    Retrospective evaluations of the relevance of primary colorectal cancer (CRC) location consistently indicate that right-sided tumors, arising in the cecum, ascending colon, hepatic bend, transverse colon and splenic flexure, are clinically, biologically and genetically different from left-sided tumors - those located in the descending colon, sigmoid colon or rectum. Location in the right-sided colon represents a negative prognostic indicator, particularly for stage III and IV carcinomas. Irrespective of treatment, the rightward location is associated with a significantly increased risk of death when compared to the left side.Key words: colorectal cancer - location - therapy - prognosis.

  7. MicroRNA-215 suppresses cell proliferation, migration and invasion of colon cancer by repressing Yin-Yang 1

    International Nuclear Information System (INIS)

    Chen, Zehong; Han, Siqi; Huang, Wensheng; Wu, Jialin; Liu, Yuyi; Cai, Shirong; He, Yulong; Wu, Suijing; Song, Wu

    2016-01-01

    Colorectal cancer is one of the most common malignant tumors worldwide with rising incidence. MicroRNAs are small non-coding RNAs that implicate in multiple physiological or pathological processes. The aberrant expression of miRNA-215 (miR-215) has been illustrated in various types of cancers. However, the expression of miR-215 in human colon cancer and the biological roles of it remain largely unknown. We conducted this study to explore the expression and the function of miR-215 in human colon cancer. The results showed that miR-215 was remarkably downregulated in colon cancer tissues and cell lines. Overexpression of miR-215 by miR-215 mimic significantly inhibited colon cancer cell proliferation, migration and invasion while knockdown of miR-215 by miR-215 inhibitor exerted reverse effects. Furthermore, we newly identified Yin-Yang 1(YY1) as a direct target of miR-215 which could rescue the effects of miR-215 on colon cancer cells. In summary, our investigation revealed that miR-215 was downregulated in colon cancer and it suppressed colon cancer cell proliferation, migration and invasion by directly targeting YY1. - Highlights: • MiR-215 expression was decreased in colon cancer tissues and cell lines. • Mir-215 inhibited colon cancer cell proliferation, migration and invasion. • MiR-215 targeted YY1 directly. • The effects of miR-215 on colon cancer cells were mediated by YY1.

  8. Regulation of APC and AXIN2 expression by intestinal tumor suppressor CDX2 in colon cancer cells

    DEFF Research Database (Denmark)

    Olsen, Anders Krüger; Coskun, Mehmet; Bzorek, Michael

    2013-01-01

    was associated with endogenous downregulation of APC and AXIN2 expression in Caco-2 cells but did not affect GSK3β expression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results......Wnt signaling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found to be transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signaling......-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3β in migrating colon cancer cells at the invasive front. CDX2-bound promoter and enhancer regions from APC, AXIN2 and GSK3β were analyzed for gene regulatory activity...

  9. Effects of treatment with antimicrobial agents on the human colonic microflora

    Directory of Open Access Journals (Sweden)

    Fatemeh Rafii

    2008-12-01

    Full Text Available Fatemeh Rafii, John B Sutherland, Carl E CernigliaDivision of Microbiology, National Center for Toxicological Research, FDA, Jefferson, AR, USAAbstract: Antimicrobial agents are the most valuable means available for treating bacterial infections. However, the administration of therapeutic doses of antimicrobial agents to patients is a leading cause of disturbance of the normal gastrointestinal microflora. This disturbance results in diminishing the natural defense mechanisms provided by the colonic microbial ecosystem, making the host vulnerable to infection by commensal microorganisms or nosocomial pathogens. In this minireview, the impacts of antimicrobials, individually and in combinations, on the human colonic microflora are discussed.Keywords: antibiotics, intestinal bacteria

  10. Clinicopathologic factors identify sporadic mismatch repair-defective colon cancers

    DEFF Research Database (Denmark)

    Halvarsson, Britta; Anderson, Harald; Domanska, Katarina

    2008-01-01

    Identification of sporadic mismatch repair (MMR)-defective colon cancers is increasingly demanded for decisions on adjuvant therapies. We evaluated clinicopathologic factors for the identification of these prognostically favorable tumors. Histopathologic features in 238 consecutive colon cancers...

  11. Procedural difficulty differences according to tumor location do not compromise the clinical outcome of laparoscopic complete mesocolic excision for colon cancer: a retrospective analysis.

    Science.gov (United States)

    Kim, Min Ki; Lee, In Kyu; Kye, Bong-Hyeon; Kim, Jun-Gi

    2017-09-08

    Laparoscopic colectomy procedures and their corresponding difficulty levels may vary depending on the tumor location within the colon, and a laparoscopic complete mesocolic excision (CME) with central vascular ligation (CVL) would require more proficiency than a conventional laparoscopic colectomy. We aimed to report our laparoscopic CME with CVL data and to investigate the clinical outcome differences of laparoscopic CME with CVL by various tumor sub-site locations. Prospectively collected clinical data of consecutive patients who received laparoscopic colectomy for primary colon cancer between April 1995 and December 2010 from single surgeon were retrospectively reviewed. All of the included surgery was performed on the basis of CME with CVL principle with no-touch isolation technique. Data were analyzed and compared among three groups; patients who received right or extended right hemicolectomy (group A, n = 142), transverse colectomy or left or extended left hemicolectomy (group B, n = 59), and sigmoidectomy or anterior resection (group C, n = 210). Female patients were more common in group A (53.5% vs. 37.3% vs. 39.5%, p = 0.020). Other baseline characteristics were comparable. Operative time was shorter in group C than the other groups (309.0 ± 74.7 vs. 324.3 ± 89.1 vs. 280.1 ± 93.1 min, p = 0.000). There was no significant difference among groups in perioperative complication and patient recovery. Five-year overall survival, disease-free survival and local recurrence rate showed no difference for a median follow up period of 73 (1-120) months. In conclusion, laparoscopic tumor-specific CME and CVL for colon cancer can be performed with comparable short- and long-term outcomes regardless of tumor sub-site location except for the operative time.

  12. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581.

    Science.gov (United States)

    Venook, Alan P; Niedzwiecki, Donna; Lopatin, Margarita; Ye, Xing; Lee, Mark; Friedman, Paula N; Frankel, Wendy; Clark-Langone, Kim; Millward, Carl; Shak, Steven; Goldberg, Richard M; Mahmoud, Najjia N; Warren, Robert S; Schilsky, Richard L; Bertagnolli, Monica M

    2013-05-10

    A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.

  13. Preclinical Characterization of a Novel Monoclonal Antibody NEO-201 for the Treatment of Human Carcinomas

    Directory of Open Access Journals (Sweden)

    Massimo Fantini

    2018-01-01

    Full Text Available NEO-201 is a novel humanized IgG1 monoclonal antibody that was derived from an immunogenic preparation of tumor-associated antigens from pooled allogeneic colon tumor tissue extracts. It was found to react against a variety of cultured human carcinoma cell lines and was highly reactive against the majority of tumor tissues from many different carcinomas, including colon, pancreatic, stomach, lung, and breast cancers. NEO-201 also exhibited tumor specificity, as the majority of normal tissues were not recognized by this antibody. Functional assays revealed that treatment with NEO-201 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC and complement-dependent cytotoxicity (CDC against tumor cells. Furthermore, the growth of human pancreatic xenograft tumors in vivo was largely attenuated by treatment with NEO-201 both alone and in combination with human peripheral blood mononuclear cells as an effector cell source for ADCC. In vivo biodistribution studies in human tumor xenograft-bearing mice revealed that NEO-201 preferentially accumulates in the tumor but not organ tissue. Finally, a single-dose toxicity study in non-human primates demonstrated safety and tolerability of NEO-201, as a transient decrease in circulating neutrophils was the only related adverse effect observed. These findings indicate that NEO-201 warrants clinical testing as both a novel diagnostic and therapeutic agent for the treatment of a broad variety of carcinomas.

  14. Matrix Stiffness Corresponding to Strictured Bowel Induces a Fibrogenic Response in Human Colonic Fibroblasts

    Science.gov (United States)

    Johnson, Laura A.; Rodansky, Eva S.; Sauder, Kay L.; Horowitz, Jeffrey C.; Mih, Justin D.; Tschumperlin, Daniel J.; Higgins, Peter D.

    2013-01-01

    Background Crohn’s disease is characterized by repeated cycles of inflammation and mucosal healing which ultimately progress to intestinal fibrosis. This inexorable progression towards fibrosis suggests that fibrosis becomes inflammation-independent and auto-propagative. We hypothesized that matrix stiffness regulates this auto-propagation of intestinal fibrosis. Methods The stiffness of fresh ex vivo samples from normal human small intestine, Crohn’s disease strictures, and the unaffected margin were measured with a microelastometer. Normal human colonic fibroblasts were cultured on physiologically normal or pathologically stiff matrices corresponding to the physiological stiffness of normal or fibrotic bowel. Cellular response was assayed for changes in cell morphology, α-smooth muscle actin (αSMA) staining, and gene expression. Results Microelastometer measurements revealed a significant increase in colonic tissue stiffness between normal human colon and Crohn’s strictures as well as between the stricture and adjacent tissue margin. In Ccd-18co cells grown on stiff matrices corresponding to Crohn’s strictures, cellular proliferation increased. Pathologic stiffness induced a marked change in cell morphology and increased αSMA protein expression. Growth on a stiff matrix induced fibrogenic gene expression, decreased matrix metalloproteinase and pro-inflammatory gene expression, and was associated with nuclear localization of the transcriptional cofactor MRTF-A. Conclusions Matrix stiffness, representative of the pathological stiffness of Crohn’s strictures, activates human colonic fibroblasts to a fibrogenic phenotype. Matrix stiffness affects multiple pathways suggesting the mechanical properties of the cellular environment are critical to fibroblast function and may contribute to autopropagation of intestinal fibrosis in the absence of inflammation, thereby contributing to the intractable intestinal fibrosis characteristic of Crohn’s disease. PMID

  15. Yttrium-90 used to treat colon cancer: Awaiting investigational new drug approval

    International Nuclear Information System (INIS)

    Anon.

    1991-01-01

    A new radiation treatment takes just 14 to 21 days to shrink colorectal tumors in laboratory mice, is under review for clinical trials with human cancer patients. The treatment has succeeded in reducing the size of tumors by up to 95%. Colon cancer, the second leading cause of cancer deaths in the US, is extremely difficult to treat unless it is detected early enough for surgical procedures. In laboratory tests over the last 5 years, a team of researchers has developed the treatment using yttrium-90. The yttrium-90 is transported to the tumors by attaching it to monoclonal antibodies that seek out the cancer cells. Once the radioisotope has been targeted to the tumor, the radiation destroys many of the cells, dramatically reducing the size of the tumor. Since this treatment usually does not completely eliminate all the cancer cells, it cannot be called a cure, but it does seem to be an effective method of shrinking colorectal tumors

  16. Coated metal stents installation for the treatment of malignant tumors complicated with colonic and rectal fistula

    International Nuclear Information System (INIS)

    Mao Aiwu; Fang Shiming; Liu Shiyi; Lin Qing; Jiang Haosheng; Jia Yiping; Gao Zhongdu

    2007-01-01

    Objective: To probe the clinical features of malignant colonic and rectal tumors together with coated metal stent placement. Methods: 24 cases of colonic fistula with late stage malignant tumors including 16 cases of intestinal cancer(66.7%), 2 cases of gastric and cervical cancers respectively(8.3%); 1 case of bladder, 1 case of prostate, 1 case of ovary and 1 case of gallbladder cancer(4.2%). The cause for the fistulas were direct invasion (37.5% )and radiotherapy (62.5%). The KPS was 30-60, and the median value was 40. CT were done preoperatively and followed by radiography of canulation contrast medium enema to ensure the location of the orifice of the fistula, the route of intestinal canal or complicated with obstruction and the condition with nearby tissues. Stents were finally implanted specifically according to the different situations of intestines. The sites of implanted stents and the occlusion of fistula should be strictly scrutinized; and then with careful follow up of patients complications and general condition. The procedure was carried out practically in 23 cases. Results: The successful rate of technique reached 96%(22/23), the failed one was due to the curve over sharpness of intestinal lock and resulting in non-expansion of the stent. The clinical successful rate was 91.3%. The two failed cased included the one with improper coherence to the intestinal wall leading to the stent migration and the other with a mild leakage after stent placement. The follow-up duration were 28-365 days, average 109 days, and the median value was 92 days. The average surviving period of 3 months and 6 months were 51% and 11% respectively. Conclusion: Intestinal fistula is the common complication after intestinal tumor operation and radiotherapy with poor prognosis. Metal covered stents provide a therapy of choice to improve the life quality and prolong the life span. (authors)

  17. Combination of capecitabine and ludartin inhibits colon cancer ...

    African Journals Online (AJOL)

    Methods: Mice model of colon cancer was used in this study. Quantitative ... mRNA. Micro-vessel density was assessed using immunohistochemical analysis. ... increase in white blood cell (WBC) count, and increased median survival time of colon cancer mice from ..... tumor cells is associated with the development of.

  18. Differential diagnosis and cancer staging of a unique case with multiple nodules in the lung - lung adenocarcinoma, metastasis of colon adenocarcinoma, and colon adenocarcinoma metastasizing to lung adenocarcinoma.

    Science.gov (United States)

    Bai, Yun; Qiu, Jianxing; Shang, Xueqian; Liu, Ping; Zhang, Ying; Wang, Ying; Xiong, Yan; Li, Ting

    2015-05-01

    Lung cancer is the most common cancer in the world. Despite this, there have been few cases of simultaneous primary and metastatic cancers in the lung reported, let alone coexisting with tumor-to-tumor metastasis. Herein, we describe an extremely unusual case. A 61-year-old man with a history of colon adenocarcinoma was revealed as having three nodules in the lung 11 months after colectomy. The nodule in the left upper lobe was primary lung adenocarcinoma, the larger one in the right upper lobe was a metastasis of colon adenocarcinoma, and the smaller one in the right upper lobe was colon adenocarcinoma metastasizing to lung adenocarcinoma. Our paper focused on the differential diagnosis and cancer staging of this unique case, and discussed the uncommon phenomenon of the lung acting as a recipient in tumor-to-tumor metastasis.

  19. Comparison of oncological outcomes of right-sided colon cancer versus left-sided colon cancer after curative resection: Which side is better outcome?

    Science.gov (United States)

    Lim, Dae Ro; Kuk, Jung Kul; Kim, Taehyung; Shin, Eung Jin

    2017-10-01

    There are embryological origins, anatomical, histological, genetic, and immunological differences between right-sided colon cancer (RCC) and left-sided colon cancer (LCC). Many studies have sought to determine the survival and prognosis according to tumor location. This study aimed to analyze outcomes between RCC and LCC. Between January 2000 and December 2012, data on 414 patients who underwent curative resection for RCC and LCC were retrieved from a retrospective database. Propensity score matching (1:1) was performed and RCC was identified in 207 and LCC in 207 patients. On average, RCC exhibited a more advanced N stage, increased tumor size, more frequently poorly differentiated tumors, more harvested lymph nodes, and more positivity of lymphovascular invasion than LCC. With a median follow-up of 66.7 months, the 5-year overall survival (OS) rates for RCC and LCC were 82.1% and 88.7%, respectively, (P cancers, the DFS rates were 61.1% (RCC) and 81.9% (LCC; P colon cancer is needed.

  20. Multifaceted Interpretation of Colon Cancer Stem Cells.

    Science.gov (United States)

    Hatano, Yuichiro; Fukuda, Shinya; Hisamatsu, Kenji; Hirata, Akihiro; Hara, Akira; Tomita, Hiroyuki

    2017-07-05

    Colon cancer is one of the leading causes of cancer-related deaths worldwide, despite recent advances in clinical oncology. Accumulating evidence sheds light on the existence of cancer stem cells and their role in conferring therapeutic resistance. Cancer stem cells are a minor fraction of cancer cells, which enable tumor heterogeneity and initiate tumor formation. In addition, these cells are resistant to various cytotoxic factors. Therefore, elimination of cancer stem cells is difficult but essential to cure the malignant foci completely. Herein, we review the recent evidence for intestinal stem cells and colon cancer stem cells, methods to detect the tumor-initiating cells, and clinical significance of cancer stem cell markers. We also describe the emerging problems of cancer stem cell theory, including bidirectional conversion and intertumoral heterogeneity of stem cell phenotype.

  1. STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH{sup +}/CD133{sup +} stem cell-like human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Li, E-mail: lin.796@osu.edu [Center for Childhood Cancer, The Research Institute at Nationwide Children' s Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205 (United States); Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China); Fuchs, James; Li, Chenglong [Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210 (United States); Olson, Veronica [Center for Childhood Cancer, The Research Institute at Nationwide Children' s Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205 (United States); Bekaii-Saab, Tanios [Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210 (United States); Lin, Jiayuh, E-mail: lin.674@osu.edu [Center for Childhood Cancer, The Research Institute at Nationwide Children' s Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205 (United States)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells. Black-Right-Pointing-Pointer STAT3 inhibitor, FLLL32 inhibits P-STAT3 and STAT3 target genes in colon cancer stem-like cells. Black-Right-Pointing-Pointer Inhibition of STAT3 resulted in decreased cell viability and reduced numbers of tumorspheres. Black-Right-Pointing-Pointer STAT3 is required for survival and tumorsphere forming capacity in colon cancer stem-like cells. Black-Right-Pointing-Pointer Targeting STAT3 in cancer stem-like cells may offer a novel treatment approach for colon cancer. -- Abstract: Persistent activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in colon cancer. Increasing evidence suggests the existence of a small population of colon cancer stem or cancer-initiating cells may be responsible for tumor initiation, metastasis, and resistance to chemotherapy and radiation. Whether STAT3 plays a role in colon cancer-initiating cells and the effect of STAT3 inhibition is still unknown. Flow cytometry was used to isolate colon cancer stem-like cells from three independent human colon cancer cell lines characterized by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulation (ALDH{sup +}/CD133{sup +}). The effects of STAT3 inhibition in colon cancer stem-like cells were examined. The phosphorylated or activated form of STAT3 was expressed in colon cancer stem-like cells and was reduced by a STAT3-selective small molecular inhibitor, FLLL32. FLLL32 also inhibited the expression of potential STAT3 downstream target genes in colon cancer stem-like cells including survivin, Bcl-XL, as well as Notch-1, -3, and -4, which may be involved in stem cell function. Furthermore, FLLL32 inhibited cell viability and tumorsphere formation as well as induced cleaved caspase-3 in colon cancer stem-like cells. FLLL32 is more potent than curcumin as evidenced with lower

  2. Distribution of some elements in human colon mucosa

    International Nuclear Information System (INIS)

    Drashkovich, R.J.

    1985-01-01

    The contents of Co, Zn, Fe, Cr and Sb were determined in human colon mucosa as a function of pathalogical alterations during development of colitis Chronica, Colitis Ulcerosa, Adenoma Tubulare and Adenocarcinoma. The sample (0.00023-0.00087 kg in weight) from 80 patients were taken during rectosigmoidoscopy by teflon coated forceps and were deep frozen (T=244 deg. K) and liophilysed. A thermal neutron fluxes 0.54-1.85x10 17 n/m 2 .s for 3 days and 4096-channel analyser with a Ge(Li) detector

  3. Basally activated nonselective cation currents regulate the resting membrane potential in human and monkey colonic smooth muscle

    Science.gov (United States)

    Dwyer, Laura; Rhee, Poong-Lyul; Lowe, Vanessa; Zheng, Haifeng; Peri, Lauren; Ro, Seungil; Sanders, Kenton M.

    2011-01-01

    Resting membrane potential (RMP) plays an important role in determining the basal excitability of gastrointestinal smooth muscle. The RMP in colonic muscles is significantly less negative than the equilibrium potential of K+, suggesting that it is regulated not only by K+ conductances but by inward conductances such as Na+ and/or Ca2+. We investigated the contribution of nonselective cation channels (NSCC) to the RMP in human and monkey colonic smooth muscle cells (SMC) using voltage- and current-clamp techniques. Qualitative reverse transcriptase-polymerase chain reaction was performed to examine potential molecular candidates for these channels among the transient receptor potential (TRP) channel superfamily. Spontaneous transient inward currents and holding currents were recorded in human and monkey SMC. Replacement of extracellular Na+ with equimolar tetraethylammonium or Ca2+ with Mn2+ inhibited basally activated nonselective cation currents. Trivalent cations inhibited these channels. Under current clamp, replacement of extracellular Na+ with N-methyl-d-glucamine or addition of trivalent cations caused hyperpolarization. Three unitary conductances of NSCC were observed in human and monkey colonic SMC. Molecular candidates for basally active NSCC were TRPC1, C3, C4, C7, M2, M4, M6, M7, V1, and V2 in human and monkey SMC. Comparison of the biophysical properties of these TRP channels with basally active NSCC (bINSCC) suggests that TRPM4 and specific TRPC heteromultimer combinations may underlie the three single-channel conductances of bINSCC. In conclusion, these findings suggest that basally activated NSCC contribute to the RMP in human and monkey colonic SMC and therefore may play an important role in determining basal excitability of colonic smooth muscle. PMID:21566016

  4. Mouse model of proximal colon-specific tumorigenesis driven by microsatellite instability-induced Cre-mediated inactivation of Apc and activation of Kras.

    Science.gov (United States)

    Kawaguchi, Yasuo; Hinoi, Takao; Saito, Yasufumi; Adachi, Tomohiro; Miguchi, Masashi; Niitsu, Hiroaki; Sasada, Tatsunari; Shimomura, Manabu; Egi, Hiroyuki; Oka, Shiro; Tanaka, Shinji; Chayama, Kazuaki; Sentani, Kazuhiro; Oue, Naohide; Yasui, Wataru; Ohdan, Hideki

    2016-05-01

    KRAS gene mutations are found in 40-50% of colorectal cancer cases, but their functional contribution is not fully understood. To address this issue, we generated genetically engineered mice with colon tumors expressing an oncogenic Kras(G12D) allele in the context of the Adenomatous polyposis coli (Apc) deficiency to compare them to tumors harboring Apc deficiency alone. CDX2P9.5-G22Cre (referred to as G22Cre) mice showing inducible Cre recombinase transgene expression in the proximal colon controlled under the CDX2 gene promoter were intercrossed with Apc (flox/flox) mice and LSL-Kras (G12D) mice carrying loxP-flanked Apc and Lox-Stop-Lox oncogenic Kras(G12D) alleles, respectively, to generate G22Cre; Apc(flox/flox); Kras(G12D) and G22Cre; Apc(flox/flox); KrasWT mice. Gene expression profiles of the tumors were analyzed using high-density oligonucleotide arrays. Morphologically, minimal difference in proximal colon tumor was observed between the two mouse models. Consistent with previous findings in vitro, Glut1 transcript and protein expression was up-regulated in the tumors of G22Cre;Apc (flox/flox) ; Kras(G12D) mice. Immunohistochemical staining analysis revealed that GLUT1 protein expression correlated with KRAS mutations in human colorectal cancer. Microarray analysis identified 11 candidate genes upregulated more than fivefold and quantitative PCR analysis confirmed that Aqp8, Ttr, Qpct, and Slc26a3 genes were upregulated 3.7- to 30.2-fold in tumors with mutant Kras. These results demonstrated the validity of the G22Cre; Apc(flox/flox) ;Kras (G12D) mice as a new mouse model with oncogenic Kras activation. We believe that this model can facilitate efforts to define novel factors that contribute to the pathogenesis of human colorectal cancer with KRAS mutations.

  5. Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings

    International Nuclear Information System (INIS)

    Bieche, Ivan; Marangoni, Elisabetta; Roman-Roman, Sergio; Decaudin, Didier; Dangles-Marie, Virginie; Vacher, Sophie; Vallerand, David; Richon, Sophie; Hatem, Rana; De Plater, Ludmilla; Dahmani, Ahmed; Némati, Fariba; Angevin, Eric

    2014-01-01

    Tumor endothelial transdifferentiation and VEGFR1/2 expression by cancer cells have been reported in glioblastoma but remain poorly documented for many other cancer types. To characterize vasculature of patient-derived tumor xenografts (PDXs), largely used in preclinical anti-angiogenic assays, we designed here species-specific real-time quantitative RT-PCR assays. Human and mouse PECAM1/CD31, ENG/CD105, FLT1/VEGFR1, KDR/VEGFR2 and VEGFA transcripts were analyzed in a large series of 150 PDXs established from 8 different tumor types (53 colorectal, 14 ovarian, 39 breast and 15 renal cell cancers, 6 small cell and 5 non small cell lung carcinomas, 13 cutaneous melanomas and 5 glioblastomas) and in two bevacizumab-treated non small cell lung carcinomas xenografts. As expected, mouse cell proportion in PDXs -evaluated by quantifying expression of the housekeeping gene TBP- correlated with all mouse endothelial markers and human VEGFA RNA levels. More interestingly, we observed human PECAM1/CD31 and ENG/CD105 expression in all tumor types, with higher rate in glioblastoma and renal cancer xenografts. Human VEGFR expression profile varied widely depending on tumor types with particularly high levels of human FLT1/VEGFR1 transcripts in colon cancers and non small cell lung carcinomas, and upper levels of human KDR/VEGFR2 transcripts in non small cell lung carcinomas. Bevacizumab treatment induced significant low expression of mouse Pecam1/Cd31, Eng/Cd105, Flt1/Vegfr1 and Kdr/Vefr2 while the human PECAM1/CD31 and VEGFA were upregulated. Taken together, our results strongly suggest existence of human tumor endothelial cells in all tumor types tested and of both stromal and tumoral autocrine VEGFA-VEGFR1/2 signalings. These findings should be considered when evaluating molecular mechanisms of preclinical response and resistance to tumor anti-angiogenic strategies

  6. Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas

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    Li Jing

    2011-06-01

    Full Text Available Abstract Background HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. Methods HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. Results Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P (P > 0.05. Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P (P = 0.146. No correlation between HER-2/neu and VEGF expression was detected (P = 0.151. Conclusions HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.

  7. Fractional laser exposure induces neutrophil infiltration (N1 phenotype into the tumor and stimulates systemic anti-tumor immune response.

    Directory of Open Access Journals (Sweden)

    Masayoshi Kawakubo

    Full Text Available Ablative fractional photothermolysis (aFP using a CO2 laser generates multiple small diameter tissue lesions within the irradiation field. aFP is commonly used for a wide variety of dermatological indications, including treatment of photodamaged skin and dyschromia, drug delivery and modification of scars due to acne, surgical procedures and burns. In this study we explore the utility of aFP for treating oncological indications, including induction of local tumor regression and inducing anti-tumor immunity, which is in marked contrast to current indications of aFP.We used a fractional CO2 laser to treat a tumor established by BALB/c colon carcinoma cell line (CT26.CL25, which expressed a tumor antigen, beta-galactosidase (beta-gal. aFP treated tumors grew significantly slower as compared to untreated controls. Complete remission after a single aFP treatment was observed in 47% of the mice. All survival mice from the tumor inoculation rejected re-inoculation of the CT26.CL25 colon carcinoma cells and moreover 80% of the survival mice rejected CT26 wild type colon carcinoma cells, which are parental cells of CT26.CL25 cells. Histologic section of the FP-treated tumors showed infiltrating neutrophil in the tumor early after aFP treatment. Flow cytometric analysis of tumor-infiltrating lymphocytes showed aFP treatment abrogated the increase in regulatory T lymphocyte (Treg, which suppresses anti-tumor immunity and elicited the expansion of epitope-specific CD8+ T lymphocytes, which were required to mediate the tumor-suppressing effect of aFP.We have demonstrated that aFP is able to induce a systemic anti-tumor adaptive immunity preventing tumor recurrence in a murine colon carcinoma in a mouse model. This study demonstrates a potential role of aFP treatments in oncology and further studies should be performed.

  8. Characterization of novel tumor stroma markers identified by gene expression profiling of human cancer tissues and 3D co-culture models

    International Nuclear Information System (INIS)

    Rupp, C.

    2010-01-01

    The tumor stroma plays an important role in tumorigenesis. During cancer progression it undergoes changes in architecture, gene expression and secretion of proteolytic enzymes that are essential for the invasive and metastatic phenotype of malignant tumors. Cancer associated fibroblasts (Cafes) represent the major cellular component of the stroma and recent studies demonstrated the prognostic and therapeutic significance of CaF-related molecular signatures. The identification and characterization of genes and signaling pathways involved in the molecular interactions between tumor and stromal cells has been the focus of this study. For that purpose we have used two complementary approaches: the identification of novel tumor stroma targets in human colon cancer samples using whole genome Affymetrix GeneChip analysis and the validation of theses targets in a newly established of 3D co-culture model that mimics the cellular and molecular heterogeneity of human cancers. We have demonstrated increased expression of gene sets related to hypoxia, epithelial-to-mesenchymal transition (EMT) and TGFβ pathway activation in CAFs vs their normal counterparts in both systems. The putative TGFβ target IGFBP7 (insulin-like growth factor binding protein 7) was identified as a tumor stroma marker of epithelial cancers and as a tumor antigen in mesenchyme-derived sarcomas. IGFPB7 was shown to promote anchorage-independent growth in malignant mesenchymal cells and malignant epithelial cells with an EMT-phenotype, whereas a tumor suppressor function was observed in tumor epithelial cells. In summary, we have demonstrated that a number of important signaling pathways involved in cancer progression and metastasis are specifically dysregulated in the tumor stroma both in our in vivo screen and in the in vitro 3D model, illustrating the value of these approaches for the identification and characterization of novel stromal markers. (author) [de

  9. Nasal colonization of humans with methicillin-resistant Staphylococcus aureus (MRSA CC398 with and without exposure to pigs.

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    Christiane Cuny

    Full Text Available BACKGROUND: Studies in several European countries and in North America revealed a frequent nasal colonization of livestock with MRSA CC398 and also in humans with direct professional exposure to colonized animals. The study presented here addresses the question of further transmission to non exposed humans. METHODS: After selecting 47 farms with colonized pigs in different regions of Germany we sampled the nares of 113 humans working daily with pigs and of their 116 non exposed family members. The same was performed in 18 veterinarians attending pig farms and in 44 of their non exposed family members. For investigating transmission beyond families we samples the nares of 462 pupils attending a secondary school in a high density pig farming area. MRSA were detected by direct culture on selective agar. The isolates were typed by means of spa-sequence typing and classification of SCCmec elements. For attribution of spa sequence types to clonal lineages as defined by multi locus sequence typing we used the BURP algorithm. Antibiotic susceptibility testing was performed by microbroth dilution assay. RESULTS: At the farms investigated 86% of humans exposed and only 4.3% of their family members were found to carry MRSA exhibiting spa-types corresponding to clonal complex CC398. Nasal colonization was also found in 45% of veterinarians caring for pig farms and in 9% of their non exposed family members. Multivariate analysis revealed that antibiotic usage prior to sampling beard no risk with respect to colonization. From 462 pupils only 3 were found colonized, all 3 were living on pig farms. CONCLUSION: These results indicate that so far the dissemination of MRSA CC398 to non exposed humans is infrequent and probably does not reach beyond familial communities.

  10. Methylselenol, a selenium metabolite, modulates p53 pathway and inhibits the growth of colon cancer xenografts in Balb/c mice.

    Science.gov (United States)

    Zeng, Huawei; Cheng, Wen-Hsing; Johnson, Luann K

    2013-05-01

    It is has been hypothesized that methylselenol is a critical selenium metabolite for anticancer activity in vivo. In this study, we used a protein array which contained 112 different antibodies known to be involved in the p53 pathway to investigate the molecular targets of methylselenol in human HCT116 colon cancer cells. The array analysis indicated that methylselenol exposure changed the expression of 11 protein targets related to the regulation of cell cycle and apoptosis. Subsequently, we confirmed these proteins with the Western blotting approach, and found that methylselenol increased the expression of GADD 153 and p21 but reduced the level of c-Myc, E2F1 and Phos p38 MAP kinase. Similar to our previous report on human HCT116 colon cancer cells, methylselenol also inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase in mouse colon cancer MC26 cells. When the MC26 cells were transplanted to their immune-competent Balb/c mice, methylselenol-treated MC26 cells had significantly less tumor growth potential than that of untreated MC26 cells. Taken together, our data suggest that methylselenol modulates the expression of key genes related to cell cycle and apoptosis and inhibits colon cancer cell proliferation and tumor growth. Copyright © 2013. Published by Elsevier Inc.

  11. Intrabiliary growth of recurrent tumor after percutaneous RF ablation for treating liver metastasis from colon cancer: a case report

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    Lee, Youn Kyung; Kim, Seung Kwon; Hong, Hyun Pyo [Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2007-12-15

    A 64-year-old man who underwent right hemicolectomy 3.5 years ago for ascending colon cancer and then RF ablation for two metastatic nodules in the liver was admitted to our hospital with a new metastatic nodule in the S6/7 segment of the liver. The CT scan showed a low attenuating metastatic nodule 2.2 cm in diameter in the S6/7 segment of the liver, and the liver showed peripheral bile duct dilatation. This nodule was treated with percutaneous RF ablation. A follow-up CT seven months after RF ablation showed the presence of a viable tumor in the RF ablation zone, with tumor extension along the dilated bile duct. These findings were confirmed on the resected specimen.

  12. RET is a potential tumor suppressor gene in colorectal cancer

    Science.gov (United States)

    Luo, Yanxin; Tsuchiya, Karen D.; Park, Dong Il; Fausel, Rebecca; Kanngurn, Samornmas; Welcsh, Piri; Dzieciatkowski, Slavomir; Wang, Jianping; Grady, William M.

    2012-01-01

    Cancer arises as the consequence of mutations and epigenetic alterations that activate oncogenes and inactivate tumor suppressor genes. Through a genome-wide screen for methylated genes in colon neoplasms, we identified aberrantly methylated RET in colorectal cancer. RET, a transmembrane receptor tyrosine kinase and a receptor for the GDNF-family ligands, was one of the first oncogenes to be identified and has been shown to be an oncogene in thyroid cancer and pheochromocytoma. However, unexpectedly, we found RET is methylated in 27% of colon adenomas and in 63% of colorectal cancers, and now provide evidence that RET has tumor suppressor activity in colon cancer. The aberrant methylation of RET correlates with decreased RET expression, whereas the restoration of RET in colorectal cancer cell lines results in apoptosis. Furthermore, in support of a tumor suppressor function of RET, mutant RET has also been found in primary colorectal cancer. We now show that these mutations inactivate RET, which is consistent with RET being a tumor suppressor gene in the colon. These findings suggest that the aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation and that RET can serve as a tumor suppressor gene in the colon. Moreover, the increased frequency of methylated RET in colon cancers compared to adenomas suggests RET inactivation is involved in the progression of colon adenomas to cancer. PMID:22751117

  13. Sigma and opioid receptors in human brain tumors

    International Nuclear Information System (INIS)

    Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J.

    1990-01-01

    Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using [ 3 H] 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: μ, [D-ala 2 , mePhe 4 , gly-ol 5 ] enkephalin (DAMGE); κ, ethylketocyclazocine (EKC) or U69,593; δ, [D-pen 2 , D-pen 5 ] enkephalin (DPDPE) or [D-ala 2 , D-leu 5 ] enkephalin (DADLE) with μ suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. κ opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed

  14. Proliferating cell nuclear antigen (PCNA): a new marker to study human colonic cell proliferation.

    OpenAIRE

    Kubben, F J; Peeters-Haesevoets, A; Engels, L G; Baeten, C G; Schutte, B; Arends, J W; Stockbrügger, R W; Blijham, G H

    1994-01-01

    Immunohistochemistry of the S phase related proliferating cell nuclear antigen (PCNA) was studied as an alternative to ex-vivo bromodeoxyuridine (BrdU) immunohistochemistry for assessment of human colonic cell proliferation. From 16 subjects without colonic disease biopsy specimens were collected from five different sites along the colorectum and processed for BrdU and PCNA immunohistochemistry. The mean proliferation index of PCNA was significantly higher at 133% of the value obtained with B...

  15. A kinetic model to study the regulation of β-catenin, APC, and Axin in the human colonic crypt.

    Science.gov (United States)

    Emerick, Brooks; Schleiniger, Gilberto; Boman, Bruce M

    2017-11-01

    The Wnt/[Formula: see text]-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The balance between [Formula: see text]-catenin and APC along the crypt axis determines its normal functionality. The mechanism that deregulates this balance may give insight into the initiation of colorectal cancer. This is significant because the spatial dysregulation of [Formula: see text]-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. We consider a regulatory function that promotes APC synthesis within the cell and its effect on the accumulation of the Wnt target protein, [Formula: see text]-catenin. It is evident that an APC gradient exists along the crypt axis; however, the mechanism by which APC expression is regulated within the cell is not well known. We investigate the dynamics of an APC regulatory mechanism with an increased level of Axin at the subcellular level. Model output shows an increase of APC for a diminished Wnt signal, which explains the APC gradient along the crypt. We find that the dynamic interplay between [Formula: see text]-catenin, APC, and Axin produces oscillatory behavior, which is controlled by the Wnt stimulus. In the presence of reduced functional APC, the oscillations are amplified, which suggests that the cell remains in a more proliferative state for longer periods of time. Increased Axin levels (typical of mammalian cells) reduce oscillatory behavior and minimize the levels of [Formula: see text]-catenin within the cell while raising the levels of APC.

  16. Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression.

    Science.gov (United States)

    Zhai, Hui-Yuan; Sui, Ming-Hua; Yu, Xiao; Qu, Zhen; Hu, Jin-Chen; Sun, Hai-Qing; Zheng, Hai-Tao; Zhou, Kai; Jiang, Li-Xin

    2016-09-16

    BACKGROUND Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. MATERIAL AND METHODS qRT-PCR was used to analyze the expression level of TUG1 and p63 in 75 colon cancer tissues and the matched adjacent non-tumor tissue. In vitro, cultured colon cancer cell lines HCT-116 and LoVo were used as cell models. TUG1 and p63 were silenced via transferring siRNA into HCT-116 or LoVo. The effects of TUG1 were investigated by examining cell proliferation, apoptosis, and migration. RESULTS Among the 75 colon cancer cases, the expression of TUG1 was significantly higher in colon cancer tissues compared with the matched adjacent non-tumor tissue, while p63 expression was lower in the tumor tissue. In HCT-116 and LoVo, the expression of TUG1 was significantly increased by p63 siRNA transfection. Furthermore, down-regulation of TUG1 by siRNA significantly inhibited the cell proliferation and promoted colon cancer cell apoptosis. In addition, inhibition of TUG1 expression significantly blocked the cell migration ability of colon cancer cells. CONCLUSIONS LncRNA TUG1 may serve as a potential oncogene for colon cancer. Overexpressed TUG1 may contribute to promoting cell proliferation and migration in colon cancer cells.

  17. Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.

    Science.gov (United States)

    Weijenberg, Matty P; Lüchtenborg, Margreet; de Goeij, Anton F P M; Brink, Mirian; van Muijen, Goos N P; de Bruïne, Adriaan P; Goldbohm, R Alexandra; van den Brandt, Piet A

    2007-10-01

    To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) oncogene. After 7.3 years of follow-up of the Netherlands Cohort Study (n = 120,852), adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were computed, based on 401 colon and 130 rectal cancer patients. Total, saturated and monounsaturated fat were not associated with the risk of colon or rectal cancer, or different molecular subgroups. There was also no association between polyunsaturated fat and the risk of overall or subgroups of rectal cancer. Linoleic acid, the most abundant polyunsaturated fatty acid in the diet, was associated with increased risk of colon tumors with only a KRAS mutation and no additional truncating APC mutation or lack of MLH1 expression (RR = 1.41, 95% CI 1.18-1.69 for one standard deviation (i.e., 7.5 g/day) increase in intake, p-trend over the quartiles of intake colon tumors without any of the gene defects, or with tumors harboring aberrations in either MLH1 or APC. Linoleic acid intake is associated with colon tumors with an aberrant KRAS gene, but an intact APC gene and MLH1 expression, suggesting a unique etiology of tumors with specific genetic aberrations.

  18. Thymidine analogues to assess microperfusion in human tumors

    International Nuclear Information System (INIS)

    Janssen, Hilde L.; Ljungkvist, Anna S.; Rijken, Paul F.; Sprong, Debbie; Bussink, Jan; Kogel, Albert J. van der; Haustermans, Karin M.; Begg, Adrian C.

    2005-01-01

    Purpose: To validate the use of the thymidine analogues as local perfusion markers in human tumors (no labeling indicates no perfusion) by comparison with the well-characterized perfusion marker Hoechst 33342. Methods and Materials: Human tumor xenografts from gliomas and head-and-neck cancers were injected with iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) and the fluorescent dye Hoechst 33342. In frozen sections, each blood vessel was scored for the presence of IdUrd/BrdUrd labeling and Hoechst in surrounding cells. The percentage of analogue-negative vessels was compared with the fraction of Hoechst-negative vessels. Collocalization of the two markers was also scored. Results: We found considerable intertumor variation in the fraction of perfused vessels, measured by analogue labeling, both in the human tumor xenografts and in a series of tumor biopsies from head-and-neck cancer patients. There was a significant correlation between the Hoechst-negative and IdUrd/BrdUrd-negative vessels in the xenografts (r 85, p = 0.0004), despite some mismatches on a per-vessel basis. Conclusions: Thymidine analogues can be successfully used to rank tumors according to their fraction of perfused vessels. Whether this fraction correlates with the extent of acute hypoxia needs further confirmation

  19. Role of blood tumor markers in predicting metastasis and local recurrence after curative resection of colon cancer

    Science.gov (United States)

    Peng, Yifan; Zhai, Zhiwei; Li, Zhongmin; Wang, Lin; Gu, Jin

    2015-01-01

    Aim: To investigate the prognostic value of carcinoembryonic antigen (CEA), CA199, CA724 and CA242 in peripheral blood and local draining venous blood in colon cancer patients after curative resection. Methods: 92 colon cancer patients who received curative resection were retrospectively analyzed. The CEA, CA199, CA724 and CA242 were detected in peripheral blood and local draining venous blood. Results: Metastasis or local recurrence was found in 29 (29/92, 31.5%) patients during follow-up period. 92 patients were divided into two groups: metastasis/local recurrence group (n = 29) and non-metastasis/local recurrence group (n = 63). Peripheral venous CEA, CA199, CA724 and CA242 (p-CEA, p-CA199, p-CA724 and p-CA242) were comparable between two groups (P > 0.05). The median draining venous CEA (d-CEA) in metastases/local recurrence group (23.7 ± 6.9 ng/ml) was significantly higher than that in non-metastases/local recurrence group (18.1 ± 6.3 ng/ml; P 0.05). The optimal cut-off value of d-CEA was 2.76 ng/ml, with the sensitivity and specificity of 90% and 40% in the prediction of metastasis or local recurrence, respectively. d-CEA correlated with tumor differentiation, T stage, TNM stage, metastasis and local recurrence. Subgroup analysis showed that, of 41 patients with stage II colon cancer, the optimal cut-off value of d-CEA was 8.78 ng/mL, and the sensitivity and specificity were 87.5% and 69.7% in the prediction of metastasis or local recurrence, respectively. Conclusion: d-CEA may be a prognostic factor for stage II colon cancer patients. PMID:25785084

  20. Colon Cancer Detection by ‘Rendezvous Colonoscopy’: Successful Removal of Stuck Colon Capsule by Conventional Colonoscopy

    Directory of Open Access Journals (Sweden)

    István Rácz

    2010-02-01

    Full Text Available Although capsule retention is a known complication of small bowel capsule endoscopy, initial studies with colon capsule endoscopy (CCE have not reported any capsule retention or sticking neither in the small bowel nor in the colon. We report a complication of CCE when the stuck colon capsule was passed through the malignant colon stricture and removed by the aid of a flexible colonoscope. During CCE in a 76-year-old iron deficiency anemia patient the real-time viewing system indicated the colon capsule to be stuck in a malignant ascending colon stricture for more than two hours. With the aim to avoid complete capsule retention, immediate colonoscopy was performed. The stuck capsule was caught by a polypectomy snare, passed through the tumor stricture and finally removed from the large bowel. The current case describes the usefulness of the real-time viewing system. Similar situations may occur during the forthcoming spread of CCE and the present case is an example of how to manage the potentially risky stuck colon capsule condition.

  1. Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon

    Directory of Open Access Journals (Sweden)

    Ann-Marie Baker

    2014-08-01

    Full Text Available Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a “functional” stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC−/+. Furthermore, we show that, in adenomatous crypts (APC−/−, there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30–40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.

  2. Radiobiological parameters of a human tumor parent line and four tumor clones of a human epidermoid carcinoma

    International Nuclear Information System (INIS)

    Weichselbaum, R.R.; Beckett, M.; Dahlberg, W.

    1987-01-01

    The authors examined the radiobiological parameters of a parent tumor line and four tumor clones of a human squamous cell carcinoma of the skin. The parent line and clones have a tumor morphology, aneuploid karyotype, and the ability to passage continuously in vitro. With the exception of clone F2A, all cell lines form tumors in nude mice. The parent line, SCC-12 has a D/sub o/ of 154 and an n 7.5 In four tumor clones, D/sub o/ ranges from 131 (clone V) to 266 (clone B2); n ranges from 22.8 in clone V to 2.1 in clone B2. PLDR following 1100 rad ranges from 1.7 in clone B2 to 13.1 in clone V. However, PLDR following equitoxic doses of radiation is similar in the parent and all sub-clones. Radiobiological heterogeneity may complicate predictive assays for clinical radiotherapy

  3. Two-dimensional electrophoretic analysis of nuclear matrix proteins in human colon adenocarcinoma.

    Science.gov (United States)

    Toumpanaki, A; Baltatzis, G E; Gaitanarou, E; Seretis, E; Toumpanakis, C; Aroni, K; Kittas, Christos; Voloudakis-Baltatzis, I E

    2009-01-01

    The aim of the present study was to observe possible qualitative and quantitative expression differences between nuclear matrix proteins (NMPs) of human colon adenocarcinoma and their mirror biopsies, using the technique of two-dimensional gel electrophoresis, in order to identify the existence of specific NMP fingerprints for colon cancer. Colon tissues were examined ultrastructurally and NMPs were isolated biochemically, by serial extraction of lipids, soluble proteins, DNA, RNA, and intermediate filaments and were separated according to their isoelectric point (pI) and their molecular weight (MW) by high-resolution two-dimensional electrophoresis (2D). By comparing the 2D electropherograms of colon cancer tissues and mirror biopsy tissues we observed qualitative and quantitative expression differences between their NMPs but also a differentiation of NMP composition between the stages of malignancy. Moreover, despite the similarities between mirror biopsy samples, a highlight percentage of exception was observed. Electrophoretic results provided in this study demonstrated that the examined NMPs could be further investigated as potential markers for detection of colorectal cancer in an early stage, for the assessment of the disease progression, as well as useful tools for individual therapy and for preventing a possible recurrence of cancer and metastasis.

  4. X-ray sensitivity of human tumor cells in vitro

    International Nuclear Information System (INIS)

    Weichselbaum, R.R.; Nove, J.; Little, J.B.

    1980-01-01

    Clonally-derived cells from ten human malignant tumors considered radiocurable (breast, neuroblastoma, medulloblastoma) or non-radiocurable (osteosarcoma, hypernephroma, glioblastoma, melanoma) were studied in cell culture and their in vitro x-ray survival curve parameters determined (anti n, D 0 ). There were no significant differences among the tumor cell lines suggesting that survival parameters in vitro do not explain differences in clinical radiocurability. Preliminary investigation with density inhibited human tumor cells indicate that such an approach may yield information regarding inherent cellular differences in radiocurability

  5. Compartment-specific immunity in the human gut: properties and functions of dendritic cells in the colon versus the ileum.

    Science.gov (United States)

    Mann, Elizabeth R; Bernardo, David; English, Nicholas R; Landy, Jon; Al-Hassi, Hafid O; Peake, Simon T C; Man, Ripple; Elliott, Timothy R; Spranger, Henning; Lee, Gui Han; Parian, Alyssa; Brant, Steven R; Lazarev, Mark; Hart, Ailsa L; Li, Xuhang; Knight, Stella C

    2016-02-01

    Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC. Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction. A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-α and interleukin (IL)-1β) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4(+)FoxP3(+)IL-10(+) (regulatory) T cells. There were enhanced proportions of CD103(+)Sirpα(-) DC in the colon, with increased proportions of CD103(+)Sirpα(+) DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103(+)Sirpα(+) DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103(+) DC, in particular CD103(+)Sirpα(+) DC. However, expression of ILT3 was associated with CD103(-) DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells. The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  6. Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53

    International Nuclear Information System (INIS)

    Kang, Han Na; Oh, Sang Cheul; Kim, Jun Suk; Yoo, Young A.

    2012-01-01

    p53, the major human tumor suppressor, appears to be related to sonic hedgehog (Shh)–Gli-mediated tumorigenesis. However, the role of p53 in tumor progression by the Shh–Gli signaling pathway is poorly understood. Herein we investigated the critical regulation of Gli3–p53 in tumorigenesis of colon cancer cells and the molecular mechanisms underlying these effects. RT-PCR analysis indicated that the mRNA level of Shh and Gli3 in colon tumor tissues was significantly higher than corresponding normal tissues (P < 0.001). The inhibition of Gli3 by treatment with Gli3 siRNA resulted in a clear decrease in cell proliferation and enhanced the level of expression of p53 proteins compared to treatment with control siRNA. The half-life of p53 was dramatically increased by treatment with Gli3 siRNA. In addition, treatment with MG132 blocked MDM2-mediated p53 ubiquitination and degradation, and led to accumulation of p53 in Gli3 siRNA-overexpressing cells. Importantly, ectopic expression of p53 siRNA reduced the ability of Gli3 siRNA to suppress proliferation of those cells compared with the cells treated with Gli3 siRNA alone. Moreover, Gli3 siRNA sensitized colon cancer cells to treatment with anti-cancer agents (5-FU and bevacizumab). Taken together, our studies demonstrate that loss of Gli3 signaling leads to disruption of the MDM2–p53 interaction and strongly potentiate p53-dependent cell growth inhibition in colon cancer cells, indicating a basis for the rational use of Gli3 antagonists as a novel treatment option for colon cancer.

  7. [In vitro and in vivo effects of mango pulp (Mangifera indica cv. Azucar) in colon carcinogenesis].

    Science.gov (United States)

    Corrales-Bernal, Andrea; Amparo Urango, Luz; Rojano, Benjamín; Maldonado, Maria Elena

    2014-03-01

    Mango pulp contains ascorbic acid, carotenoids, polyphenols, terpenoids and fiber which are healthy and could protect against colon cancer. The aim of this study was to evaluate the antiproliferative and preventive capacity of an aqueous extract of Mangifera indica cv. Azúcar on a human colon adenocarcinoma cell line (SW480) and in a rodent model of colorectal cancer, respectively. The content of total phenolics, flavonoids and carotenoids were also analyzed in the extract. SW480 cell growth was inhibited in a dose and time dependent manner by 22.3% after a 72h exposure to the extract (200 µg/ mL). Colon carcinogenesis was initiated in Balb/c mice by two intra-peritoneal injections of azoxymethane (AOM) at the third and fourth week of giving mango in drinking water (0.3%, 0.6%, 1.25%). After 10 weeks of treatment, in the colon of mice receiving 0.3% mango, aberrant crypt foci formation was inhibited more than 60% (p=0,05) and the inhibition was dose-dependent when compared with controls receiving water. These results show that mango pulp, a natural food, non toxic, part of human being diet, contains bioactive compounds able to reduce growth of tumor cells and to prevent the appearance of precancerous lesions in colon during carcinogenesis initiation.

  8. A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.

    Science.gov (United States)

    Thompson, Bryony A; Goldgar, David E; Paterson, Carol; Clendenning, Mark; Walters, Rhiannon; Arnold, Sven; Parsons, Michael T; Michael D, Walsh; Gallinger, Steven; Haile, Robert W; Hopper, John L; Jenkins, Mark A; Lemarchand, Loic; Lindor, Noralane M; Newcomb, Polly A; Thibodeau, Stephen N; Young, Joanne P; Buchanan, Daniel D; Tavtigian, Sean V; Spurdle, Amanda B

    2013-01-01

    Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ~12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing. © 2012 Wiley Periodicals, Inc.

  9. Laterally Spreading Tumors of the Colon During High Resolution Colonoscopy with Narrow Band Imaging and Acetic Acid Chromoscopy

    Directory of Open Access Journals (Sweden)

    V.A. Yakovenko

    2015-02-01

    Materials and Methods. 1632 colonoscopy protocols were studied: 735 — by using video colonoscope Olympus CF-HQ190L and 897 — Olympus CF-150. Results and Discussion. In study group, adenoma detection rate was higher than in control one: 0.78 (571/735 vs. 0.47 (422/897, p < 0.00001; c2 = 157.9. Adenoma detection index was 3.6 times higher in study group than in control one: 2.9 (2,104/735 vs. 0.8 (708/897. Laterally spreading tumors were diagnosed 2.2 times more often in study group than in control one: 22 % (187/735 vs. 10 % (85/897, p < 0.00001; c2 = 53.6. Conclusions. High resolution colonoscopy with narrow band imaging and acetic acid chromoscopy has a high diagnostic value for detection of laterally spreading tumors of the colon.

  10. Sensitive detection of viral transcripts in human tumor transcriptomes.

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    Sven-Eric Schelhorn

    Full Text Available In excess of 12% of human cancer incidents have a viral cofactor. Epidemiological studies of idiopathic human cancers indicate that additional tumor viruses remain to be discovered. Recent advances in sequencing technology have enabled systematic screenings of human tumor transcriptomes for viral transcripts. However, technical problems such as low abundances of viral transcripts in large volumes of sequencing data, viral sequence divergence, and homology between viral and human factors significantly confound identification of tumor viruses. We have developed a novel computational approach for detecting viral transcripts in human cancers that takes the aforementioned confounding factors into account and is applicable to a wide variety of viruses and tumors. We apply the approach to conducting the first systematic search for viruses in neuroblastoma, the most common cancer in infancy. The diverse clinical progression of this disease as well as related epidemiological and virological findings are highly suggestive of a pathogenic cofactor. However, a viral etiology of neuroblastoma is currently contested. We mapped 14 transcriptomes of neuroblastoma as well as positive and negative controls to the human and all known viral genomes in order to detect both known and unknown viruses. Analysis of controls, comparisons with related methods, and statistical estimates demonstrate the high sensitivity of our approach. Detailed investigation of putative viral transcripts within neuroblastoma samples did not provide evidence for the existence of any known human viruses. Likewise, de-novo assembly and analysis of chimeric transcripts did not result in expression signatures associated with novel human pathogens. While confounding factors such as sample dilution or viral clearance in progressed tumors may mask viral cofactors in the data, in principle, this is rendered less likely by the high sensitivity of our approach and the number of biological replicates

  11. Radioimmunotherapy of Nude Mice Bearing Human Colon Carcinoma with I-131 Labeled Anti-carcinoembryonic Antigen

    International Nuclear Information System (INIS)

    Kim, Byung Tae; Lee, Kyung Han; Kim, Sang Eun; Choi, Yong; Chi, Dae Yoon; Chung, June Key; Lee, Myung Chul; Koh, Chang Soon; Chung, Hong Keun

    1995-01-01

    This study was designed to evaluate the effects of various factors on the therapeutic effect of the I-l3l labeled anti-carcinoembryonic antigen monoclonal antibody(anti-CEA antibody). Tetrazolium-based colorimetric assay (MTT) was used to compare in vitro cytotoxicity of 3 Korean colon cancer cell lines (SNU-C2A, SNU-C4, SNU-C5) for selection of proper 2 cell lines in this study. The changes of the size of tumor which was xenografted to nude mice (balb/c nu/nu) were compared in 4 groups (group treated I-131 labeled anti-CEA antibody, group treated with non-radiolabeled anti-CEA antibody, group treated with I-131. labeled anti-human chorionic gonadotropin monoclonal antibody (anti-hCG antibody) as nonspecific antibody, and group injected with normal saline as a control). Immunohistochemical staining and in vivo autoradiography were performed after excision of the xenografted tumor. The results were as below mentioned. The in vitro cytotoxic effect of I-131 labeled anti-CEA antibody is most prominent in SNU-C5 cell line between 3 cancer cell lines. The changes of xenografted tumor size in both SNU-C4 and SNU-C5 cell tumors at the thirteenth day after injection of the antibodies were smallest in the group treated with I-131 labeled anti-CEA antibody (SNU-C4/SNU-C5; 324/342%) comparing with other groups, group treated with anti-CEA antibody (622/660%), group treated with I-131 anti-hCG antibody (538/546%), and control group(1030/724%) (p<0.02 in SNU-C4 and p<0.1in SNU-C5 at the 13th day after injection of antibodies). On the thirteenth day after injection of the antibodies nude mice were sacreficed to count the radiouptake of tumor and to check the changes of tumor size. Correlations between radiouptake and change of tumor size were calculated in each groups and significant negative correlation was only obtained in the group treated with I-131 anti-CEA antibody (p<0.05). There were no correlations between antigenic expression of carcinoembryonic antigen and

  12. Carbogen Breathing Differentially Enhances Blood Plasma Volume and 5-Fluorouracil Uptake in Two Murine Colon Tumor Models with a Distinct Vascular Structure

    Directory of Open Access Journals (Sweden)

    Hanneke W.M. van Laarhoven

    2006-06-01

    Full Text Available For the systemic treatment of colorectal cancer, 5-fluorouracil (FU-based chemotherapy is the standard. However, only a subset of patients responds to chemotherapy. Breathing of carbogen (95% O2 and 5% CO2 may increase the uptake of FU through changes in tumor physiology. This study aims to monitor in animal models in vivo the effects of carbogen breathing on tumor blood plasma volume, pH, and energy status, and on FU uptake and metabolism in two colon tumor models C38 and C26a, which differ in their vascular structure and hypoxic status. Phosphorus-31 magnetic resonance spectroscopy (MRS was used to assess tumor pH and energy status, and fluorine-19 MRS was used to follow FU uptake and metabolism. Advanced magnetic resonance imaging methods using ultrasmall particles of iron oxide were performed to assess blood plasma volume. The results showed that carbogen breathing significantly decreased extracellular pH and increased tumor blood plasma volume and FU uptake in tumors. These effects were most significant in the C38 tumor line, which has the largest relative vascular area. In the C26a tumor line, carbogen breathing increased tumor growth delay by FU. In this study, carbogen breathing also enhanced systemic toxicity by FU.

  13. The Human Cell Surfaceome of Breast Tumors

    Science.gov (United States)

    da Cunha, Júlia Pinheiro Chagas; Galante, Pedro Alexandre Favoretto; de Souza, Jorge Estefano Santana; Pieprzyk, Martin; Carraro, Dirce Maria; Old, Lloyd J.; Camargo, Anamaria Aranha; de Souza, Sandro José

    2013-01-01

    Introduction. Cell surface proteins are ideal targets for cancer therapy and diagnosis. We have identified a set of more than 3700 genes that code for transmembrane proteins believed to be at human cell surface. Methods. We used a high-throuput qPCR system for the analysis of 573 cell surface protein-coding genes in 12 primary breast tumors, 8 breast cell lines, and 21 normal human tissues including breast. To better understand the role of these genes in breast tumors, we used a series of bioinformatics strategies to integrates different type, of the datasets, such as KEGG, protein-protein interaction databases, ONCOMINE, and data from, literature. Results. We found that at least 77 genes are overexpressed in breast primary tumors while at least 2 of them have also a restricted expression pattern in normal tissues. We found common signaling pathways that may be regulated in breast tumors through the overexpression of these cell surface protein-coding genes. Furthermore, a comparison was made between the genes found in this report and other genes associated with features clinically relevant for breast tumorigenesis. Conclusions. The expression profiling generated in this study, together with an integrative bioinformatics analysis, allowed us to identify putative targets for breast tumors. PMID:24195083

  14. Spontaneous regression of transverse colon cancer: a case report.

    Science.gov (United States)

    Chida, Keigo; Nakanishi, Kazuaki; Shomura, Hiroki; Homma, Shigenori; Hattori, Atsuo; Kazui, Keizo; Taketomi, Akinobu

    2017-12-01

    Spontaneous regression (SR) of many malignant tumors has been well documented, with an approximate incidence of one per 60,000-100,000 cancer patients. However, SR of colorectal cancer (CRC) is very rare, accounting for less than 2% of such cases. We report a case of SR of transverse colon cancer in an 80-year-old man undergoing outpatient follow-up after surgical treatment of early gastric cancer. Colonoscopy (CS) revealed a Borrmann type II tumor in the transverse colon measuring 30 × 30 mm. Because the patient underwent anticoagulant therapy, we did not perform a biopsy at that time. A second CS was performed 1 week after the initial examination and revealed tumor shrinkage to a diameter of 20 mm and a shift to the Borrmann type III morphology. Biopsy revealed a poorly differentiated adenocarcinoma. One week after the second CS, we performed a partial resection of the transverse colon and D2 lymph node dissection. Histopathology revealed inflammatory cell infiltration and fibrosis from the submucosal to muscularis propria layers in the absence of cancer cells, leading to pathological staging of pStage 0 (T0N0). The patient had an uneventful recovery, and CS performed at 5 months postoperatively revealed the absence of a tumor in the colon and rectum. The patient continues to be followed up as an outpatient at 12 months postoperatively, and no recurrence has been observed.

  15. The nonfermentable dietary fiber lignin alters putative colon cancer risk factors but does not protect against DMH-induced colon cancer in rats.

    Science.gov (United States)

    Cameron, I L; Hardman, W E; Heitman, D W

    1997-01-01

    The effect of supplementation of the diet with autohydrolyzed lignin on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis was studied using 112 male Sprague-Dawley rats. Rats received eight weekly injections of DMH (9.5 mg/kg s.c.) or the saline vehicle solution and then were maintained on a basal AIN-76 fiber-free diet or the basal fiber-free diet plus 5% or 10% (wt/wt) lignin for 24 weeks. Rats were killed 32 weeks after the start of the experiment. Colon tumor incidence, location, and multiplicity were determined. Body weight, caloric intake, fecal dry weight, gut transit time, pH of cecal contents, and total fecal bile acid excretion were measured. Supplementation of the diet with 5% or 10% lignin resulted in increased fecal dry weight and total fecal bile acid excretion and in decreased gut transit time, colon pH, and fecal bile acid concentration. Dietary lignin did not significantly affect colon tumor incidence or multiplicity compared with the fiber-free diet. Thus dietary supplementation with autohydrolyzed lignin, a food fiber with good bulking characteristics, had a significant effect on several factors that have previously been linked to reduction of colon cancer risk, but the consumption of high levels of lignin did not decrease the risk for colon cancer.

  16. Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

    International Nuclear Information System (INIS)

    Ahmed, Kamran A.; Fulp, William J.; Berglund, Anders E.; Hoffe, Sarah E.; Dilling, Thomas J.; Eschrich, Steven A.; Shridhar, Ravi; Torres-Roca, Javier F.

    2015-01-01

    Purpose: We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases. Methods and Materials: Patients were identified from our institutional review board–approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation. Results: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026). Conclusions: Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger

  17. Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Kamran A. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Fulp, William J.; Berglund, Anders E. [Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Hoffe, Sarah E.; Dilling, Thomas J. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Eschrich, Steven A. [Department of Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Shridhar, Ravi [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Torres-Roca, Javier F., E-mail: javier.torresroca@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States)

    2015-07-15

    Purpose: We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases. Methods and Materials: Patients were identified from our institutional review board–approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation. Results: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026). Conclusions: Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger

  18. Stem cell carcinoma of the colon and rectum. Report of two cases and review of the literature

    DEFF Research Database (Denmark)

    Palvio, D H; Sørensen, Flemming Brandt; Kløve-Mogensen, M

    1985-01-01

    Two cases of highly malignant tumors, one originating in the sigmoid colon and the other in the rectum, are presented. Both tumors showed light microscopic, electron microscopic, and immunohistochemical evidence of multidirectional differentiation. The tumors were composed mainly of undifferentia......Two cases of highly malignant tumors, one originating in the sigmoid colon and the other in the rectum, are presented. Both tumors showed light microscopic, electron microscopic, and immunohistochemical evidence of multidirectional differentiation. The tumors were composed mainly...

  19. Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

    Science.gov (United States)

    Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

    2016-05-01

    Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

  20. Peroxiredoxin 5 promotes the epithelial-mesenchymal transition in colon cancer

    International Nuclear Information System (INIS)

    Ahn, Hye-Mi; Yoo, Jin-Woo; Lee, Seunghoon; Lee, Hong Jun; Lee, Hyun-Shik; Lee, Dong-Seok

    2017-01-01

    Globally, colorectal cancer (CRC) is common cause of cancer-related deaths. The high mortality rate of patients with colon cancer is due to cancer cell invasion and metastasis. Initiation of the epithelial-to-mesenchymal transition (EMT) is essential for the tumorigenesis. Peroxiredoinxs (PRX1-6) have been reported to be overexpressed in various tumor tissues, and involved to be responsible for tumor progression. However, the exact role of PRX5 in colon cancer remains to be investigated enhancing proliferation and promoting EMT properties. In this study, we constructed stably overexpressing PRX5 and suppressed PRX5 expression in CRC cells. Our results revealed that PRX5 overexpression significantly enhanced CRC cell proliferation, migration, and invasion. On the other hand, PRX5 suppression markedly inhibited these EMT properties. PRX5 was also demonstrated to regulate the expression of two hallmark EMT proteins, E-cadherin and Vimentin, and the EMT-inducing transcription factors, Snail and Slug. Moreover, in the xenograft mouse model, showed that PRX5 overexpression enhances tumor growth of CRC cells. Thus, our findings first provide evidence in CRC that PRX5 promotes EMT properties by inducing the expression of EMT-inducing transcription factors. Therefore, PRX5 can be used as a predictive biomarker and serves as a putative therapeutic target for the development of clinical treatments for human CRC. - Highlights: • PRX5 promoted colorectal cancer cell proliferation. • PRX5 enhanced EMT properties in colorectal cancer. • PRX5 mediated the EMT by inducing the expression of Snail and Slug. • PRX5 promoted tumor growth of colorectal cancer cells.

  1. Current management of liver metastases of colon cancer

    International Nuclear Information System (INIS)

    Mainieri Breedy, Giovanna

    2010-01-01

    Colon cancer has been one of the major tumors in the world, both men and women; and it is constituted the third most commonly diagnosed tumor, with approximately 1.2 million of new cases per year. This cancer type is considered of great importance in Costa Rica and has occupied the fifth place. Age is the main risk factor, followed by environmental, diabetic and genetic factors. An IV colon cancer has been manifested with any T, with any N and metastases. Metastases from colon cancer to liver can be classified according to whether have been synchronous (20 to 25%) or metachronous (15 to 29%). In turn, they can be synchronous, resectable or unresectable or mechanical resectable or unresectable. The liver has been the most common site of metastases, and the status of this organ has been an important determinant of overall survival in patients with advanced disease. Half of the patients developed metastases during the course of the disease. Metastases has represented the leading cause of death from this tumor. With the advent of new surgical techniques, new anesthetic care, new chemotherapeutic and molecular agents, together with new radiofrequency modalities and ablative treatment, the approach of metastases from colon cancer to the liver has been shown to be decisive in the prolongation of survival of the patient, who in the past was considered a terminal patient [es

  2. Dysregulation of microRNAs in colonic field carcinogenesis: implications for screening.

    Directory of Open Access Journals (Sweden)

    Dhananjay P Kunte

    Full Text Available Colorectal cancer (CRC screening tests often have a trade-off between efficacy and patient acceptability/cost. Fecal tests (occult blood, methylation engender excellent patient compliance but lack requisite performance underscoring the need for better population screening tests. We assessed the utility of microRNAs (miRNAs as markers of field carcinogenesis and their potential role for CRC screening using the azoxymethane (AOM-treated rat model. We found that 63 miRNAs were upregulated and miR-122, miR-296-5p and miR-503# were downregulated in the uninvolved colonic mucosa of AOM rats. We monitored the expression of selected miRNAs in colonic biopsies of AOM rats at 16 weeks and correlated it with tumor development. We noted that the tumor bearing rats had significantly greater miRNA modulation compared to those without tumors. The miRNAs showed good diagnostic performance with an area under the receiver operator curve (AUROC of >0.7. We also noted that the miRNA induction in the colonic mucosa was mirrorred in the mucus layer fecal colonocytes isolated from AOM rat stool and the degree of miRNA induction was greater in the tumor bearing rats compared to those without tumors. Lastly, we also noted significant miRNA modulation in the Pirc rats- the genetic model of colon carcinogenesis, both in the uninvolved colonic mucosa and the fecal colonocytes. We thus demonstrate that miRNAs are excellent markers of field carcinogenesis and could accurately predict future neoplasia. Based on our results, we propose an accurate, inexpensive, non-invasive miRNA test for CRC risk stratification based on rectal brushings or from abraded fecal colonocytes.

  3. Self-renewing Monolayer of Primary Colonic or Rectal Epithelial CellsSummary

    Directory of Open Access Journals (Sweden)

    Yuli Wang

    2017-07-01

    Full Text Available Background & Aims: Three-dimensional organoid culture has fundamentally changed the in vitro study of intestinal biology enabling novel assays; however, its use is limited because of an inaccessible luminal compartment and challenges to data gathering in a three-dimensional hydrogel matrix. Long-lived, self-renewing 2-dimensional (2-D tissue cultured from primary colon cells has not been accomplished. Methods: The surface matrix and chemical factors that sustain 2-D mouse colonic and human rectal epithelial cell monolayers with cell repertoires comparable to that in vivo were identified. Results: The monolayers formed organoids or colonoids when placed in standard Matrigel culture. As with the colonoids, the monolayers exhibited compartmentalization of proliferative and differentiated cells, with proliferative cells located near the peripheral edges of growing monolayers and differentiated cells predominated in the central regions. Screening of 77 dietary compounds and metabolites revealed altered proliferation or differentiation of the murine colonic epithelium. When exposed to a subset of the compound library, murine organoids exhibited similar responses to that of the monolayer but with differences that were likely attributable to the inaccessible organoid lumen. The response of the human primary epithelium to a compound subset was distinct from that of both the murine primary epithelium and human tumor cells. Conclusions: This study demonstrates that a self-renewing 2-D murine and human monolayer derived from primary cells can serve as a physiologically relevant assay system for study of stem cell renewal and differentiation and for compound screening. The platform holds transformative potential for personalized and precision medicine and can be applied to emerging areas of disease modeling and microbiome studies. Keywords: Colonic Epithelial Cells, Monolayer, Organoids, Compound Screening

  4. Neoadjuvant chemotherapy in locally advanced colon cancer

    DEFF Research Database (Denmark)

    Jakobsen, Anders; Andersen, Fahimeh; Fischer, Anders

    2015-01-01

    BACKGROUND: Neoadjuvant chemotherapy has proven valuable in several tumors, but it has not been elucidated in colon cancer. The present phase II trial addressed the issue in high-risk patients selected by computed tomography (CT) scan. MATERIAL AND METHODS: Patients with resectable colon cancer...... 32% (p = 0.005) translating into a three-year DFS of 94% versus 63% (p = 0.005). CONCLUSION: Neoadjuvant chemotherapy in colon cancer is feasible and the results suggest that a major part of the patients can be spared adjuvant chemotherapy. Validation in a randomized trial is warranted....

  5. Imaging of intraperitoneal tumors with technetium-99m GSA

    International Nuclear Information System (INIS)

    Yao, Zhengsheng; Zhang, Meili; Sakahara, Harumi; Saga, Tsuneo; Nakamoto, Yuji; Sato, Noriko; Zhao, Songji; Konishi, Junji; Arano, Yasushi

    1998-01-01

    99m Tc labeled galactosyl serum albumin (GSA) has been used clinically as a receptor-binding agent for the assessment of liver function. The aim of this study was to investigate the usefulness of 99m Tc-GSA in intraperitoneal (i.p.) tumor imaging. A tumor model was established by i.p. inoculating nude mice with human ovarian cancer cell SHIN-3, or colon cancer cell LS180. Radiolabels were i.p. injected into the tumor-bearing mice and the biodistribution of radioactivity was examined. After administration, 99m Tc-GSA rapidly accumulated in the tumor. The tumor uptake was 5.82-8.46% ID/g from 30 min to 6 h after the injection. Radioactivity in the blood was very low, less than 0.3% ID/g, resulting in high tumor-to-blood ratio. Tumors could be clearly seen by scintigraphic imaging. Accumulation of i.p.-injected 99m Tc labeled human serum albumin (HSA) in i.p. tumors was similar to that of 99m Tc-GSA, but radioactivity of 99m Tc-HSA in the circulation was high, resulting in a significantly lower tumor-to-blood ratio. In conclusion, 99m Tc-GSA, when i.p. injected, accumulated in i.p. tumors and cleared from circulation rapidly, which would make it useful for the imaging of i.p. tumors. (author)

  6. Integrin α6Bβ4 inhibits colon cancer cell proliferation and c-Myc activity

    International Nuclear Information System (INIS)

    Dydensborg, Anders Bondo; Teller, Inga C; Groulx, Jean-François; Basora, Nuria; Paré, Fréderic; Herring, Elizabeth; Gauthier, Rémy; Jean, Dominique; Beaulieu, Jean-François

    2009-01-01

    Integrins are known to be important contributors to cancer progression. We have previously shown that the integrin β4 subunit is up-regulated in primary colon cancer. Its partner, the integrin α6 subunit, exists as two different mRNA splice variants, α6A and α6B, that differ in their cytoplasmic domains but evidence for distinct biological functions of these α6 splice variants is still lacking. In this work, we first analyzed the expression of integrin α6A and α6B at the protein and transcript levels in normal human colonic cells as well as colorectal adenocarcinoma cells from both primary tumors and established cell lines. Then, using forced expression experiments, we investigated the effect of α6A and α6B on the regulation of cell proliferation in a colon cancer cell line. Using variant-specific antibodies, we observed that α6A and α6B are differentially expressed both within the normal adult colonic epithelium and between normal and diseased colonic tissues. Proliferative cells located in the lower half of the glands were found to predominantly express α6A, while the differentiated and quiescent colonocytes in the upper half of the glands and surface epithelium expressed α6B. A relative decrease of α6B expression was also identified in primary colon tumors and adenocarcinoma cell lines suggesting that the α6A/α6B ratios may be linked to the proliferative status of colonic cells. Additional studies in colon cancer cells showed that experimentally restoring the α6A/α6B balance in favor of α6B caused a decrease in cellular S-phase entry and repressed the activity of c-Myc. The findings that the α6Bβ4 integrin is expressed in quiescent normal colonic cells and is significantly down-regulated in colon cancer cells relative to its α6Aβ4 counterpart are consistent with the anti-proliferative influence and inhibitory effect on c-Myc activity identified for this α6Bβ4 integrin. Taken together, these findings point out the importance of integrin

  7. A paraptosis-like cell death induced by δ-tocotrienol in human colon carcinoma SW620 cells is associated with the suppression of the Wnt signaling pathway

    International Nuclear Information System (INIS)

    Zhang, Jing-Shu; Li, Da-Ming; He, Ning; Liu, Ying-Hua; Wang, Chun-Hua; Jiang, Shu-Qing; Chen, Bing-Qing; Liu, Jia-Ren

    2011-01-01

    Tocotrienol is considered a beneficial effect agent on inhibition of tumor development. In this study, we focused on the effects of δ-tocotrienol and its possible mechanism on induction of death in human colon cancer SW620 cells. δ-Tocotrienol inhibited proliferation of SW620 cell in a dose-dependent manner. Our findings showed that δ-tocotrienol effectively induced paraptosis-like death in SW620 cells, correlated with the vacuolation that may be from welling and fusion of mitochondria and/or the endoplasmic reticulum (ER) as well as caspase-3 nonactivated. However, there were no changes in apoptosis based on flow cytometry analysis. Of being noted, δ-tocotrienol reduced the expression of β-catenin and wnt-1 proteins by about 50% at the highest dose (20 μmol/L). δ-Tocotrienol also decreased cyclin D1, c-jun and MMP-7 protein levels in SW620 cells. Altogether, these data indicate that δ-tocotrienol induces paraptosis-like cell death, which is associated with the suppression of the Wnt signaling pathway. Thus, our findings may provide a novel application in treatment of human colon carcinoma.

  8. Sigma and opioid receptors in human brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J. (St. Louis Univ. School of Medicine, MO (USA))

    1990-01-01

    Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using ({sup 3}H) 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: {mu}, (D-ala{sup 2}, mePhe{sup 4}, gly-ol{sup 5}) enkephalin (DAMGE); {kappa}, ethylketocyclazocine (EKC) or U69,593; {delta}, (D-pen{sup 2}, D-pen{sup 5}) enkephalin (DPDPE) or (D-ala{sup 2}, D-leu{sup 5}) enkephalin (DADLE) with {mu} suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. {kappa} opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed.

  9. Improved radioimaging and tumor localization with monoclonal F(ab')2

    International Nuclear Information System (INIS)

    Wahl, R.L.; Parker, C.W.; Philpott, G.W.

    1983-01-01

    Monoclonal anti-tumor antibodies have great promise for radioimmunodetection and localization of tumors. Fab and F(ab')2 fragments, which lack the Fc fragment of antibody (Ab), are cleared more rapidly from the circulation and may have less nonspecific tissue binding than intact Ab. In radioimaging studies using a murine monoclonal antibody to carcinoembryonic antigen in a human colon carcinoma xenografted into hamsters, F(ab')2 fragments were shown superior to Fab fragments and intact antibody for scintiscanning. In double-label experiments with anti-CEA antibody and control monoclonal IgG, F(ab')2 fragments were found to give better and more rapid specific tumor localization than intact antibody or Fab fragments. F(ab')2 fragments offer significant promise for tumor imaging and possibly therapy

  10. Ablation of human colon carcinoma in nude mice by 131I-labeled monoclonal anti-carcinoembryonic antigen antibody F(ab')2 fragments

    International Nuclear Information System (INIS)

    Buchegger, F.; Pfister, C.; Fournier, K.; Prevel, F.; Schreyer, M.; Carrel, S.; Mach, J.P.

    1989-01-01

    Pooled F(ab')2 fragments of three MAbs against distinct epitopes of carcinoembryonic antigen (CEA) were used for radioimmunotherapy of nude mice bearing a subcutaneous human colon carcinoma xenograft. 9-10 d after transplantation when tumor nodules were in exponential growth, 36 mice were treated by intravenous injection of different amounts of 131 I-labeled MAb F(ab')2. All 14 mice injected with a single dose of 2,200 (n = 10) or 2,800 microCi (n = 4) showed complete tumor remission. 8 of the 10 mice treated with 2,200 microCi survived in good health for 1 yr when they were killed and shown to be tumor free. Four of nine other mice treated with four fractionated doses of 400 microCi showed no tumor relapse for more than 9 mo. In contrast, all 15 mice injected with 1,600-3,000 microCi 131 I-control IgG F(ab')2 showed tumor growth retardation of only 1-4 wk, and 15 of 16 mice injected with unlabeled anti-CEA MAb F(ab')2 showed unmodified tumor progression as compared with untreated mice. From tissue radioactivity distributions it was calculated that by an injection of 2,200 microCi 131 I-MAb F(ab')2 a mean dose of 8,335 rad was selectively delivered to the tumor, while the tissue-absorbed radiation doses for the normal organs were: peripheral blood, 2,093; stomach, 1,668; kidney, 1,289; lung, 1,185; liver, 617; spleen, 501; small intestine, 427; large intestine, 367; bone, 337; and muscle, 198. These treatments were well tolerated since out of 19 mice with complete tumor remission only 4 required bone marrow transplantation and 17 were in good health for 6-12 mo of observation

  11. Feasibility of full-field optical coherence microscopy in ultra-structural imaging of human colon tissues

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Eun Seo [Chosun University, Gwangju (Korea, Republic of); Choi, Woo June; Ryu, Seon Young; Lee, Byeong Ha [Gwangju Institute of Science and Technology, Gwangju (Korea, Republic of); Lee, Jae Hyuk; Bom, Hee Seung; Lee, Byeong Il [Chonnam National University Hospital, Gwangju (Korea, Republic of)

    2010-06-15

    We demonstrated the imaging feasibility of full-field optical coherence microscopy (FF-OCM) in pathological diagnosis of human colon tissues. FF-OCM images with high transverse resolution were obtained at different depths of the samples without any dye staining or physical slicing, and detailed microstructures of human colon tissues were visualized. Morphological differences in normal tissues, cancer tissues, and tissues under transition were observed and matched with results seen in conventional optical microscope images. The optical biopsy based on FF-OCM could overcome the limitations on the number of physical cuttings of tissues and could perform high-throughput mass diagnosis of diseased tissues. The proved utility of FF-OCM as a comprehensive and efficient imaging modality of human tissues showed it to be a good alternative to conventional biopsy.

  12. Feasibility of full-field optical coherence microscopy in ultra-structural imaging of human colon tissues

    International Nuclear Information System (INIS)

    Choi, Eun Seo; Choi, Woo June; Ryu, Seon Young; Lee, Byeong Ha; Lee, Jae Hyuk; Bom, Hee Seung; Lee, Byeong Il

    2010-01-01

    We demonstrated the imaging feasibility of full-field optical coherence microscopy (FF-OCM) in pathological diagnosis of human colon tissues. FF-OCM images with high transverse resolution were obtained at different depths of the samples without any dye staining or physical slicing, and detailed microstructures of human colon tissues were visualized. Morphological differences in normal tissues, cancer tissues, and tissues under transition were observed and matched with results seen in conventional optical microscope images. The optical biopsy based on FF-OCM could overcome the limitations on the number of physical cuttings of tissues and could perform high-throughput mass diagnosis of diseased tissues. The proved utility of FF-OCM as a comprehensive and efficient imaging modality of human tissues showed it to be a good alternative to conventional biopsy.

  13. Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells

    Science.gov (United States)

    Santarmaki, Valentina; Aindelis, Georgios; Tompoulidou, Evgenia; Lamprianidou, Eleftheria E.; Saxami, Georgia; Ypsilantis, Petros; Lampri, Evangeli S.; Simopoulos, Constantinos; Kotsianidis, Ioannis; Galanis, Alex; Kourkoutas, Yiannis; Dimitrellou, Dimitra; Chlichlia, Katerina

    2016-01-01

    Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 109 CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 109 CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain. PMID:26849051

  14. Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.

    Directory of Open Access Journals (Sweden)

    Angeliki Tiptiri-Kourpeti

    Full Text Available Probiotic microorganisms such as lactic acid bacteria (LAB exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof on murine (CT26 and human (HT29 colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 10(9 CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells. In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 10(9 CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.

  15. Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.

    Science.gov (United States)

    Tiptiri-Kourpeti, Angeliki; Spyridopoulou, Katerina; Santarmaki, Valentina; Aindelis, Georgios; Tompoulidou, Evgenia; Lamprianidou, Eleftheria E; Saxami, Georgia; Ypsilantis, Petros; Lampri, Evangeli S; Simopoulos, Constantinos; Kotsianidis, Ioannis; Galanis, Alex; Kourkoutas, Yiannis; Dimitrellou, Dimitra; Chlichlia, Katerina

    2016-01-01

    Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 10(9) CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 10(9) CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.

  16. Recombinant human endostatin improves tumor vasculature and alleviates hypoxia in Lewis lung carcinoma

    International Nuclear Information System (INIS)

    Peng Fang; Wang Jin; Zou Yi; Bao Yong; Huang Wenlin; Chen Guangming; Luo Xianrong; Chen Ming

    2011-01-01

    Objective: To investigate whether recombinant human endostatin can create a time window of vascular normalization prior to vascular pruning to alleviate hypoxia in Lewis lung carcinoma in mice. Methods: Kinetic changes in morphology of tumor vasculature in response to recombinant human endostatin were detected under a confocal microscope with immunofluorescent staining in Lewis lung carcinomas in mice. The hypoxic cell fraction of different time was assessed with immunohistochemical staining . Effects on tumor growth were monitored as indicated in the growth curve of tumors . Results: Compared with the control group vascularity of the tumors was reduced over time by recombinant human endostatin treatment and significantly regressed for 9 days. During the treatment, pericyte coverage increased at day 3, increased markedly at day 5, and fell again at day 7. The vascular basement membrane was thin and closely associated with endothelial cells after recombinant human endostatin treatment, but appeared thickened, loosely associated with endothelial cells in control tumors. The decrease in hypoxic cell fraction at day 5 after treatment was also found. Tumor growth was not accelerated 5 days after recombinant human endostatin treatment. Conclusions: Recombinant human endostatin can normalize tumor vasculature within day 3 to 7, leading to improved tumor oxygenation. The results provide important experimental basis for combining recombinant human endostatin with radiation therapy in human tumors. (authors)

  17. Methylation of the estrogen receptor CpG island distinguishes spontaneous and plutonium-induced tumors from nitrosamine-induced lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Belinsky, S.A.; Baylin, S.B.; Issa, J.J. [Johns Hopkins Univ., Baltimore, MD (United States)

    1995-12-01

    CpG islands located in the promoter region of genes constitute one mechanism for regulating transcription. These islands are normally free of methylation, regardless of the expression state of the gene. Hypermethylation of CpG islands, the addition of a methyl group to the internal cytosine within CpG dinucleotides, can cause silencing of a gene. Hypermethylation has been detected as an early event at specific chromosome loci during the development of colon cancer and represents one mechanism used by neoplatic cells to inactivate tumor suppressor genes. Recent studies have demonstrated this mechanism in inactivation of the VHL tumor suppressor gene in 19% of sporadic renal tumors and the p16 {sup INK4a} tumor suppressor gene in 30% of non-small cell lung cancers. A recent report indicates that the estrogen receptor gene could also be inactivated through methylation. In addition, estrogen receptor CpG island methylation arises as a direct function of age in normal colonic mucosa and is present in virtually all colonic tumors. In cultured colon cancer cells, methylation-associated loss of expression of the estrogen receptor gene results in deregulated growth, suggesting a role for the estrogen receptor in colon cancer development. These results provide further evidence that gene silencing through methylation could be a predominant epigenetic mechanism underlying the development of many different types of cancer. The purpose of the current investigation was to determine whether estrogen receptor CpG island methylation is involved in the development of lung cancer. The frequency for methylation of the estrogen receptor CpG island in rodent lung tumors is summarized.

  18. The expression of Egfl7 in human normal tissues and epithelial tumors.

    Science.gov (United States)

    Fan, Chun; Yang, Lian-Yue; Wu, Fan; Tao, Yi-Ming; Liu, Lin-Sen; Zhang, Jin-Fan; He, Ya-Ning; Tang, Li-Li; Chen, Guo-Dong; Guo, Lei

    2013-04-23

    To investigate the expression of Egfl7 in normal adult human tissues and human epithelial tumors.
 RT-PCR and Western blot were employed to detect Egfl7 expression in normal adult human tissues and 10 human epithelial tumors including hepatocellular carcinoma (HCC), lung cancer, breast cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, malignant glioma, ovarian cancer and renal cancer. Immunohistochemistry and cytoimmunofluorescence were subsequently used to determine the localization of Egfl7 in human epithelial tumor tissues and cell lines. ELISA was also carried out to examine the serum Egfl7 levels in cancer patients. In addition, correlations between Egfl7 expression and clinicopathological features as well as prognosis of HCC and breast cancer were also analyzed on the basis of immunohistochemistry results.
 Egfl7 was differentially expressed in 19 adult human normal tissues and was overexpressed in all 10 human epithelial tumor tissues. The serum Egfl7 level was also significantly elevated in cancer patients. The increased Egfl7 expression in HCC correlated with vein invasion, absence of capsule formation, multiple tumor nodes and poor prognosis. Similarly, upregulation of Egfl7 in breast cancer correlated strongly with TNM stage, lymphatic metastasis, estrogen receptor positivity, Her2 positivity and poor prognosis. 
 Egfl7 is significantly upregulated in human epithelial tumor tissues, suggesting Egfl7 to be a potential biomarker for human epithelial tumors, especially HCC and breast cancer.

  19. Enrichment of tumor cells for cell kinetic analysis in human tumor biopsies using cytokeratin gating

    International Nuclear Information System (INIS)

    Haustermans, K.; Hofland, I.; Ramaekers, M.; Ivanyi, D.; Balm, A.J.M.; Geboes, K.; Lerut, T.; Schueren, E. van der; Begg, A.C.

    1996-01-01

    Purpose: To determine the feasibility of using cytokeratin antibodies to distinguish normal and malignant cells in human tumors using flow cytometry. The goal was ultimately to increase the accuracy of cell kinetic measurements on human tumor biopsies. Material and methods: A panel of four antibodies was screened on a series of 48 tumors from two centres; 22 head and neck tumors (Amsterdam) and 26 esophagus carcinomas (Leuven). First, screening was carried out by immunohistochemistry on frozen sections to test intensity of staining and the fraction of cytokeratin-positive tumor cells. The antibody showing the most positive staining was then used for flow cytometry on the same tumor. Results: The two broadest spectrum antibodies (AE1/AE3, E3/C4) showed overall the best results with immunohistochemical staining, being positive in over 95% of tumors. Good cell suspensions for DNA flow cytometry could be made from frozen material by a mechanical method, whereas enzymatic methods with trypsin or collagenase were judged failures in almost all cases. >From fresh material, both collagenase and trypsin produced good suspensions for flow cytometry, although the fraction of tumor cells, judged by proportion aneuploid cells, was markedly higher for trypsin. Using the best cytokeratin antibody for each tumor, two parameter flow cytometry was done (cytokeratin versus DNA content). Enrichment of tumor cells was then tested by measuring the fraction of aneuploid cells (the presumed malignant population) of cytokeratin-positive cells versus all cells. An enrichment factor ranging between 0 (no enrichment) and 1 (perfect enrichment, tumor cells only) was then calculated. The average enrichment was 0.60 for head and neck tumors and 0.59 for esophagus tumors. Conclusions: We conclude that this method can substantially enrich the proportion of tumor cells in biopsies from carcinomas. Application of this method could significantly enhance accuracy of tumor cell kinetic measurements

  20. Neurofibromatosis tipo 1 asociado a tumor maligno de la vaina de nervio periférico y a carcinoma de colon

    Directory of Open Access Journals (Sweden)

    Rubén Valle

    2009-09-01

    Full Text Available La neurofibromatosis tipo 1 es una enfermedad autosómica dominante, producida por la mutación del gen de la neurofibrina, localizado en el cromosoma 17q11.2. Esta enfermedad presenta una diversidad de manifestaciones clínicas y predisposición al desarrollo de tumores, lo cual explica la elevada mortalidad. Presentamos el caso de una paciente con diagnóstico de neurofibromatosis tipo 1, quién desarrolló un tumor maligno de la vaina del nervio periférico y cáncer de colon. Se revisa la literatura y los factores clínicos, de imagen e histológicos que se asocian a la transformación maligna de los neurofibromas.

  1. Prevention and treatment of colon cancer by peroral administration of HAMLET (human α-lactalbumin made lethal to tumour cells).

    Science.gov (United States)

    Puthia, Manoj; Storm, Petter; Nadeem, Aftab; Hsiung, Sabrina; Svanborg, Catharina

    2014-01-01

    Most colon cancers start with dysregulated Wnt/β-catenin signalling and remain a major therapeutic challenge. Examining whether HAMLET (human α-lactalbumin made lethal to tumour cells) may be used for colon cancer treatment is logical, based on the properties of the complex and its biological context. To investigate if HAMLET can be used for colon cancer treatment and prevention. Apc(Min)(/+) mice, which carry mutations relevant to hereditary and sporadic human colorectal tumours, were used as a model for human disease. HAMLET was given perorally in therapeutic and prophylactic regimens. Tumour burden and animal survival of HAMLET-treated and sham-fed mice were compared. Tissue analysis focused on Wnt/β-catenin signalling, proliferation markers and gene expression, using microarrays, immunoblotting, immunohistochemistry and ELISA. Confocal microscopy, reporter assay, immunoprecipitation, immunoblotting, ion flux assays and holographic imaging were used to determine effects on colon cancer cells. Peroral HAMLET administration reduced tumour progression and mortality in Apc(Min)(/+) mice. HAMLET accumulated specifically in tumour tissue, reduced β-catenin and related tumour markers. Gene expression analysis detected inhibition of Wnt signalling and a shift to a more differentiated phenotype. In colon cancer cells with APC mutations, HAMLET altered β-catenin integrity and localisation through an ion channel-dependent pathway, defining a new mechanism for controlling β-catenin signalling. Remarkably, supplying HAMLET to the drinking water from the time of weaning also significantly prevented tumour development. These data identify HAMLET as a new, peroral agent for colon cancer prevention and treatment, especially needed in people carrying APC mutations, where colon cancer remains a leading cause of death.

  2. Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zehua; Cui, Feifei; Yu, Fudong; Peng, Xiao; Jiang, Tao; Chen, Dawei [Department of General Surgery, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Lu, Su [Department of Pathology, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Tang, Huamei, E-mail: tanghuamei@gmail.com [Department of Pathology, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Peng, Zhihai, E-mail: zhihai.peng@hotmail.com [Department of General Surgery, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China)

    2014-06-27

    Highlights: • We identified that CHAF1A was up-regulated in colon tumor mucosa in TMA. • The expression pattern of CHAF1A was validated with qPCR and western-blot. • CHAF1A overexpression is an independent indicator for poor colon cancer survival. • CHAF1A facilitates cell proliferation of colon cancer both in vitro and in vivo. - Abstract: Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) was significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation.

  3. Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

    International Nuclear Information System (INIS)

    Wu, Zehua; Cui, Feifei; Yu, Fudong; Peng, Xiao; Jiang, Tao; Chen, Dawei; Lu, Su; Tang, Huamei; Peng, Zhihai

    2014-01-01

    Highlights: • We identified that CHAF1A was up-regulated in colon tumor mucosa in TMA. • The expression pattern of CHAF1A was validated with qPCR and western-blot. • CHAF1A overexpression is an independent indicator for poor colon cancer survival. • CHAF1A facilitates cell proliferation of colon cancer both in vitro and in vivo. - Abstract: Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) was significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation

  4. Parenteral and Early Enteral Feeding in Patients with Colonic Tumor

    Directory of Open Access Journals (Sweden)

    O. A. Malkov

    2008-01-01

    Full Text Available Objective: to provide evidence whether it is expedient to use an early enteral feeding protocol in patients with colonic malignancies in the postoperative period to prevent and to correct hemodynamic disorders, oxygen imbalance, and malnutrition. Subjects and methods. A hundred patients (61 males and 39 females aged 66.2±5.0 years, who had Stages 2—3 colonic malignancies, were examined. Two algorithms of postoperative management were analyzed using the traditional diet and early enteral feeding. Results. The early enteral feeding protocol improves central hemodynamics and oxygen and nutritional status, prevents moderate protein-energy deficiency in the early postoperative period and reduces the number of complications and fatal outcomes in patients with colonic malignancies. Key words: malignancies, malnutrition, hemo-dynamics, oxygen status, enteral feeding.

  5. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth.

    Directory of Open Access Journals (Sweden)

    Ron Firestein

    2008-04-01

    Full Text Available Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR, a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.

  6. Peroxiredoxin 2 is essential for maintaining cancer stem cell-like phenotype through activation of Hedgehog signaling pathway in colon cancer.

    Science.gov (United States)

    Wang, Rong; Wei, Jinlai; Zhang, Shouru; Wu, Xingye; Guo, Jinbao; Liu, Maoxi; Du, Kunli; Xu, Jun; Peng, Linglong; Lv, Zhenbing; You, Wenxian; Xiong, Yongfu; Fu, Zhongxue

    2016-12-27

    Cancer stem cells (CSCs) are a key target for reducing tumor growth, metastasis, and recurrence. Redox status is a critical factor in the maintenance of CSCs, and the antioxidant enzyme Peroxiredoxin 2 (Prdx2) plays an important role in the development of colon cancer. Therefore, we investigated the contribution of Prdx2 to the maintenance of stemness of colon CSCs. Here, we used short-hairpin RNAs and a Prdx2-overexpression vector to determine the effects of Prdx2. We demonstrated that knockdown of Prdx2 reduced the self-renewal and sphere formation and resulted in increased 5-FU-induced apoptosis in human colon CSCs. Prdx2 overexpression induced reversion of the self-renewal and sphere formation. Furthermore, the effects of Prdx2 resulted in an altered expression of stemness associated with the Hh/Gli1 signaling pathway. Finally, knockdown of Prdx2 in CD133+ cells reduced the volume of xenograft tumors in BALB/c-nu mice. Taken together, colon CSCs overexpress Prdx2, which promotes their stem cell properties via the Hh/Gli1 signaling pathway. The results suggest that Prdx2 may be an effective therapeutic target for the elimination of CSCs in colorectal cancer.

  7. Radiobiological hypoxic fraction does not correlate with pO2 measurements in eight human tumor xenografts into nude mice

    International Nuclear Information System (INIS)

    Taghian, A.; Huang, P.; Griffon, G.; Hartford, A.; Allam, A.; Costa, A. da; Kozin, S.; Suit, H.D.

    1997-01-01

    Purpose/Objective: Clinical and laboratory reports suggest that hypoxia limits local control probability in tumors treated by radiation. Significant increase in the TCD 50 (the dose of radiation needed to control 50% of the tumors) was obtained in a number of tumor models when the tumors were rendered hypoxic by clamping. Furthermore, recent data have shown the value of measuring the pO2 using electrodes in predicting the tumor response to radiation in cervical cancer. The aim of this study is to investigate the correlation between the radiobiological hypoxic fraction (HF) and the pO2 measurements of human tumor xenografts. Materials and Methods: Eight human tumor xenografts (five glioblastoma, one squamous cell carcinoma, one colon cancer, and one soft tissue sarcoma) were used in these experiments. Tumor chunks 2 mm in diameter were implanted into the hindleg of 5 Gy whole-body irradiated nude mice. When the tumor size reached 110 mm 3 , radiation was administered in a single dose ranging from 17.5 Gy to 90 Gy in hypoxic conditions. Acute hypoxia was induced by clamping the tumor bearing leg three minutes before and during the treatment. When aerobic conditions were required, the tumor bearing leg was immobilized by a hook which fitted around the ankle. Seven to 10 tumors were assigned to each dose level in each assay; there were 6 to 8 dose levels per assay. Starting at 2-3 weeks after irradiation, the animals were examined once per week and scored for presence of local tumor; if present, tumor diameters were measured. Tumor response is described in terms of radiation dose (in Gy) required to control 50% of the xenografts (TCD 50 ). The (HF) was determined using the formula of Howes (HF=e - ((TCD 50 hypoxic-TCD 50 air)(Do hypoxic)) and assuming an oxygen enhancement ratio of 3.0: (D o hyp=D o air x 3.0) (the D o air was separately determined in vitro for the corresponding cell lines). The pO2 measurements used electrodes as published (Boucher et al

  8. Experimental studies of colon carcinoma imaging with 99Tcm labeled neurotension peptide

    International Nuclear Information System (INIS)

    Zhang Kaijun; Zhang Yongxue; An Rui; Gao Zairong

    2004-01-01

    Objective: To prepare neurotension (NT) peptide labeled with 99 Tc m for the early diagnosis of colon carcinoma and to evaluate the advantages of the tracer. Methods: Biodistribution studies were performed at 3 and 12 h, respectively after injection of 99 Tc m -NT, and tissue distribution analysis after receptor-blocking was performed at 3 h in nude mice bearing colon carcinoma. Imaging with 99 Tc m -NT was performed at different time points in nude mice bearing colon carcinoma, and imaging after receptor-blocking was also performed at 3 h. The affinity of 99 Tc m -NT binding to the cell of colon carcinoma was studied in vitro. Results: The affinity constant of 99 Tc m -NT binding to the cells of colon carcinoma was obtained (Kd=0.91 nmol/L). The labeling yield of 99 Tc m -NT was more than 94% and the complex was stable in vitro and in vivo. Biodistribution analysis in nude mice bearing colon carcinoma showed that 99 Tc m -NT was excreted chiefly from the kidney, the ratios of tumor to muscle at 3 and 12 h were 3.25 ± 1.02 and 4.15 ± 1.46, respectively. In mice pretreated with unlabeled NT, the uptake of 99 Tc m -NT decreased in the tumor, the ratio of tumor to muscle at 3 h (1.21 ± 0.62) was significantly different from that of the mice without unlabeled NT treatment. Tumor lesion was detected with 99 Tc m -NT earlier (the lesion image showed up at 0.5 h postinjection), the ratio of tumor to contralateral limb at 3 h postinjection was 2.68 ± 0.44 obtained by technique of region of interest (ROI) . The ratio at 3 h was 1.14 ± 0.36 and that was significantly different from the ratio at 3 h postinjection in mice pretreated with unlabeled NT. Conclusion: The results of all studies in vitro and in vivo indicate that this labeling procedure of 99 Tc m -NT is simple and its specific binding to the cells of colon carcinoma is high, and it is a promising method for diagnosis of colon carcinoma

  9. Personalized Proteome Profiles of Healthy and Tumor Human Colon Organoids Reveal Both Individual Diversity and Basic Features of Colorectal Cancer.

    Science.gov (United States)

    Cristobal, Alba; van den Toorn, Henk W P; van de Wetering, Marc; Clevers, Hans; Heck, Albert J R; Mohammed, Shabaz

    2017-01-03

    Diseases at the molecular level are complex and patient dependent, necessitating development of strategies that enable precision treatment to optimize clinical outcomes. Organoid technology has recently been shown to have the potential to recapitulate the in vivo characteristics of the original individual's tissue in a three-dimensional in vitro culture system. Here, we present a quantitative mass-spectrometry-based proteomic analysis and a comparative transcriptomic analysis of human colorectal tumor and healthy organoids derived, in parallel, from seven patients. Although gene and protein signatures can be derived to distinguish the tumor organoid population from healthy organoids, our data clearly reveal that each patient possesses a distinct organoid signature at the proteomic level. We demonstrate that a personalized patient-specific organoid proteome profile can be related to the diagnosis of a patient and with future development contribute to the generation of personalized therapies. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Prophylactic effects of triptolide on colon cancer development in ...

    African Journals Online (AJOL)

    Purpose: To investigate effects of triptolide on colon cancer cell growth and its capacity to prevent tumor development in an azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model of colon cancer. Methods: HCT116 cell viability and migration potential were assessed. Control and AOM/DSS-treated mice (with and ...

  11. T3 receptors in human pituitary tumors.

    Science.gov (United States)

    Machiavelli, Gloria A; Pauni, Micaela; Heredia Sereno, Gastón M; Szijan, Irene; Basso, Armando; Burdman, José A

    2009-11-01

    The purpose of this work was to investigate the synthesis of T3 receptors in human tumors of the anterior pituitary gland, its relationship with the hormone synthesized and/or secreted by the tumor and the post-surgical evolution of the patient. Patients were evaluated clinically and by magnetic nuclear resonance to classify the adenoma according to their size. Hormonal concentrations in sera were determined by radioimmunoassay. Immunohistochemistry of the pituitary hormones was performed in the tumors. Tumors were obtained at surgery and immediately frozen in ice, transported to the laboratory and stored at -70 degrees C. Reverse transcription was performed with purified RNA from the tumors. Out of 33 pituitary tumors, 29 had RNA for T3 receptors synthesis (88%). They were present in different histological specimens, the tumors were grades 1-4 according to their size, and there was no relationship between the size of the tumor and the presence of T3 receptor RNAs. The post-surgical evolution of the patient was mostly dependent on the size and not on the presence of T3 receptors. The presence of thyroid hormone receptors in pituitary tumors is in line with two important characteristics of these tumors: they are histologically benign and well differentiated.

  12. Clinical investigation of TROP-2 as an independent biomarker and potential therapeutic target in colon cancer.

    Science.gov (United States)

    Zhao, Peng; Yu, Hai-Zheng; Cai, Jian-Hui

    2015-09-01

    Colon cancer is associated with a severe demographic and economic burden worldwide. The pathogenesis of colon cancer is highly complex and involves sequential genetic and epigenetic mechanisms. Despite extensive investigation, the pathogenesis of colon cancer remains to be elucidated. As the third most common type of cancer worldwide, the treatment options for colon cancer are currently limited. Human trophoblast cell‑surface marker (TROP‑2), is a cell‑surface transmembrane glycoprotein overexpressed by several types of epithelial carcinoma. In addition, TROP‑2 has been demonstrated to be associated with tumorigenesis and invasiveness in solid types of tumor. The aim of the present study was to investigate the protein expression of TROP‑2 in colon cancer tissues, and further explore the association between the expression of TROP‑2 and clinicopathological features of patients with colon cancer. The expression and localization of the TROP‑2 protein was examined using western blot analysis and immunofluorescence staining. Finally, the expression of TROP‑2 expression was correlated to conventional clinicopathological features of colon cancer using a χ2 test. The results revealed that TROP‑2 protein was expressed at high levels in the colon cancer tissues, which was associated with the development and pathological process of colon cancer. Therefore, TROP‑2 may be used as a biomarker to determine the clinical prognosis, and as a potential therapeutic target in colon cancer.

  13. [A case of obstruction due to right-sided colon cancer in which good quality of life was achieved after colonic stenting].

    Science.gov (United States)

    Nakao, Shigetomi; Hori, Takeshi; Miura, Kotaro; Tendo, Masashige; Nakata, Bunzo; Ishikawa, Tetsuro; Hirakawa, Kosei

    2013-11-01

    We report a case of a 60-year-old woman with abdominal distension who was treated with self-expandable metal stent (SEMS) placement in the proximal transverse colon. She was found to have severe bowel obstruction due to advanced transverse colon cancer on plain computed tomography (CT) and colonoscopy. We performed colonic stenting safely, and the symptom promptly improved. Defecation and flatus were observed on the same day of stenting, and the patient was able to start drinking and eating on the next day. Enhanced abdominal CT revealed multiple liver metastasis, peritoneal dissemination, ascites, and cystic ovarian tumor. After treatment with 1 course of 5-fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX6), the patient was discharged on day 14 after admission. The rapidly enlarging ovarian tumors and primary colonic lesion with SEMS were surgically removed after treatment with mFOLFOX6 for 4 months in an outpatient basis. The patient has been alive with a good quality of life (QOL) and being treated with bevacizumab plus mFOLFOX6/Leucovorin, 5-fluorouracil, and irinotecan( FOLFIRI) for 6 months. SEMS placement could be safe and effective for the treatment of obstruction of the right colon, and could maintain a good QOL in patients.

  14. [A Case of Transverse Colon Cancer Metastasized to the Spermatic Cord after Resection of Peritoneal Dissemination].

    Science.gov (United States)

    Kikuchi, Isao; Kimura, Tomoaki; Azuma, Saya; Shimbo, Tomonori; Wakabayashi, Toshiki; Ota, Sakae; Sato, Tsutomu; Itoh, Seiji; Ishida, Toshiya; Sageshima, Masato

    2017-11-01

    We report a rare case of spermatic cord metastasis from colon cancer. A man in his 50s underwent extended right hemicolectomy for transverse colon cancer followed by resection of a peritoneal recurrence. After receiving adjuvant chemotherapy for 6 months, he became aware of a right inguinal mass. A spermatic cord tumor was noted on computed tomography(CT) and FDG/PET-CT. He underwent radical orchiectomy. The resected tumor was histologically compatible with the colon cancer. Although he received additional chemotherapy, right inguinal recurrence was resected 6 months after orchiectomy. Colon cancer is the second most common origin, after gastric cancer, of metastatic spermatic tumor. As several metastatic routes have been reported, peritoneal seeding is mostly suspected in this case.

  15. A comparison of 12-gene colon cancer assay gene expression in African American and Caucasian patients with stage II colon cancer.

    Science.gov (United States)

    Govindarajan, Rangaswamy; Posey, James; Chao, Calvin Y; Lu, Ruixiao; Jadhav, Trafina; Javed, Ahmed Y; Javed, Awais; Mahmoud, Fade A; Osarogiagbon, Raymond U; Manne, Upender

    2016-06-18

    African American (AA) colon cancer patients have a worse prognosis than Caucasian (CA) colon cancer patients, however, reasons for this disparity are not well understood. To determine if tumor biology might contribute to differential prognosis, we measured recurrence risk and gene expression using the Oncotype DX® Colon Cancer Assay (12-gene assay) and compared the Recurrence Score results and gene expression profiles between AA patients and CA patients with stage II colon cancer. We retrieved demographic, clinical, and archived tumor tissues from stage II colon cancer patients at four institutions. The 12-gene assay and mismatch repair (MMR) status were performed by Genomic Health (Redwood City, California). Student's t-test and the Wilcoxon rank sum test were used to compare Recurrence Score data and gene expression data from AA and CA patients (SAS Enterprise Guide 5.1). Samples from 122 AA and 122 CA patients were analyzed. There were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median age was 66 years for AA patients and 68 for CA patients. Age, gender, year of surgery, pathologic T-stage, tumor location, the number of lymph nodes examined, lymphovascular invasion, and MMR status were not significantly different between groups (p = 0.93). The mean Recurrence Score result for AA patients (27.9 ± 12.8) and CA patients (28.1 ± 11.8) was not significantly different and the proportions of patients with high Recurrence Score values (≥41) were similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC and GADD45B), was significantly different between the racial groups. After controlling for clinical and pathologic covariates, the means and distributions of Recurrence Score results and gene expression profiles showed no statistically significant difference between patient groups. The distribution of

  16. A comparison of 12-gene colon cancer assay gene expression in African American and Caucasian patients with stage II colon cancer

    International Nuclear Information System (INIS)

    Govindarajan, Rangaswamy; Posey, James; Chao, Calvin Y.; Lu, Ruixiao; Jadhav, Trafina; Javed, Ahmed Y.; Javed, Awais; Mahmoud, Fade A.; Osarogiagbon, Raymond University; Manne, Upender

    2016-01-01

    African American (AA) colon cancer patients have a worse prognosis than Caucasian (CA) colon cancer patients, however, reasons for this disparity are not well understood. To determine if tumor biology might contribute to differential prognosis, we measured recurrence risk and gene expression using the Oncotype DX® Colon Cancer Assay (12-gene assay) and compared the Recurrence Score results and gene expression profiles between AA patients and CA patients with stage II colon cancer. We retrieved demographic, clinical, and archived tumor tissues from stage II colon cancer patients at four institutions. The 12-gene assay and mismatch repair (MMR) status were performed by Genomic Health (Redwood City, California). Student’s t-test and the Wilcoxon rank sum test were used to compare Recurrence Score data and gene expression data from AA and CA patients (SAS Enterprise Guide 5.1). Samples from 122 AA and 122 CA patients were analyzed. There were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median age was 66 years for AA patients and 68 for CA patients. Age, gender, year of surgery, pathologic T-stage, tumor location, the number of lymph nodes examined, lymphovascular invasion, and MMR status were not significantly different between groups (p = 0.93). The mean Recurrence Score result for AA patients (27.9 ± 12.8) and CA patients (28.1 ± 11.8) was not significantly different and the proportions of patients with high Recurrence Score values (≥41) were similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC and GADD45B), was significantly different between the racial groups. After controlling for clinical and pathologic covariates, the means and distributions of Recurrence Score results and gene expression profiles showed no statistically significant difference between patient groups. The distribution of Recurrence Score

  17. [A Case of Huge Colon Cancer Accompanied with Severe Hypoproteinemia].

    Science.gov (United States)

    Hiraki, Sakurao; Kanesada, Kou; Harada, Toshio; Tada, Kousuke; Fukuda, Shintaro

    2017-11-01

    We report a case of huge colon cancer accompanied with severe hypoproteinemia. A7 4-year-old woman was referred to our hospital because of abdominal fullness. Blood examinations revealed anemia(hemoglobin 8.8 g/dL)and sever hypopro- teinemia(total protein 4.5 g/dL, albumin 1.1 g/dL). Computed tomography examination of abdomen revealed ascites and large tumor(12.5×10.5 cm)at the right side colon. By further examinations ascending colon cancer without distant metastasis was diagnosed, then we performed right hemicolectomy and primary intestinal anastomosis by open surgery. Ahuge type 1 tumor(18×12 cm)was observed in the excised specimen, which invaded to terminal ileum directly. The tumor was diagnosed moderately differentiated adenocarcinoma without lymph node metastasis(pT3N0M0, fStage II ). Postoperative course was uneventful and serum protein concentration recovered gradually to normal range. Protein leakage from the tumor cannot be proved by this case, so we can't diagnose as protein-losing enteropathy, but we strongly doubt this etiology from postoperative course in this case.

  18. Neurological manifestation of colonic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Uzair Chaudhary

    2012-04-01

    Full Text Available Paraneoplastic neurologic disorders are extremely rare in cancer patients and are most commonly associated with certain tumors, such as ovarian cancer, small cell lung cancer, and breast cancer. We report here a paraneoplastic neurological syndrome in a 53-year-old man with colonic adenocarcinoma with a solitary liver metastasis. His paraneoplastic syndrome was successfully treated by methylprednisolone and primary oncologic therapies including neoadjuvant chemotherapy and definitive surgery. This is also the first documented case of simultaneous manifestation of a sensory neuropathy and limbic encephalitis with colon cancer.

  19. Selection of monoclonal anti-CEA antibody fragments for tumor detection by immunoscintigraphy

    International Nuclear Information System (INIS)

    Mach, J.P.; Buchegger, F.

    1986-01-01

    It is described how individual MAb directed against carcinoembryotic antigen (CEA) is selected which does not crossreact with granulocytes and gives the best tumor localization in the model of nude mice grafted with human colon carcinoma. Using this model, the superiority of F(ab')/sub 2/ and particularly Fab fragments from high affinity MAb for the localization of relatively small tumor nodules is demonstrated. These MAb fragments are also successfully used in an ongoing clinical trial for the detection of primary and metastatic colorectal carcinomas

  20. Caveolin-1-mediated post-transcriptional regulation of inducible nitric oxide synthase in human colon carcinoma cells

    Directory of Open Access Journals (Sweden)

    EMANUELA FELLEY-BOSCO

    2002-01-01

    Full Text Available Reactive oxygen species are now widely recognized as important players contributing both to cell homeostasis and the development of disease. In this respect nitric oxide (NO is no exception. The discussion here will center on regulation of the inducible form of nitric oxide synthase (iNOS for two reasons. First, only iNOS produces micromolar NO concentrations, amounts that are high by comparison with the picomolar to nanomolar concentrations resulting from Ca2+-controlled NO production by endothelial eNOS or neuronal nNOS. Second, iNOS is not constitutively expressed in cells and regulation of this isoenzyme, in contrast to endothelial eNOS or neuronal nNOS, is widely considered to occur at the transcriptional level only. In particular, we were interested in the possibility that caveolin-1, a protein that functions as a tumor suppressor in colon carcinoma cells (Bender et al., 2002; this issue, might regulate iNOS activity. Our results provide evidence for the existence of a post-transcriptional mechanism controlling iNOS protein levels that involves caveolin-1-dependent sequestration of iNOS within a detergent-insoluble compartment. Interestingly, despite the high degree of conservation of the caveolin-1 scaffolding domain binding motif within all NOS enzymes, the interaction detected between caveolin-1 and iNOS in vitro is crucially dependent on presence of a caveolin-1 sequence element immediately adjacent to the scaffolding domain. A model is presented summarizing the salient aspects of these results. These observations are important in the context of tumor biology, since down-regulation of caveolin-1 is predicted to promote uncontrolled iNOS activity, genotoxic damage and thereby facilitate tumor development in humans

  1. MicroRNA classifier and nomogram for metastasis prediction in colon cancer.

    Science.gov (United States)

    Goossens-Beumer, Inès J; Derr, Remco S; Buermans, Henk P J; Goeman, Jelle J; Böhringer, Stefan; Morreau, Hans; Nitsche, Ulrich; Janssen, Klaus-Peter; van de Velde, Cornelis J H; Kuppen, Peter J K

    2015-01-01

    Colon cancer prognosis and treatment are currently based on a classification system still showing large heterogeneity in clinical outcome, especially in TNM stages II and III. Prognostic biomarkers for metastasis risk are warranted as development of distant recurrent disease mainly accounts for the high lethality rates of colon cancer. miRNAs have been proposed as potential biomarkers for cancer. Furthermore, a verified standard for normalization of the amount of input material in PCR-based relative quantification of miRNA expression is lacking. A selection of frozen tumor specimens from two independent patient cohorts with TNM stage II-III microsatellite stable primary adenocarcinomas was used for laser capture microdissection. Next-generation sequencing was performed on small RNAs isolated from colorectal tumors from the Dutch cohort (N = 50). Differential expression analysis, comparing in metastasized and nonmetastasized tumors, identified prognostic miRNAs. Validation was performed on colon tumors from the German cohort (N = 43) using quantitative PCR (qPCR). miR25-3p and miR339-5p were identified and validated as independent prognostic markers and used to construct a multivariate nomogram for metastasis risk prediction. The nomogram showed good probability prediction in validation. In addition, we recommend combination of miR16-5p and miR26a-5p as standard for normalization in qPCR of colon cancer tissue-derived miRNA expression. In this international study, we identified and validated a miRNA classifier in primary cancers, and propose a nomogram capable of predicting metastasis risk in microsatellite stable TNM stage II-III colon cancer. In conjunction with TNM staging, by means of a nomogram, this miRNA classifier may allow for personalized treatment decisions based on individual tumor characteristics. ©2014 American Association for Cancer Research.

  2. miR-4458 suppresses glycolysis and lactate production by directly targeting hexokinase2 in colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Yaguang; Cheng, Chuanyao; Lu, Hong, E-mail: honglu6512@163.com; Wang, Yaqiu

    2016-01-01

    miR-4458, a new tumor-suppressor, was reported to down-regulated in human hepatocellular carcinoma. The expression status, roles and inhibitory mechanisms of miR-4458 in other tumors still need to be clarified. The aim of this study is to investigate the effects of miR-4458 and to elucidate the potential mechanism in colon cancer cells. Using bioinformatic databases, we predicted that hexokinase2 (HK2), a rate-limiting enzyme in the glycolytic pathway, was a target of miR-4458, so the effects of miR-4458 on glycolysis and lactate production was assessed in colon cancer cells. We found that miR-4458 was down-regulated and HK2 was up-regulated in colon cancer cells. Overexpression of miR-4458 inhibited proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. Luciferase activity assays showed that HK2 was a direct target of miR-4458. Moreover, knockdown of HK2 by specific RNAi also suppressed proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. In conclusion, our findings suggested that miR-4458 inhibited the progression of colon cancer cells by inhibition of glycolysis and lactate production via directly targeting HK2 mRNA. - Highlights: • miR-4458 is down-regulated in colon cancer cells. • miR-4458 suppresses proliferation, glycolysis, and lactate production. • HK2 is a target of miR-4458. • HK2 knockdown inhibits proliferation, glycolysis, and lactate production.

  3. Carotenoids and colon cancer.

    Science.gov (United States)

    Slattery, M L; Benson, J; Curtin, K; Ma, K N; Schaeffer, D; Potter, J D

    2000-02-01

    Carotenoids have numerous biological properties that may underpin a role for them as chemopreventive agents. However, except for beta-carotene, little is known about how dietary carotenoids are associated with common cancers, including colon cancer. The objective of this study was to evaluate associations between dietary alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin and the risk of colon cancer. Data were collected from 1993 case subjects with first primary incident adenocarcinoma of the colon and from 2410 population-based control subjects. Dietary data were collected from a detailed diet-history questionnaire and nutrient values for dietary carotenoids were obtained from the US Department of Agriculture-Nutrition Coordinating Center carotenoid database (1998 updated version). Lutein was inversely associated with colon cancer in both men and women [odds ratio (OR) for upper quintile of intake relative to lowest quintile of intake: 0.83; 95% CI: 0.66, 1.04; P = 0.04 for linear trend]. The greatest inverse association was observed among subjects in whom colon cancer was diagnosed when they were young (OR: 0.66; 95% CI: 0.48, 0.92; P = 0.02 for linear trend) and among those with tumors located in the proximal segment of the colon (OR: 0.65; 95% CI: 0.51, 0.91; P lettuce, tomatoes, oranges and orange juice, carrots, celery, and greens. These data suggest that incorporating these foods into the diet may help reduce the risk of developing colon cancer.

  4. [A Case of Chemotherapy with FOLFOXIRI plus Cetuximab for Liver Metastasis of Sigmoid ColonCan cer].

    Science.gov (United States)

    Saito, Akina; Konishi, Ken; Fukunaga, Mutsumi; Takiguchi, Nobuo; Nakai, Shigeto; Honda, Shoko; Yukimoto, Ryohei; Okamoto, Aoi; Takeoka, Tomohira; Matsuno, Hiroshi; Okada, Kazuyuki; Ota, Hideo; Yokoyama, Shigekazu; Konishi, Muneharu; Kobayashi, Kenji

    2018-03-01

    We report a case of chemotherapy with FOLFOXIRI plus cetuximab for liver metastasis of sigmoid colon cancer. The patient was a 40's man who was diagnosed with sigmoid colon cancer with liver metastasis. Colonoscopy revealed a type 2 tumor with stenosis in the sigmoid colon. He underwent sigmoidectomy under laparotomy, and after the operation, received 7 courses of chemotherapy with FOLFOXIRI plus cetuximab. The liver tumor was sufficiently reduced, and laparotomy and liver right lobectomy were performed. Histopathology revealed a modified, Grade 2 tumor regression. He has been followed for 1 year 4months after the operation.

  5. Galectin-3-independent Down-regulation of GABABR1 due to Treatment with Korean Herbal Extract HAD-B Reduces Proliferation of Human Colon Cancer Cells

    Directory of Open Access Journals (Sweden)

    Kim Kyung-Hee

    2012-09-01

    Full Text Available Objectives: Many efforts have shown multi-oncologic roles of galectin-3 for cell proliferation, angiogenesis, and apoptosis. However, the mechanisms by which galectin-3 is involved in cell proliferation are not yet fully understood, especially in human colon cancer cells. Methods: To cluster genes showing positively or negatively correlated expression with galectin-3, we employed human colon cancer cell lines, SNU-61, SNU-81, SNU-769B, SNU-C4 and SNU-C5 in high-throughput gene expression profiling. Gene and protein expression levels were determined by using real-time quantitative polymerase chain reaction (PCR and western blot analysis, respectively. The proliferation rate of human colon cancer cells was measured by using a 3-(4, 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide (MTT assay. Results: Expression of γ-aminobutyric acid B receptor 1 (GABABR1 showed a positive correlation with galectin-3 at both the transcriptional and the translational levels. Downregulation of galectin-3 decreased not only GABABR1 expression but also the proliferation rate of human colon cancer cells. However, Korean herbal extract, HangAmDan-B (HAD-B, decreased expression of GABABR1 without any expressional change of galectin-3, and offset γ-aminobutyric acid (GABA-enhanced human colon cancer cell proliferation. Conclusions: Our present study confirmed that GABABR1 expression was regulated by galectin-3. HAD-B induced galectin-3-independent down-regulation of GABABR1, which resulted in a decreased proliferation of human colon cancer cells. The therapeutic effect of HAD-B for the treatment of human colon cancer needs to be further validated.

  6. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon

    DEFF Research Database (Denmark)

    Autrup, Herman; Essigmann, John M.; Croy, Robert G.

    1979-01-01

    Aflatoxin B1 and benzo(a)pyrene were activated by both cultured human bronchus and human colon as measured by binding to cellular DNA and protein. The binding of aflatoxin B1 to DNA was dose dependent, and the level of binding was higher in cultured human bronchus than it was in the colon. When c...

  7. Monitoring Cell Death in Regorafenib-Treated Experimental Colon Carcinomas Using Annexin-Based Optical Fluorescence Imaging Validated by Perfusion MRI.

    Directory of Open Access Journals (Sweden)

    Philipp M Kazmierczak

    Full Text Available To investigate annexin-based optical fluorescence imaging (OI for monitoring regorafenib-induced early cell death in experimental colon carcinomas in rats, validated by perfusion MRI and multiparametric immunohistochemistry.Subcutaneous human colon carcinomas (HT-29 in athymic rats (n = 16 were imaged before and after a one-week therapy with regorafenib (n = 8 or placebo (n = 8 using annexin-based OI and perfusion MRI at 3 Tesla. Optical signal-to-noise ratio (SNR and MRI tumor perfusion parameters (plasma flow PF, mL/100mL/min; plasma volume PV, % were assessed. On day 7, tumors underwent immunohistochemical analysis for tumor cell apoptosis (TUNEL, proliferation (Ki-67, and microvascular density (CD31.Apoptosis-targeted OI demonstrated a tumor-specific probe accumulation with a significant increase of tumor SNR under therapy (mean Δ +7.78±2.95, control: -0.80±2.48, p = 0.021. MRI detected a significant reduction of tumor perfusion in the therapy group (mean ΔPF -8.17±2.32 mL/100 mL/min, control -0.11±3.36 mL/100 mL/min, p = 0.036. Immunohistochemistry showed significantly more apoptosis (TUNEL; 11392±1486 vs. 2921±334, p = 0.001, significantly less proliferation (Ki-67; 1754±184 vs. 2883±323, p = 0.012, and significantly lower microvascular density (CD31; 107±10 vs. 182±22, p = 0.006 in the therapy group.Annexin-based OI allowed for the non-invasive monitoring of regorafenib-induced early cell death in experimental colon carcinomas, validated by perfusion MRI and multiparametric immunohistochemistry.

  8. Comparative expression pathway analysis of human and canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Marconato Laura

    2009-03-01

    Full Text Available Abstract Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved. Results We analyzed human and dog gene expression data derived from both tumor and normal mammary samples. By analyzing the expression levels of about ten thousand dog/human orthologous genes we observed a significant overlap of genes deregulated in the mammary tumor samples, as compared to their normal counterparts. Pathway analysis of gene expression data revealed a great degree of similarity in the perturbation of many cancer-related pathways, including the 'PI3K/AKT', 'KRAS', 'PTEN', 'WNT-beta catenin' and 'MAPK cascade'. Moreover, we show that the transcriptional relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Conclusion Our data confirm and further strengthen the value of the canine mammary cancer model and open up new perspectives for the evaluation of novel cancer therapeutics and the development of prognostic and diagnostic biomarkers to be used in clinical studies.

  9. In Vitro Efficient Expansion of Tumor Cells Deriving from Different Types of Human Tumor Samples

    Directory of Open Access Journals (Sweden)

    Ilaria Turin

    2014-03-01

    Full Text Available Obtaining human tumor cell lines from fresh tumors is essential to advance our understanding of antitumor immune surveillance mechanisms and to develop new ex vivo strategies to generate an efficient anti-tumor response. The present study delineates a simple and rapid method for efficiently establishing primary cultures starting from tumor samples of different types, while maintaining the immuno-histochemical characteristics of the original tumor. We compared two different strategies to disaggregate tumor specimens. After short or long term in vitro expansion, cells analyzed for the presence of malignant cells demonstrated their neoplastic origin. Considering that tumor cells may be isolated in a closed system with high efficiency, we propose this methodology for the ex vivo expansion of tumor cells to be used to evaluate suitable new drugs or to generate tumor-specific cytotoxic T lymphocytes or vaccines.

  10. Right colon cancer: Left behind.

    Science.gov (United States)

    Gervaz, P; Usel, M; Rapiti, E; Chappuis, P; Neyroud-Kaspar, I; Bouchardy, C

    2016-09-01

    Prognosis of colon cancer (CC) has steadily improved during the past three decades. This trend, however, may vary according to proximal (right) or distal (left) tumor location. We studied if improvement in survival was greater for left than for right CC. We included all CC recorded at the Geneva population-based registry between 1980 and 2006. We compared patients, tumor and treatment characteristics between left and right CC by logistic regression and compared CC specific survival by Cox models taking into account putative confounders. We also compared changes in survival between CC location in early and late years of observation. Among the 3396 CC patients, 1334 (39%) had right-sided and 2062 (61%) left-sided tumors. In the early 1980s, 5-year specific survival was identical for right and left CCs (49% vs. 48%). During the study period, a dramatic improvement in survival was observed for patients with left-sided cancers (Hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.29-0.62, p colon cancer patients, those with right-sided lesions have by far the worse prognosis. Change of strategic management in this subgroup is warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Redox-responsive microbeads containing thiolated pectin-doxorubicin conjugate inhibit tumor growth and metastasis: An in vitro and in vivo study.

    Science.gov (United States)

    Cheewatanakornkool, Kamonrak; Niratisai, Sathit; Dass, Crispin R; Sriamornsak, Pornsak

    2018-07-10

    The objective of this study was to investigate the in vitro cytotoxicity and in vivo anticancer efficacy of redox-responsive microbeads containing thiolated pectin-doxorubicin (DOX) conjugate. Oral microbeads were coated with an enteric polymer to protect the drug from release in the upper gastrointestinal (GI) tract and allow redox-triggered drug release in the colon. Morphology, particle size, drug content, and in vitro drug release behavior of the microbeads were characterized; in vitro cytotoxicity was tested on mouse colon carcinoma, human colorectal adenocarcinoma, and human bone osteosarcoma cell lines. In vivo anticancer efficacy of coated microbeads was examined in BALB/c mice with murine colon carcinoma. These coated microbeads significantly inhibited the growth of all cell lines. The in vivo study confirmed delivery of DOX to the colorectal tumor site, redox-responsiveness, and anticancer efficacy of coated microbeads. Coated microbeads also effectively inhibited primary tumor growth and suppressed tumor metastases without gross toxicity to the non-target tissue. No noticeable damage was found in mouse GI tissues, indicating lack of DOX toxicity. These novel coated microbeads containing thiolated pectin-DOX conjugate may be a promising vehicle for targeted clinical delivery of DOX to the colorectal cancer site by oral administration. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

  12. Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer.

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    Eva Pastille

    2017-09-01

    Full Text Available Inflammatory bowel diseases (IBD are chronic inflammatory disorders of the gastrointestinal tract, strongly associated with an increased risk of colorectal cancer development. Parasitic infections caused by helminths have been shown to modulate the host's immune response by releasing immunomodulatory molecules and inducing regulatory T cells (Tregs. This immunosuppressive state provoked in the host has been considered as a novel and promising approach to treat IBD patients and alleviate acute intestinal inflammation. On the contrary, specific parasite infections are well known to be directly linked to carcinogenesis. Whether a helminth infection interferes with the development of colitis-associated colon cancer (CAC is not yet known. In the present study, we demonstrate that the treatment of mice with the intestinal helminth Heligmosomoides polygyrus at the onset of tumor progression in a mouse model of CAC does not alter tumor growth and distribution. In contrast, H. polygyrus infection in the early inflammatory phase of CAC strengthens the inflammatory response and significantly boosts tumor development. Here, H. polygyrus infection was accompanied by long-lasting alterations in the colonic immune cell compartment, with reduced frequencies of colonic CD8+ effector T cells. Moreover, H. polygyrus infection in the course of dextran sulfate sodium (DSS mediated colitis significantly exacerbates intestinal inflammation by amplifying the release of colonic IL-6 and CXCL1. Thus, our findings indicate that the therapeutic application of helminths during CAC might have tumor-promoting effects and therefore should be well-considered.

  13. Locally advanced transverse colon cancer with Trousseau’s syndrome

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    V. A. Aliyev

    2012-01-01

    Full Text Available Migratory venous thrombosis is a manifestation of the rare paraneoplastic syndrome in patients with malignant neoplasms. The paper describes successful surgical treatment in a young patient with a colon tumor associated with Trousseau’s syndrome. The latter manifesting itself as ischemia forced urgent surgeons to amputate the lower third of the left leg. Locally advanced transverse colon cancer spreading to the great vessels was subsequently diagnosed. All paraneoplastic manifestations disappeared after tumor removal. The patient was professionally given surgical, anesthesiological, and resuscitative aids that not only improved his quality of life, but also gave the chance to prolong it.

  14. Standard colonic lavage alters the natural state of mucosal-associated microbiota in the human colon.

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    Laura Harrell

    Full Text Available Past studies of the human intestinal microbiota are potentially confounded by the common practice of using bowel-cleansing preparations. We examined if colonic lavage changes the natural state of enteric mucosal-adherent microbes in healthy human subjects.Twelve healthy individuals were divided into three groups; experimental group, control group one, and control group two. Subjects in the experimental group underwent an un-prepped flexible sigmoidoscopy with biopsies. Within two weeks, subjects were given a standard polyethylene glycol-based bowel cleansing preparation followed by a second flexible sigmoidoscopy. Subjects in control group one underwent two un-prepped flexible sigmoidoscopies within one week. Subjects in the second control group underwent an un-prepped flexible sigmoidoscopy followed by a second flexible sigmoidoscopy after a 24-hour clear liquid diet within one week. The mucosa-associated microbial communities from the two procedures in each subject were compared using 16S rRNA gene based terminal restriction fragment length polymorphism (T-RFLP, and library cloning and sequencing.Clone library sequencing analysis showed that there were changes in the composition of the mucosa-associated microbiota in subjects after colonic lavage. These changes were not observed in our control groups. Standard bowel preparation altered the diversity of mucosa-associated microbiota. Taxonomic classification did not reveal significant changes at the phylum level, but there were differences observed at the genus level.Standard bowel cleansing preparation altered the mucosal-adherent microbiota in all of our subjects, although the degree of change was variable. These findings underscore the importance of considering the confounding effects of bowel preparation when designing experiments exploring the gut microbiota.

  15. Increased expression of CD133 and reduced dystroglycan expression are strong predictors of poor outcome in colon cancer patients

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    Coco Claudio

    2012-09-01

    Full Text Available Abstract Background Expression levels of CD133, a cancer stem cell marker, and of the α-subunit of the dystroglycan (α-DG complex, have been previously reported to be altered in colorectal cancers. Methods Expression levels of CD133 and α-DG were assessed by immunohistochemistry in a series of colon cancers and their prognostic significance was evaluated. Results Scattered cells positive for CD133 were rarely detected at the bases of the crypts in normal colonic mucosa while in cancer cells the median percentage of positive cells was 5% (range 0–80. A significant correlation was observed with pT parameter and tumor stage but not with tumor grade and N status. Recurrence and death from disease were significantly more frequent in CD133-high expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor groups for both disease-free (p = 0.002 and overall (p = 0.008 survival. Expression of α-DG was reduced in a significant fraction of tumors but low α-DG staining did not correlate with any of the classical clinical-pathological parameters. Recurrence and death from the disease were significantly more frequent in α-DG-low expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor tumors for both disease-free (p = 0.02 and overall (p = 0.02 survival. Increased expression of CD133, but not loss of α-DG, confirmed to be an independent prognostic parameters at a multivariate analysis associated with an increased risk of recurrence (RR = 2.4; p = 0.002 and death (RR = 2.3; p = 0.003. Conclusions Loss of α-DG and increased CD133 expression are frequent events in human colon cancer and evaluation of CD133 expression could help to identify high-risk colon cancer patients.

  16. Synchronous Adenocarcinoma of the Colon and Rectal Carcinoid

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    Vamshidhar Vootla

    2016-10-01

    Full Text Available Primary colonic adenocarcinoma and synchronous rectal carcinoids are rare tumors. Whenever a synchronous tumor with a nonmetastatic carcinoid component is encountered, its prognosis is determined by the associate malignancy. The discovery of an asymptomatic gastrointestinal carcinoid during the operative treatment of another malignancy will usually only require resection without additional treatment and will have little effect on the prognosis of the individual. This article reports a synchronous rectal carcinoid in a patient with hepatic flexure adenocarcinoma. We present a case of a 46-year-old Hispanic woman with a history of hypothyroidism, uterine fibroids and hypercholesterolemia presenting with a 2-week history of intermittent abdominal pain, mainly in the right upper quadrant. She had no family history of cancers. Physical examination was significant for pallor. Laboratory findings showed microcytic anemia with a hemoglobin of 6.6 g/dl. CT abdomen showed circumferential wall thickening in the ascending colon near the hepatic flexure and pulmonary nodules. Colonoscopy showed hepatic flexure mass and rectal nodule which were biopsied. Pathology showed a moderately differentiated invasive adenocarcinoma of the colon (hepatic flexure mass and a low-grade neuroendocrine neoplasm (carcinoid of rectum. The patient underwent laparoscopic right hemicolectomy and chemotherapy. In patients diagnosed with adenocarcinoma of the colon and rectum, carcinoids could be missed due to their submucosal location, multicentricity and indolent growth pattern. Studies suggest a closer surveillance of the GI tract for noncarcinoid synchronous malignancy when a carcinoid tumor is detected and vice versa.

  17. 12/15 Lipoxygenase regulation of colorectal tumorigenesis is determined by the relative tumor levels of its metabolite 12-HETE and 13-HODE in animal models.

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    Chang, Jian; Jiang, Li; Wang, Yinqiu; Yao, Bing; Yang, Shilin; Zhang, Bixiang; Zhang, Ming-Zhi

    2015-02-20

    Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. The arachidonic acid (AA) pathway and linoleic acid (LA) pathway have been implicated as important contributors to CRC development and growth. Human 15-lipoxygenase 1 (15-LOX-1) converts LA to anti-tumor 13-S-hydroxyoctadecadienoic acid (13-HODE)and 15-LOX-2 converts AA to 15-hydroxyeicosatetraenoic acid (15-HETE). In addition, human 12-LOX metabolizes AA to pro-tumor 12-HETE. In rodents, the function of 12-LOX and 15-LOX-1 and 15-LOX-2 is carried out by a single enzyme, 12/15-LOX. As a result, conflicting conclusions concerning the role of 12-LOX and 15-LOX have been obtained in animal studies. In the present studies, we determined that PD146176, a selective 15-LOX-1 inhibitor, markedly suppressed 13-HODE generation in human colon cancer HCA-7 cells and HCA-7 tumors, in association with increased tumor growth. In contrast, PD146176 treatment led to decreases in 12-HETE generation in mouse colon cancer MC38 cells and MC38 tumors, in association with tumor inhibition. Surprisingly, deletion of host 12/15-LOX alone led to increased MC38 tumor growth, in association with decreased tumor 13-HODE levels, possibly due to inhibition of 12/15-LOX activity in stroma. Therefore, the effect of 12/15-LOX on colorectal tumorigenesis in mouse models could be affected by tumor cell type (human or mouse), relative 12/15 LOX activity in tumor cells and stroma as well as the relative tumor 13-HODE and 12-HETE levels.

  18. Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

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    Ferrone Soldano

    2007-06-01

    Full Text Available Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs, has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8+ CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular

  19. Decoding NADPH oxidase 4 expression in human tumors

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    Jennifer L. Meitzler

    2017-10-01

    Full Text Available NADPH oxidase 4 (NOX4 is a redox active, membrane-associated protein that contributes to genomic instability, redox signaling, and radiation sensitivity in human cancers based on its capacity to generate H2O2 constitutively. Most studies of NOX4 in malignancy have focused on the evaluation of a small number of tumor cell lines and not on human tumor specimens themselves; furthermore, these studies have often employed immunological tools that have not been well characterized. To determine the prevalence of NOX4 expression across a broad range of solid tumors, we developed a novel monoclonal antibody that recognizes a specific extracellular region of the human NOX4 protein, and that does not cross-react with any of the other six members of the NOX gene family. Evaluation of 20 sets of epithelial tumors revealed, for the first time, high levels of NOX4 expression in carcinomas of the head and neck (15/19 patients, esophagus (12/18 patients, bladder (10/19 patients, ovary (6/17 patients, and prostate (7/19 patients, as well as malignant melanoma (7/15 patients when these tumors were compared to histologically-uninvolved specimens from the same organs. Detection of NOX4 protein upregulation by low levels of TGF-β1 demonstrated the sensitivity of this new probe; and immunofluorescence experiments found that high levels of endogenous NOX4 expression in ovarian cancer cells were only demonstrable associated with perinuclear membranes. These studies suggest that NOX4 expression is upregulated, compared to normal tissues, in a well-defined, and specific group of human carcinomas, and that its expression is localized on intracellular membranes in a fashion that could modulate oxidative DNA damage.

  20. Colonization of plants by human pathogenic bacteria in the course of organic vegetable production

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    Andreas eHofmann

    2014-05-01

    Full Text Available In recent years, increasing numbers of outbreaks caused by the consumption of vegetables contaminated with human pathogenic bacteria were reported. The application of organic fertilizers during vegetable production is one of the possible reasons for contamination with those pathogens. In this study laboratory experiments in axenic and soil systems following common practices in organic farming were conducted to identify the minimal dose needed for bacterial colonization of plants and to identify possible factors like bacterial species or serovariation, plant species or organic fertilizer types used, influencing the success of plant colonization by human pathogenic bacteria. Spinach and corn salad were chosen as model plants and were inoculated with different concentrations of Salmonella enterica sv. Weltevreden, Listeria monocytogenes sv. 4b and EGD-E sv. 1/2a either directly (axenic system or via agricultural soil amended with spiked organic fertilizers (soil system. In addition to PCR- and culture-based detection methods, fluorescence in situ hybridization (FISH was applied in order to localize bacteria on or in plant tissues. Our results demonstrate that shoots were colonized by the pathogenic bacteria at inoculation doses as low as 4x10CFU/ml in the axenic system or 4x105CFU/g in the soil system. In addition, plant species dependent effects were observed. Spinach was colonized more often and at lower inoculation doses compared to corn salad. Differential colonization sites on roots, depending on the plant species could be detected using FISH-CLSM analysis. Furthermore, the transfer of pathogenic bacteria to plants via organic fertilizers was observed more often and at lower initial inoculation doses when fertilization was performed with inoculated slurry compared to inoculated manure. Finally, it could be shown that by introducing a simple washing step, the bacterial contamination was reduced in most cases or even was removed completely in