Sample records for rat tumor cell

  1. Experimental induction of ovarian Sertoli cell tumors in rats by N-nitrosoureas.

    Maekawa, A; Onodera, H.; H. Tanigawa; Furuta, K; Kanno, J; Ogiu, T; Hayashi, Y


    Spontaneous ovarian tumors are very rare in ACI, Wistar, F344 and Donryu rats; the few neoplasms found are of the granulosa/theca cell type. Ovarian tumors were also rare in these strains of rats when given high doses of N-alkyl-N-nitrosoureas continuously in the drinking water for their life-span; however, relatively high incidences of Sertoli cell tumors or Sertoli cell tumors mixed with granulosa cell tumors were induced in Donryu rats after administration of either a 400 ppm N-ethyl-N-nit...


    Potassium bromate (KBrO3) is a rat renal carcinogen and a major drinking water disinfection by-product in water disinfected with ozone. Clear cell renal tumors, the most common form of human renal epithelial neoplasm, are rare in animals but are inducible by KBrO3 in F344 rats. ...

  3. Establishment of 9L/F344 rat intracerebral glioma model of brain tumor stem cells

    Zong-yu XIAO


    Full Text Available Objective To establish the 9L/F344 rat intracerebral glioma model of brain tumor stem cells.  Methods Rat 9L gliosarcoma stem-like cells were cultured in serum-free suspension. The expression of CD133 and nestin were tested by immunohistochemistry. A total of 48 inbredline male F344 rats were randomly divided into 2 groups, and 9L tumor sphere cells and 9L monolayer cells were respectively implanted into the right caudate nucleus of F344 rats in 2 groups. Survival time was observed and determined using the method of Kaplan-Meier survival analysis. Fourteen days after implantation or when the rats were dying, their brains were perfused and sectioned for HE staining, and CD133 and nestin were detected by immunohistochemistry.  Results Rat 9L tumor spheres were formed with suspension culture in serum-free medium. The gliomas formed in both groups were invasive without obvious capsule. More new vessels, bleeding and necrosis could be detected in 9L tumor spheres group. The tumor cells in both groups were positive for CD133 and nestin. There was no significant difference in the expression of CD133 and nestin between 2 groups (P > 0.05, for all. According to the expression of nestin, the tumors formed by 9L tumor sphere cells were more invasive. The median survival time of the rats bearing 9L tumor sphere cells was 15 d (95%CI: 15.219-15.781, and the median survival time of the rats bearing 9L monolayer cells was 21 d (95%CI: 20.395-21.605. There was significant difference between 2 groups (χ2 = 12.800, P = 0.000.  Conclusions 9L/F344 rat intracerebral glioma model of brain tumor stem cells is successfully established, which provides a glioma model for the future research. DOI: 10.3969/j.issn.1672-6731.2015.04.012

  4. The role of chemokines in regualating mast cell recruitment around rat liver tumor

    ZHANGZhi-Yong; RUANYou-Bing


    Aim To explore the correlation of stem cell factor (SCF)and monocyte chemoattractant protein-1 (MCP-1) with number difference of mast cell (MC) around the liver tumor.Methods 40 male wistar rats with liver neoplasm were divided into three different groups by numbers of MC in the surroundings of tumor. We performed ELISA for SCF and MCP-1 in serums. And chemotaxis assays of rat peritoneal MCs to SCF and MCP-1 in serums were measured in 48-wellmicroboyden chambers. We also used immunohistochemistryto investigate whether rat MCs express SCF positively.RESULTE There were marked differences in MC numbersaround tumor between different groups. The group that has more MCs around tumor has the higher levels of SCF andMCP-1 in serums and the stronger chemotaxis to ratperitoneal MCs. SCF washigher than MCP-1 in bothchemotactic activity to MCs and levels in serums. And ratMCs positively express SCF.Conclusion SCF and MCP-1 were found to be two particularly efficacious chemoattractants for MCs. The levels of SCF and MCP-1 in serums may be closely correlated with MCs numbers around tumor. The production of SCF by MCs might act on mast cell migration and proliferation of MC.

  5. Evaluation of cytotoxic properties of a cyclopamine glucuronide prodrug in rat glioblastoma cells and tumors.

    Bensalma, Souheyla; Chadeneau, Corinne; Legigan, Thibaut; Renoux, Brigitte; Gaillard, Afsaneh; de Boisvilliers, Madryssa; Pinet-Charvet, Caroline; Papot, Sébastien; Muller, Jean Marc


    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of β-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of β-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of β-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.

  6. Swarm rat chondrosarcoma cells as an in vivo model: lung colonization and effects of tissue environment on tumor growth.

    Morcuende, Jose A; Stevens, Jeff W; Scheetz, Todd E; de Fatima Bonaldoc, Maria; Casavant, Thomas L; Otero, Jesse E; Soares, Marcelo B


    Swarm rat chondrosarcoma cells have been used extensively for biochemical studies of extra-cellular matrix metabolism in cartilage. However, these cells also possess tumor-like behavior in vivo and are useful in investigation of chondrosarcoma biology. the current study was designed to develop a metastatic model using swarm rat chondrosarcoma cells, and to assess the effect of tissue-environment on tumor behavior in vivo. Tumors were implanted subcutaneously or into bone, and animals were assessed radiographically and microscopically for tumor growth and metastasis. The subcutaneous tumor grew to an average mass of 35 g, while tumor implanted into bone grew 75 mg. Transplantation of the cells into the bone led to extensive bone remodeling with invasion of the medullary cavity and destruction of the bone cortex. Light microscopy demonstrated no significant differences in the number of mitoses, cellular atypia or extracellular matrix staining between the two sites of tumor implantation. Interestingly, lung colonization was observed in none of the animals in the subcutaneous tumor injection group, while tumors colonized the lungs in 95% of the rats with tumor injected into bone. Analysis of cDNA libraries from subcutaneous and bone-transplanted tumors demonstrated a complex and diverse array of expressed transcripts, and there were significant differences in gene expression between tumors at different sites. The results of this study suggest swarm rat chondrosarcoma is a model that resembles human chondrosarcoma mimicking its ability to infiltrate and remodel local bone and to colonize the lungs. Furthermore, the interaction between host-tissue and tumor cells plays a major role in the tumor behavior in this model. Identifying these interactions will lead to further understanding of chondrosarcoma and contribute to therapeutic targets in the future.

  7. Hsp70 confines tumor progression of rat histiocytoma and impedes the cytotoxicity induced by natural killer cells and peritoneal macrophages

    Amere Subbarao Sreedhar


    Objective:To study the role of inducible form of heat shock protein 70 (Hsp70) in the host tumor regression of rat tumor model.Methods: We examined the role of Hsp70 in host tumorigenicity andin vitro cellular cytotoxicity using a rat histocytoma. The differential tumor growth and regression kinetics were studied and correlated with the expression of Hsp70, activation of macrophages and natural killer (NK) cells, and circulating or tumor infiltrating immune molecules in the host system.Results: The sub cuteaneous (s.c.) tumor regression was correlated with increased serum cytokines such as IL-12, TNFα,IFNγ and Hsp70. Despite of similar increase of Hsp70 in intraperitoneal (i.p.) tumor implanted animals, animals succumb to tumor growth, further, evidently, no immune molecule activation was observed. The viral promoter driven Hsp70 over expression in these tumor cells restrained solid tumor growth, however, failed to inhibit ascites growth. The NK cells from s.c. immunized animals induces cytotoxicity in the presence of anti-tumor antibody, which necessitated CD40-L expression, conversely, NK cells from i.p. immunized animals failed to induce cytotoxicity. The NK cells from s.c. or i.p. implanted animals with Hsp70 positive tumor cells failed to induce such cytotoxicity. The peritoneal macrophages isolated from s.c. tumor implanted animals when co-cultured with parental BC-8 cells lyses tumor cells, nevertheless entail macrophage specific TNFα expression. On the contrary, Hsp70 expressing BC-8 tumor cells were resistant to peritoneal macrophage induced cytolysis.Conclusions:This study brings out that Hsp70 possibly involved in regulating the host tumor response and cellular cytotoxicity.

  8. Elimination of acute muelogenous leukemic cells from marrow and tumor suspensions in the rat with 4-hydroperoxycyclophosphamide

    Sharkis, S.J.; Santos, G.W.; Colvin, M.


    Cell suspensions of normal rat marrow mixed with rat acute myelogenous leukemic cells were prepared and incubated in vitro with graded doses of 4-hydroperoxycyclophosphamide (4HC). The cell suspensions were injected into rats prepared with a lethal dose of total body irradiation. Animals injected with these cells survived fatal irradiation induced aplasia. In a dose related manner 4HC was able to purge tumor cells from the cell mixtures. Thus, animals given cell suspensions incubated with the lower doses of 4HC showed prolonged survived before death from leukemia and animals given cell suspensions incubated with higher doses of 4HC survival lethal irradiation without the subsequent appearance of leukemia. These studies clearly establish that tumor cells may be eliminated from normal marrow suspensions without completely destroying the pluripotent stem cells.

  9. Experimental rat lung tumor model with intrabronchial tumor cell implantation Modelo experimental de tumor de pulmão em rato por via intrabrônquica

    Antero Gomes Neto


    Full Text Available PURPOSE: The objective of this study was to develop a rat lung tumor model for anticancer drug testing. METHODS: Sixty-two female Wistar rats weighing 208 ± 20 g were anesthetized intraperitoneally with 2.5% tribromoethanol (1 ml/100 g live weight, tracheotomized and intubated with an ultrafine catheter for inoculation with Walker's tumor cells. In the first step of the experiment, a technique was established for intrabronchial implantation of 10(5 to 5×10(5 tumor cells, and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from high-resolution computed tomography (HRCT with findings from necropsia and determining time of survival. RESULTS: The tumor take rate was 94.7% for implants with 4×10(5 tumor cells, HRCT and necropsia findings matched closely (r=0.953; pOBJETIVO: O objetivo foi desenvolver um modelo de tumor de pulmão em rato que permita o teste de fármacos no tratamento deste câncer. MÉTODOS: Sessenta e dois ratos Wistar fêmeas, peso médio de 208±20 g, foram anestesiados com tribromo-etanol 2,5% IP (1ml/100g de rato, traqueostomizados e intubados com cateter ultrafino para injetar células do tumor de Walker. Na 1ª etapa, estabeleceu-se a técnica do implante de células tumorais por via intrabrônquica e o índice de pega tumoral, usando-se de 10(5 a 5×10(5 células. Na 2ª, avaliou-se o volume tumoral e a correlação dos achados obtidos na tomografia computadorizada de alta resolução (TCAR de tórax com os da necropsia e verificou-se a sobrevida. RESULTADOS: O índice de pega foi de 94,7, com o implante de 4×10(5 células do tumor; as medidas do tumor feitas na TCAR e comparadas com as da necropsia foram semelhantes (r=0, 953, p<0,0001; a sobrevida mediana foi de 11 dias; e a mortalidade cirúrgica de 4,8 %. CONCLUSÃO: O modelo mostrou-se viável, com alto índice de pega, mortalidade cirúrgica desprezível, de execução simples e f

  10. Menaquinone-4 enhances testosterone production in rats and testis-derived tumor cells

    Ohsaki Yusuke


    Full Text Available Abstract Background Vitamin K is essential for the posttranslational modification of various Gla proteins. Although it is widespread in several organs, including the testis, the function of vitamin K in these organs is not well characterized. In this study, we investigated the function of vitamin K in the testis and analyzed its role in steroidogenesis. Methods Eight-week-old male Wistar rats were fed a diet supplemented with menaquinone-4 (MK-4, 75 mg/kg diet, one of the predominant K2 vitamins present in the testis, for 5 weeks. In vivo testosterone levels of the rats' plasma and testes were measured by enzyme-linked immunosorbent assay, and in vitro testosterone levels of testis-derived tumor cells (I-10 cells maintained in Ham's F-10 medium with 10% fetal bovine serum were measured following treatment with MK-4 (0 to 100 μM at several time points. Testosterone and cellular protein levels were analyzed with respect to their effects on steroidogenesis. Results Testosterone levels in the plasma and testes of MK-4-fed rats were significantly increased compared to those of control rats, with no obvious differences in plasma luteinizing hormone levels. Secreted testosterone levels from I-10 cells were elevated by MK-4, but not by vitamin K1, in a dose-dependent manner independent of cAMP treatment. Western blot analysis revealed that expression of CYP11A, the rate-limiting enzyme in steroidogenesis, and phosphorylation levels of protein kinase A (PKA and the cAMP response element-binding protein were all stimulated by the presence of MK-4. Enhancement of testosterone production was inhibited by H89, a specific inhibitor of PKA, but not by warfarin, an inhibitor of γ-glutamylcarboxylation. Conclusions MK-4 stimulates testosterone production in rats and testis-derived tumor cells via activation of PKA. MK-4 may be involved in steroidogenesis in the testis, and its supplementation could reverse the downregulation of testosterone production in

  11. Effect of trans-acting factor on rat glutathione S-transferase P1 gene transcription regulation in tumor cells

    刘东远; 廖名湘; 左瑾; 方福德


    Objective To investigate the effect of trans-acting factor(s) on rat glutathione S-transferase P1 gene (rGSTP1) transcription regulation in tumor cells. Methods The binding of trans-acting factor(s) to two enhancers of the rGSTP1 gene, glutathione S-transferase P enhancer Ⅰ (GPEI) and glutathione S-transferase P enhancer Ⅱ-1 (GPEⅡ-1), was identified by an electrophoretic mobility shift assay (EMSA). The molecular weight of trans-acting factor was measured in a UV cross-linking experiment. Results Trans-acting factor interacting with the core sequence of GPEI (cGPEI) were found in human cervical adenocarcinoma cell line (HeLa) and rat hepatoma cell line (CBRH7919). These proteins were not expressed in normal rat liver. Although specific binding proteins that bound to GPEⅡ-1 were detected in all three cell types, a 64 kDa binding protein that exists in HeLa and CBRH7919 cells was absent in normal rat liver. Conclusion cGPEI, GPEII specific binding proteins expressed in HeLa and CBRH7919 cells may play an important role in the high transcriptional level of the rGSTP1 gene in tumor cells.

  12. Inhibition of tumor necrosis factor-α reduces alveolar septal cell apoptosis in passive smoking rats

    ZHANG Cheng; CAI Shan; CHEN Ping; CHEN Jian-bo; WU Jie; WU Shang-jie; ZHOU Rui


    Background Recent studies have revealed that lung cell apoptosis plays an important role in pathogenesis of cigarette-induced chronic obstructive pulmonary disease (COPD).Tumor necrosis factor alpha(TNF-α)is one of the most important cytokines which are involved in COPD.This study aimed at investigating the jnfluence of its inhibitor,recombinant human necrosis factor-alpha receptor Ⅱ:IgG Fc fusion protein(rhTNFR:Fc)on alveolar septal cell apoptosis in passive smoking rats.Methods Forty-eight rats were randomly divided into a normal control group,a passive smoking group,an rhTNFR:Fc intervention group and a sham intervention group.The passive smoking rats were treated by exposure to cigarette smoking daily for 80 days.Afcer smoking for one month the rhTNFR:Fc Intervention group was treated with rhTNFR:Fc by subcutaneous injection,the sham intervention group injected subcutaneousIv with a neutral preparation(normal saline 0.1 ml,manicol 0.8 ml,cane sugar 0.2 mg,Tris 0.024 mg as a control.Lung function was determined and the levels of TNF-α in serum and broncho-alveolar lavage fluid(BALF)were measured with enzyme-linked immunosorbnent assay (ELISA).Lung tissue sections stained by hematoxylin and eosin(HE)were observed for study of morphological alternations.Mean linear intercept(MLI)and mean alveolar numbers(MAN)were measured and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)method was carried out to determine the percentage of positive cells and distribution of apoptotic cells.Results Increased MLI and decreased MAN were found in the passive smoking group compared with both the normal control group and the rhTNFR:Fc intervention group(P<0.05).Forced expiratory volume in 0.3 second(FEV0.3)/forced vital capacity(FVC)and peak expiratory flow(PEF)were lower in the passive smoking group than that in the normal control group(P<0.05).Compared with the sham intervention group,FEV0.3/FVC and PEF increased in the rhTNFR:Fc intervention

  13. Inverse relationship of tumors and mononuclear cell leukemia infiltration in the lungs of F344 rats

    Lundgren, D.L.; Griffith, W.C.; Hahn, F.F.


    In 1970 and F344 rat, along with the B6C3F{sub 1} mouse, were selected as the standard rodents for the National Cancer Institute Carcinogenic Bioassay program for studies of potentially carcinogenic chemicals. The F344 rat has also been used in a variety of other carcinogenesis studies, including numerous studies at ITRI. A major concern to be considered in evaluating carcinogenic bioassay studies using the F344 rat is the relatively high background incidence of mononuclear cell leukemia (MCL) (also referred to as large granular lymphocytic leukemia, Fischer rat leukemia, or monocytic leukemia). Incidences of MCL ranging from 10 to 72% in male F344 rats to 6 to 31% in female F344 rats have been reported. Gaining the understanding of the mechanisms involved in the negative correlations noted should enhance our understanding of the mechanisms involved in the development of lung cancer.

  14. Two-stage model of radon-induced malignant lung tumors in rats: effects of cell killing

    Luebeck, E. G.; Curtis, S. B.; Cross, F. T.; Moolgavkar, S. H.


    A two-stage stochastic model of carcinogenesis is used to analyze lung tumor incidence in 3750 rats exposed to varying regimens of radon carried on a constant-concentration uranium ore dust aerosol. New to this analysis is the parameterization of the model such that cell killing by the alpha particles could be included. The model contains parameters characterizing the rate of the first mutation, the net proliferation rate of initiated cells, the ratio of the rates of cell loss (cell killing plus differentiation) and cell division, and the lag time between the appearance of the first malignant cell and the tumor. Data analysis was by standard maximum likelihood estimation techniques. Results indicate that the rate of the first mutation is dependent on radon and consistent with in vitro rates measured experimentally, and that the rate of the second mutation is not dependent on radon. An initial sharp rise in the net proliferation rate of initiated cell was found with increasing exposure rate (denoted model I), which leads to an unrealistically high cell-killing coefficient. A second model (model II) was studied, in which the initial rise was attributed to promotion via a step function, implying that it is due not to radon but to the uranium ore dust. This model resulted in values for the cell-killing coefficient consistent with those found for in vitro cells. An "inverse dose-rate" effect is seen, i.e. an increase in the lifetime probability of tumor with a decrease in exposure rate. This is attributed in large part to promotion of intermediate lesions. Since model II is preferable on biological grounds (it yields a plausible cell-killing coefficient), such as uranium ore dust. This analysis presents evidence that a two-stage model describes the data adequately and generates hypotheses regarding the mechanism of radon-induced carcinogenesis.

  15. Specific Antitumor Effects of Tumor Vaccine Produced by Electrofusion between Osteosarcoma Cell and Dendritic Cell in Rats

    ZheYu; QingyuFan; XinbaoHao; HuaLong


    Dendritic cells (DCs) are potent antigen-presenting cells capable of inducing primary T-cell responses. Several immunotherapy treatment strategies involve manipulation of DCs, both in vivo and ex vivo, to promote the immunogenic presentation of tumor-associated antigens. In this study, an electrofusion protocol was developed to induce fusion between osteosarcoma cells and allogeneic bone marrow-derived DCs. Preimmunization with irradiated electrofusion products was found to provide partial or complete protection from tumor challenge in the UMR106 tumor model. Vaccinated survivors developed long immunological memory. The therapeutic potential of this type of approach was suggested by the ability of UMR106-DC electrofusion products which could induce tumor rejection in a substantial percentage (60%) of hosts bearing pre-established tumor cells.These results tended to indicate that treatment with electrofused tumor cells and allogeneic DCs might be capable of inducing a potent antitumor response and could conceivably be applied to a wide range of cancer indications for which tumor-associated antigens have not been identified. Cellular & Molecular Immunology.2004;1(6):454-460.

  16. Imaging Tumor Cell Movement In Vivo

    Entenberg, David; Kedrin, Dmitriy; Wyckoff, Jeffrey; Sahai, Erik; Condeelis, John; Segall, Jeffrey E


    This unit describes the methods that we have been developing for analyzing tumor cell motility in mouse and rat models of breast cancer metastasis. Rodents are commonly used both to provide a mammalian system for studying human tumor cells (as xenografts in immunocompromised mice) as well as for following the development of tumors from a specific tissue type in transgenic lines. The Basic Protocol in this unit describes the standard methods used for generation of mammary tumors and imaging th...

  17. Metaphyseal giant cell tumor

    Pereira, L.F.; Hemais, P.M.P.G.; Aymore, I.L.; Carmo, M.C.R. do; Cunha, M.E.P.R. da; Resende, C.M.C.

    Three cases of metaphyseal giant cell tumor are presented. A review of the literature is done, demostrating the lesion is rare and that there are few articles about it. Age incidence and characteristics of the tumor are discussed.

  18. Human chorionic somatomammotropin and growth hormone gene expression in rat pituitary tumor cells is dependent on proximal promoter sequences

    Nachtigal, M.W.; Nickel, B.E.; Klassen, M.E.; Cattini, P.A. (Univ. of Manitoba, Winnipeg (Canada)); Zhang, Wengang; Eberhardt, N.L. (Univ. of California, San Francisco (USA))


    Human placental chorionic somatomammotropin (hCS-A or hCS-B) and pituitary growth hormone (hGH-N) are related by structure and function. The hCS-A gene is expressed in rat pituitary tumor (GC) cells after gene transfer. Deletion of hCS-A 5{prime}-flanking DNA reveals repressor activity upstream of nucleotide {minus}132, and a region essential for expression in GC cells between nucleotides {minus}94 and {minus}61. The sequences in this region differ from the equivalent hGH-N gene DNA by one nucleotide, and include the binding site for a pituitary-specific factor (GHF-1), required for hGH-N expression in GC cells. Exchange of hGH-N with hCS-A gene DNA in this region maintains expression in GC cells. By contrast, modification of these sequences blocks expression. These data indicate that proximal promoter sequences, equivalent to those bound by GHF-1 on the hGH-N gene, are required for hCS-A expression in GC cells.

  19. A Truncated form of CD200 (CD200S Expressed on Glioma Cells Prolonged Survival in a Rat Glioma Model by Induction of a Dendritic Cell-Like Phenotype in Tumor-Associated Macrophages

    Kana Kobayashi


    Full Text Available CD200 induces immunosuppression in myeloid cells expressing its receptor CD200R, which may have consequences for tumor immunity. We found that human carcinoma tissues express not only full-length CD200 (CD200L but also its truncated form, CD200S. Although CD200S is reported to antagonize the immunosuppressive actions of CD200L, the role of CD200S in tumor immunity has never been investigated. We established rat C6 glioma cell lines that expressed either CD200L or CD200S; the original C6 cell line did not express CD200 molecules. The cell lines showed no significant differences in growth. Upon transplantation into the neonatal Wistar rat forebrain parenchyma, rats transplanted with C6-CD200S cells survived for a significantly longer period than those transplanted with the original C6 and C6-CD200L cells. The C6-CD200S tumors were smaller than the C6-CD200L or C6-original tumors, and many apoptotic cells were found in the tumor cell aggregates. Tumor-associated macrophages (TAMs in C6-CD200S tumors displayed dendritic cell (DC-like morphology with multiple processes and CD86 expression. Furthermore, CD3+, CD4+ or CD8+ cells were more frequently found in C6-CD200S tumors, and the expression of DC markers, granzyme, and perforin was increased in C6-CD200S tumors. Isolated TAMs from original C6 tumors were co-cultured with C6-CD200S cells and showed increased expression of DC markers. These results suggest that CD200S activates TAMs to become DC-like antigen presenting cells, leading to the activation of CD8+ cytotoxic T lymphocytes, which induce apoptotic elimination of tumor cells. The findings on CD200S action may provide a novel therapeutic modality for the treatment of carcinomas.

  20. Tumor cell metabolism

    Romero-Garcia, Susana; Lopez-Gonzalez, Jose Sullivan; B´ez-Viveros, José Luis; Aguilar-Cazares, Dolores


    Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism. PMID:22057267

  1. Non-Invasive In Vivo Imaging and Quantification of Tumor Growth and Metastasis in Rats Using Cells Expressing Far-Red Fluorescence Protein.

    Jon Christensen

    Full Text Available Non-invasive in vivo imaging is emerging as an important tool for basic and preclinical research. Near-infrared (NIR fluorescence dyes and probes have been used for non-invasive optical imaging since in the NIR region absorption and auto fluorescence by body tissue is low, thus permitting for greater penetration depths and high signal to noise ratio. Currently, cell tracking systems rely on labeling cells prior to injection or administering probes targeting the cell population of choice right before imaging. These approaches do not enable imaging of tumor growth, as the cell label is diluted during cell division. In this study we have developed cell lines stably expressing the far-red fluorescence protein E2-Crimson, thus enabling continuous detection and quantification of tumor growth. In a xenograft rat model, we show that E2-Crimson expressing cells can be detected over a 5 week period using optical imaging. Fluorescence intensities correlated with tumor volume and weight and allowed for a reliable and robust quantification of the entire tumor compartment. Using a novel injection regime, the seeding of MDA-MB-231 breast cancer cells in the lungs in a rat model was established and verified.

  2. Non-Invasive In Vivo Imaging and Quantification of Tumor Growth and Metastasis in Rats Using Cells Expressing Far-Red Fluorescence Protein.

    Christensen, Jon; Vonwil, Daniel; Shastri, V Prasad


    Non-invasive in vivo imaging is emerging as an important tool for basic and preclinical research. Near-infrared (NIR) fluorescence dyes and probes have been used for non-invasive optical imaging since in the NIR region absorption and auto fluorescence by body tissue is low, thus permitting for greater penetration depths and high signal to noise ratio. Currently, cell tracking systems rely on labeling cells prior to injection or administering probes targeting the cell population of choice right before imaging. These approaches do not enable imaging of tumor growth, as the cell label is diluted during cell division. In this study we have developed cell lines stably expressing the far-red fluorescence protein E2-Crimson, thus enabling continuous detection and quantification of tumor growth. In a xenograft rat model, we show that E2-Crimson expressing cells can be detected over a 5 week period using optical imaging. Fluorescence intensities correlated with tumor volume and weight and allowed for a reliable and robust quantification of the entire tumor compartment. Using a novel injection regime, the seeding of MDA-MB-231 breast cancer cells in the lungs in a rat model was established and verified.

  3. Changes in red blood cell osmotic fragility induced by total plasma and plasma fractions obtained from rats bearing progressive and regressive variants of the Walker 256 tumor

    Cavalcanti T.C.


    Full Text Available Two variants (A and B of the widely employed Walker 256 rat tumor cells are known. When inoculated sc, the A variant produces solid, invasive, highly metastasizing tumors that cause severe systemic effects and death. We have obtained a regressive variant (AR whose sc growth is slower, resulting in 70-80% regression followed by development of immunity against A and AR variants. Simultaneously with the beginning of tumor regression, a temporary anemia developed (~8 days duration, accompanied by marked splenomegaly (~300% and changes in red blood cell osmotic fragility, with mean corpuscular fragility increasing from 4.1 to 6.5 g/l NaCl. The possibility was raised that plasma factors associated with the immune response induced these changes. In the present study, we identify and compare the osmotic fragility increasing activity of plasma fractions obtained from A and AR tumor bearers at different stages of tumor development. The results showed that by day 4 compounds precipitating in 60% (NH42SO4 and able to increase red blood cell osmotic fragility appeared in the plasma of A and AR tumor bearers. Later, these compounds disappeared from the plasma of A tumor bearers but slightly increased in the plasma of AR tumor bearers. Furthermore, by day 10, compounds precipitating between 60 and 80% (NH42SO4 and with similar effects appeared only in plasma of AR tumor bearers. The salt solubility, production kinetics and hemolytic activity of these compounds resemble those of the immunoglobulins. This, together with their preferential increase in rats bearing the AR variant, suggest their association with an immune response against this tumor.

  4. Dentinogenic ghost cell tumor

    Singhaniya Shikha


    Full Text Available Dentinogenic ghost cell tumor (DGCT is a rare tumorous form of calcifying odontogenic cyst and only a small number of cases have been described. It is a locally invasive neoplasm that is characterized by ameloblastoma-like epithelial islands, ghost cells and dentinoid. The present report describes a case of a 21-year-old male with a tumor in the posterior region of the mandible, showing features of DGCT.

  5. Olfactory ensheathing cell tumor

    Ippili Kaushal


    Full Text Available Olfactory ensheathing cells (OECs are found in the olfactory bulb and olfactory nasal mucosa. They resemble Schwann cells on light and electron microscopy, however, immunohistochemical staining can distinguish between the two. There are less than 30 cases of olfactory groove schwannomas reported in the literature while there is only one reported case of OEC tumor. We report an OEC tumor in a 42-year-old male and discuss the pathology and origin of this rare tumor.

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

    Yingjen Jeffrey Wu


    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.

  7. Merkel cell tumor.

    Kitazawa, M; Watanabe, H; Kobayashi, H; Ohnishi, Y; Shitara, A; Nitto, H


    A Merkel cell tumor appeared on the left cheek of an 83-year-old female was reported. The tumor was located mainly in the dermis and infiltrated to the subcutaneous adipose tissue with an involvement of the blood vessels and lymphatics at the periphery. Electron-microscopically, few of the dense-cored granules and the single globular aggregates of intermediate filaments at the nuclear indentations were observed. Electron-microscopic uranaffin reaction proved positive reaction on the dense-cored granules. Half of the cytoplasmic border was smooth, while the rest had short projections. Desmosomes or junctional complexes were not detected among the tumor cells. Immunohistochemically, the cytoplasm of tumor cell showed positive reaction to both neuron-specific enolase (NSE) and keratin. The single globular positive spots of the latter were localized in accordance with the aggregates of intermediate filaments. These findings suggested a neurogenic origin with double differentiation, epithelial and neuroendocrine, of the Merkel cell tumor.

  8. Cisplatin treatment of C6 rat glioma in vivo did not influence copy number alterations and growth pattern of tumor-derived resistant cells

    Stepanenko A. A.


    Full Text Available Aim. To investigate whether the cisplatin treatment of C6 rat glioma in vivo impacts the copy number alterations (CNAs, proliferation and colony formation efficiency (CFE of tumor-derived cisplatin-resistant cells. Methods. The glioma modeling was performed by means of intracerebral stereotactic implantation of rat glioma C6 cells into the striatum region of rats. The rats received 20 % dimethyl sulfoxide DMSO (C6R1 or cisplatin (C6R4CIS and C6R5CIS injected intraperitoneally (5 mg/kg three times per week. After 10 injections, gliomas were resected and the cells were cultured for in vitro analysis. CNAs were analyzed by array comparative genome hybridization, proliferation by direct cell counting in hemocytometer, CFE by soft agar assay. Results. No significant changes in the CNAs and CFE of cisplatin-treated rat glioma C6R4CIS and C6R5CIS cell lines were observed compared to the vehicle-treated control C6R1 cells. However, C6R5CIS but not C6R4CIS had a reduced proliferation. Interestingly, both cisplatin- and vehicle-treated brain-grown cells had a reduced proliferation and CFE in comparison to the parental C6 cells. Conclusions. Despite numerous reports on the destabilizing effects of cisplatin on genome and phenotype, the cisplatin treatment of C6 cells in vivo did not affect genome stability, CFE, and had an inconsistent effect on the proliferation in vitro. The rat brain microenvironment may potentially impact the growth characteristics of rat glioma cells.

  9. [Pathologic changes of spontaneous tumors in Sprague-Dawley and Wistar rats].

    He, Y N; Zhang, S C; Zhang, H M


    Objective: To investigate the spontaneous neoplastic lesions and their incidences in Sprague-Dawley (SD) and Wistar rats, and to accumulate background data for carcinogenicity studies. Methods: One hundred and eighty SD rats and 240 Wistar rats (4-week old) , half in each sex, were used in this study. The rats were housed routinely under specific pathogen-free environment and euthanized after 104 weeks. Histopathological examination was undertaken for all animals including deaths and scheduled euthanasia. The types and incidences of spontaneous tumors were gathered statistically. Results: Total 411 rats (176 SD rats and 235 Wistar rats) were examined in this study. The total tumor incidence of the 411 rats was 57.7%(237/411). The total tumor incidence in SD rats was 55.7%(98/176), benign tumor incidence was 48.9%(86/176) and malignant tumor incidence was 15.9%(28/176). The total tumor incidence in Wistar rats was 59.1%(139/235), benign tumor incidence was 51.5%(121/235) and malignant tumor incidence was 14.5%(34/235). The main benign tumors were pituitary adenoma (23.3% in SD rats, 12.3% in Wistar rats), breast fibroadenoma (21.3% in SD rats, 12.9% in Wistar rats) and breast adenoma (16.9% in SD rats, 9.5% in Wistar rats) in females; testis Leydig cell tumor (0 in SD rats, 14.3% in Wistar rats) in males. The main malignant tumors were breast carcinoma (10.1% in SD rats, 3.4% in Wistar rats) and uterine leiomyosarcoma (0 in SD rats, 2.6% in Wistar rats) in females; squamous cell carcinoma of skin (2.3% in SD rats, 0.9% in Wistar rats); subcutaneous fibrosarcoma (1.1% in SD rats, 2.1% in Wistar rats); brain malignant glioma (1.1% in SD rats, 1.7% in Wistar rats). Conclusions: In the study, a high incidence of spontaneous tumors is reported in both SD and Wistar rats housed for 2 years. The incidence of benign tumors is higher than that of malignant rumors. The benign tumors mainly are pituitary adenoma, breast fibroadenoma and breast adenoma in females, and testis

  10. Mouse Leydig Tumor Cells

    Bo-Syong Pan


    Full Text Available Cordycepin is a natural pure compound extracted from Cordyceps sinensis (CS. We have demonstrated that CS stimulates steroidogenesis in primary mouse Leydig cell and activates apoptosis in MA-10 mouse Leydig tumor cells. It is highly possible that cordycepin is the main component in CS modulating Leydig cell functions. Thus, our aim was to investigate the steroidogenic and apoptotic effects with potential mechanism of cordycepin on MA-10 mouse Leydig tumor cells. Results showed that cordycepin significantly stimulated progesterone production in dose- and time-dependent manners. Adenosine receptor (AR subtype agonists were further used to treat MA-10 cells, showing that A1, A 2A , A 2B , and A3, AR agonists could stimulate progesterone production. However, StAR promoter activity and protein expression remained of no difference among all cordycepin treatments, suggesting that cordycepin might activate AR, but not stimulated StAR protein to regulate MA-10 cell steroidogenesis. Meanwhile, cordycepin could also induce apoptotic cell death in MA-10 cells. Moreover, four AR subtype agonists induced cell death in a dose-dependent manner, and four AR subtype antagonists could all rescue cell death under cordycepin treatment in MA-10 cells. In conclusion, cordycepin could activate adenosine subtype receptors and simultaneously induce steroidogenesis and apoptosis in MA-10 mouse Leydig tumor cells.

  11. Nonislet Cell Tumor Hypoglycemia

    Johnson Thomas


    Full Text Available Nonislet cell tumor hypoglycemia (NICTH is a rare cause of hypoglycemia. It is characterized by increased glucose utilization by tissues mediated by a tumor resulting in hypoglycemia. NICTH is usually seen in large mesenchymal tumors including tumors involving the GI tract. Here we will discuss a case, its pathophysiology, and recent advances in the management of NICTH. Our patient was diagnosed with poorly differentiated squamous cell carcinoma of esophagus. He continued to be hypoglycemic even after starting continuous tube feeds and D5W. General workup for hypoglycemia was negative and insulin-like growth factor II (IGF II was in the normal range. Hypoglycemia secondary to “big” IGF II was considered, and patient was started on steroids. His hypoglycemia resolved within a day of treatment with steroids. Initially patient had hypoglycemia unawareness, which he regained after maintaining euglycemia for 48 hours.

  12. Brain tumor imaging of rat fresh tissue using terahertz spectroscopy

    Yamaguchi, Sayuri; Fukushi, Yasuko; Kubota, Oichi; Itsuji, Takeaki; Ouchi, Toshihiko; Yamamoto, Seiji


    Tumor imaging by terahertz spectroscopy of fresh tissue without dye is demonstrated using samples from a rat glioma model. The complex refractive index spectrum obtained by a reflection terahertz time-domain spectroscopy system can discriminate between normal and tumor tissues. Both the refractive index and absorption coefficient of tumor tissues are higher than those of normal tissues and can be attributed to the higher cell density and water content of the tumor region. The results of this study indicate that terahertz technology is useful for detecting brain tumor tissue.

  13. The in vitro and in vivo effects of human growth hormone administration on tumor growth of rats bearing a transplantable rat pituitary tumor (7315b)

    A. Binnerts (Arjen); P. Uitterlinden (Piet); L.J. Hofland (Leo); P.M. van Koetsveld (Peter); S.W.J. Lamberts (Steven)


    markdownabstractAbstract The direct effects of human GH and IGF-I on PRL secretion and cell proliferation were studied on PRL secreting rat pituitary tumor 7315b cells in vitro, as well as the effects in vivo of human GH administration on body weight, IGF-I levels and tumor size in rats bearing th

  14. Tubocurarine blocks a calcium-dependent potassium current in rat tumoral pituitary cells.

    Vacher, P; Vacher, A M; Mollard, P


    We investigated the effects of potassium channel inhibitors on electrical activity, membrane ionic currents, intracellular calcium concentration ([Ca2+]i) and hormone release in GH3/B6 cells (a line of pituitary origin). Patch-clamp recordings show a two-component after hyperpolarization (AHP) following each action potential (current clamp) or a two-component tail current (voltage-clamp). Both components can be blocked by inhibiting Ca2+ influx. Application of D-tubocurarine (dTc) (20-500 microM) reversibly suppressed the slowly decaying Ca2+-activated K+ tail current (I AHPs) in a concentration-dependent manner. On the other hand, low doses of tetraethylammonium ions (TEA+) only blocked the rapidly decaying voltage- and Ca2+-activated K+ tail current (I AHPf). Therefore, GH3/B6 cells exhibit at least two quite distinct Ca2+-dependent K+ currents, which differ in size, voltage- and Ca2+-sensitivity, kinetics and pharmacology. These two currents also play quite separate roles in shaping the action potential. d-tubocurarine increased spontaneous Ca2+ action potential firing, whereas TEA increased action potential duration. Thus, both agents stimulated Ca2+ entry. I AHPs is activated by a transient increase in [Ca2+]i such as a thyrotrophin releasing hormone-induced Ca2+ mobilization. All the K+ channel inhibitors we tested: TEA, apamin, dTC and charybdotoxin, stimulated prolactin and growth hormone release in GH3/B6 cells. Our results show that I AHPs is a good sensor for subplasmalemmal Ca2+ and that dTc is a good pharmacological tool for studying this current.

  15. Comparison of drug and cell-based delivery: engineered adult mesenchymal stem cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models.

    Liu, Linda N; Wang, Gang; Hendricks, Kyle; Lee, Keunmyoung; Bohnlein, Ernst; Junker, Uwe; Mosca, Joseph D


    Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown etiology where tumor necrosis factor-α (TNFα) plays a critical role. Etanercept, a recombinant fusion protein of human soluble tumor necrosis factor receptor II (hsTNFR) linked to the Fc portion of human IgG1, is used to treat RA based on the rationale that sTNFR binds TNFα and blocks TNFα-mediated inflammation. We compared hsTNFR protein delivery from genetically engineered human mesenchymal stem cells (hMSCs) with etanercept. Blocking TNFα-dependent intercellular adhesion molecule-1 expression on transduced hMSCs and inhibition of nitric oxide production from TNFα-treated bovine chondrocytes by conditioned culture media from transduced hMSCs demonstrated the functionality of the hsTNFR construction. Implanted hsTNFR-transduced mesenchymal stem cells (MSCs) reduced mouse serum circulating TNFα generated from either implanted TNFα-expressing cells or lipopolysaccharide induction more effectively than etanercept (TNFα, 100%; interleukin [IL]-1α, 90%; and IL-6, 60% within 6 hours), suggesting faster clearance of the soluble tumor necrosis factor receptor (sTNFR)-TNFα complex from the animals. In vivo efficacy of sTNFR-transduced MSCs was illustrated in two (immune-deficient and immune-competent) arthritic rodent models. In the antibody-induced arthritis BalbC/SCID mouse model, intramuscular injection of hsTNFR-transduced hMSCs reduced joint inflammation by 90% compared with untransduced hMSCs; in the collagen-induced arthritis Fischer rat model, both sTNFR-transduced rat MSCs and etanercept inhibited joint inflammation by 30%. In vitro chondrogenesis assays showed the ability of TNFα and IL1α, but not interferon γ, to inhibit hMSC differentiation to chondrocytes, illustrating an additional negative role for inflammatory cytokines in joint repair. The data support the utility of hMSCs as therapeutic gene delivery vehicles and their potential to be used in alleviating inflammation

  16. Brain tumors induced in rats by human adenovirus type 12



    Full Text Available Oncogenesis of human adenovirus type 12 in the brain of rats was examined. Newborn rats of Sprague-Dawley and Donryu strains were injected intracranially with human adenovirus type 12. The incidence of intracranial tumors was 91% (30/33 in SpragueDawley and 56% (14/25 in Donryu rats. Except for one tumor nodule located in the parietal cortex of a Sprague.Dawley rat, all tumors developed in the paraventricular areas or in the meninges. Tumors were quite similar histologically to those induced in hamsters and mice resembling the undifferentiated human brain tumors such as medulloblastoma, ependymoblastoma and embryonic gliomas. From the histological features and primary sites of tumor development, it is suggested that the tumors in the brain of rats induced by adenovirus type 12 originate from the embryonic cells in the paraventricular area and also from the undifferentiated supporting cells of the peripheral nerves in the leptomeninges.

  17. Ghost Cell Tumors.

    Sheikh, Jason; Cohen, Molly D; Ramer, Naomi; Payami, Ali


    Ghost cell tumors are a family of lesions that range in presentation from cyst to solid neoplasm and in behavior from benign to locally aggressive or metastatic. All are characterized by the presence of ameloblastic epithelium, ghost cells, and calcifications. This report presents the cases of a 14-year-old girl with a calcifying cystic odontogenic tumor (CCOT) and a 65-year-old woman with a peripheral dentinogenic ghost cell tumor (DGCT) with dysplastic changes, a rare locally invasive tumor of odontogenic epithelium. The first patient presented with a 1-year history of slowly progressing pain and swelling at the left body of the mandible. Initial panoramic radiograph displayed a mixed radiolucent and radiopaque lesion. An incisional biopsy yielded a diagnosis of CCOT. Decompression of the mass was completed; after 3 months, it was enucleated and immediately grafted with bone harvested from the anterior iliac crest. The second patient presented with a 3-month history of slowly progressing pain and swelling at the left body of the mandible. Initial panoramic radiograph depicted a mixed radiolucent and radiopaque lesion with saucerization of the buccal mandibular cortex. An incisional biopsy examination suggested a diagnosis of DGCT because of the presence of ghost cells, dentinoid, and islands of ameloblastic epithelium. Excision of the mass with peripheral ostectomy was completed. At 6 and 12 months of follow-up, no evidence of recurrence was noted.

  18. Effect of complex amino acid imbalance on growth of tumor in tumor-bearing rats

    Yin-Cheng He; Yuan-Hong Wang; Jun Cao; Ji-Wei Chen; Ding-Yu Pan; Ya-Kui Zhou


    AIM: To investigate the effect of complex amino acid imbalance on the growth of tumor in tumor-bearing (TB) rats.METHODS: Sprague-Dawlley (SD) rats underwent jejunostomy for nutritional support. A suspension of Walker256 carcinosarcoma cells was subcutaneously inoculated.TB rats were randomly divided into groups A, B, C and D according to the formula of amino acids in enteral nutritional solutions, respectively. TB rats received jejunal feedings supplemented with balanced amino acids (group A),methionine-depleted amino acids (group B), valine-depleted amino acids (group C) and methionine- and valine-depleted complex amino acid imbalance (group D) for 10 days. Tumor volume, inhibitory rates of tumor, cell cycle and life span of TB rats were investigated.RESULTS: The G0/G1 ratio of tumor cells in group D (80.5±9.0) % was higher than that in groups A, B and C which was 67.0±5.1 %, 78.9±8.5 %, 69.2±6.2 %, respectively (P<0.05). The ratio of S/G2M and PI in group D were lower than those in groups A, B and C. The inhibitory rate of tumor in groups B, C and D was 37.2 %, 33.3 % and 43.9 %,respectively (P<0.05). The life span of TB rats in group D was significantly longer than that in groups B, C, and A.CONCLUSION: Methionine/valine-depleted amino acid imbalance can inhibit tumor growth. Complex amino acids of methionine and valine depleted imbalance have stronger inhibitory effects on tumor growth.

  19. Benign notochordal cell tumors.

    Martínez Gamarra, C; Bernabéu Taboada, D; Pozo Kreilinger, J J; Tapia Viñé, M


    Benign notochordal cell tumors (TBCN) are lesions with notochordal differentiation which affect the axial skeleton. They are characterized by asymptomatic or non-specific symptomatology and are radiologically unnoticed because of their small size, or because they are mistaken with other benign bone lesions, such as vertebral hemangiomas. When they are large, or symptomatic, can be differential diagnosis with metastases, primary bone tumors and chordomas. We present a case of a TBCN in a 50-year-old woman, with a sacral lesion seen in MRI. A CT-guided biopsy was scheduled to analyze the lesion, finding that the tumor was not clearly recognizable on CT, so the anatomical references of MRI were used to select the appropriate plane. The planning of the approach and the radio-pathological correlation were determinant to reach the definitive diagnosis. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. Extraovarian granulosa cell tumor

    Paul Prabir


    Full Text Available Extraovarian granulosa cell tumor (GCT is a very uncommon tumor, assumed to arise from the ectopic gonadal tissue along the embryonal route of the genital ridge. One such rare case of extraovarian GCT was encountered in a 58-year-old female who presented with a large intraabdominal lump. Computerized tomography revealed one large retroperitoneal mass measuring 15cm x 16cm and another mesenteric mass of 8cm x 5cm size. The patient had a history of hysterectomy with bilateral salpingooophorectomy 20 years ago for uterine leiomyoma. Ultrasonography-guided aspiration smears revealed cytological features suggestive of GCT. Histopathological examination of the excised masses showed features of adult-type GCT. Because metastatic epithelial tumors, particularly from the ovaries, may show identical morphology, immunostains for inhibin and epithelial membrane antigen (EMA were performed. The tumor showed positivity for inhibin while EMA was negative thus confirming the diagnosis of GCT. As this patient had no previous history of GCT and was oophorectomized 20 years ago, the tumor was considered as extraovarian. A diagnosis of extraovarian GCT should be carried out after excluding any previous history of GCT of the ovary. Immunostains help to differentiate GCTs from other neoplasms.

  1. Inhibitory effect of α-lipoic acid on thioacetamide-induced tumor promotion through suppression of inflammatory cell responses in a two-stage hepatocarcinogenesis model in rats.

    Fujii, Yuta; Segawa, Risa; Kimura, Masayuki; Wang, Liyun; Ishii, Yuji; Yamamoto, Ryuichi; Morita, Reiko; Mitsumori, Kunitoshi; Shibutani, Makoto


    To investigate the protective effect of α-lipoic acid (a-LA) on the hepatocarcinogenic process promoted by thioacetamide (TAA), we used a two-stage liver carcinogenesis model in N-diethylnitrosamine (DEN)-initiated and TAA-promoted rats. We examined the modifying effect of co-administered a-LA on the liver tissue environment surrounding preneoplastic hepatocellular lesions, with particular focus on hepatic macrophages and the mechanism behind the decrease in apoptosis of cells surrounding preneoplastic hepatocellular lesions during the early stages of hepatocellular tumor promotion. TAA increased the number and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of proliferating and apoptotic cells in the liver. Co-administration with a-LA suppressed these effects. TAA also increased the numbers of ED2(+), cyclooxygenase-2(+), and heme oxygenase-1(+) hepatic macrophages as well as the number of CD3(+) lymphocytes. These effects were also suppressed by a-LA. Transcript levels of some inflammation-related genes were upregulated by TAA and downregulated by a-LA in real-time RT-PCR analysis. Outside the GST-P(+) foci, a-LA reduced the numbers of apoptotic cells, active caspase-8(+) cells and death receptor (DR)-5(+) cells. These results suggest that hepatic macrophages producing proinflammatory factors may be activated in TAA-induced tumor promotion. a-LA may suppress tumor-promoting activity by suppressing the activation of these macrophages and the subsequent inflammatory responses. Furthermore, a-LA may suppress tumor-promoting activity by suppressing the DR5-mediated extrinsic pathway of apoptosis and the subsequent regeneration of liver cells outside GST-P(+) foci.

  2. Chemopreventive Activity of Ferulago angulate against Breast Tumor in Rats and the Apoptotic Effect of Polycerasoidin in MCF7 Cells: A Bioassay-Guided Approach.

    Karimian, Hamed; Fadaeinasab, Mehran; Zorofchian Moghadamtousi, Soheil; Hajrezaei, Maryam; Razavi, Mahboubeh; Safi, Sher Zaman; Ameen Abdulla, Mahmood; Mohd Ali, Hapipah; Ibrahim Noordin, Mohamad


    Ferulago angulata leaf hexane extract (FALHE) was found to be a potent inducer of MCF7 cell apoptosis. The aims of the present study were to investigate the in vivo chemopreventive effect of FALHE in rats, to identify the contributing anticancer compound in FALHE and to determine its potential mechanism of action against MCF7 cells. Thirty rats harboring LA7-induced breast tumors were divided into five groups: tumor control, low-dose FALHE, high-dose FALHE, treatment control (tamoxifen) and normal control. Breast tissues were then subjected to histopathological and immunohistochemical analyses. A bioassay-guided investigation on FALHE was performed to identify the cytotoxic compound and its mechanism of action through flow cytometry, real-time qPCR and western blotting analyses. An in vivo study showed that FALHE suppressed the expression of the tumor markers PCNA and Ki67. The tumor size was reduced from 2031 ± 281 mm3 to 432 ± 201 mm3 after FALHE treatment. FALHE administration induced apoptosis in breast tumor cells, and this was confirmed by high expression levels of Bax, p53 and caspase 3. Cell cycle arrest was suggested by the expression of p21 and p27. The in vitro experimental results resulted in the isolation of polycerasoidin as a bioactive ingredient of FALHE with an IC50 value of 3.16 ± 0.31 μg/ml against MCF7 cells. Polycerasoidin induced mitochondrial-dependent apoptosis in breast cancer cells via caspase activation and changes in the mRNA and protein expression of Bax and Bcl-2. In addition, flow cytometric analysis demonstrated that the treated MCF7 cells were arrested at the G1 phase, and this was associated with the up-regulation of p21 and p27 at both the mRNA and protein levels. The results of the present study reinforce further investigations scrutinizing the promising potential of the F. angulata chemical constituents as breast cancer chemopreventive agents.

  3. Transforming growth factor-alpha abrogates glucocorticoid-stimulated tight junction formation and growth suppression in rat mammary epithelial tumor cells.

    Buse, P; Woo, P L; Alexander, D B; Cha, H H; Reza, A; Sirota, N D; Firestone, G L


    The glucocorticoid and transforming growth factor-alpha (TGF-alpha) regulation of growth and cell-cell contact was investigated in the Con8 mammary epithelial tumor cell line derived from a 7,12-dimethylbenz(alpha)anthracene-induced rat mammary adenocarcinoma. In Con8 cell monolayers cultured on permeable filter supports, the synthetic glucocorticoid, dexamethasone, coordinately suppressed [3H]thymidine incorporation, stimulated monolayer transepithelial electrical resistance (TER), and decreased the paracellular leakage of [3H]inulin or [14C]mannitol across the monolayer. These processes dose dependently correlated with glucocorticoid receptor occupancy and function. Constitutive production of TGF-alpha in transfected cells or exogenous treatment with TGF-alpha prevented the glucocorticoid growth suppression response and disrupted tight junction formation without affecting glucocorticoid responsiveness. Treatment with hydroxyurea or araC demonstrated that de novo DNA synthesis is not a requirement for the growth factor disruption of tight junctions. Immunofluorescence analysis revealed that the ZO-1 tight junction protein is localized exclusively at the cell periphery in dexamethasone-treated cells and that TGF-alpha caused-ZO-1 to relocalize from the cell periphery back to a cytoplasmic compartment. Taken together, our results demonstrate that glucocorticoids can coordinately regulate growth inhibition and cell-cell contact of mammary tumor cells and that TGF-alpha, can override both effects of glucocorticoids. These results have uncovered a novel functional "cross-talk" between glucocorticoids and TGF-alpha which potentially regulates the proliferation and differentiation of mammary epithelial cells.

  4. Pericytes limit tumor cell metastasis

    Xian, Xiaojie; Håkansson, Joakim; Ståhlberg, Anders


    Previously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions...... and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing...... the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role...

  5. Microenvironment influence on human colon adenocarcinoma phenotypes and matrix metalloproteinase-2, p53 and β-catenin tumor expressions from identical monoclonal cell tumor in the orthotopic model in athymic nude rats.

    Priolli, Denise Gonçalves; Abrantes, Ana Margarida; Neves, Silvia; Gonçalves, Ana Cristina; Lopes, Camila Oliveira; Martinez, Natalia Peres; Cardinalli, Izilda Aparecida; Ribeiro, Ana Bela Sarmento; Botelho, Maria Filomena


    The present study aims to identify differences between left and right colon adenocarcinoma arising from identical clonal cell and to find out if microenvironment has any influence on matrix metalloproteinase-2 (MMP2), p53 and β-catenin tumor expressions. MATERIAL AND METHODS. Rats (RNU) were submitted to cecostomy to obtain the orthotopic model of right colon tumor (n = 10), while for the left colon model (n = 10), a colon diversion and distal mucous fistula in the descending colon was used. Cultivated human colon adenocarcinoma cells (WiDr) were inoculated in stomas submucosa. Histopathological analysis, real-time reverse transcription-PCR for β-catenin, p53 and MMP2, as well as immunohistochemical analysis for p53 and β-catenin expression were conducted. Central tendency, variance analysis and the Livak delta-delta-CT method were used for statistical analysis, adopting a 5% significance level. RESULTS. All tumors from the left colon exhibited infiltrative ulceration, while in the right colon tumor growth was predominantly exophytic (67%). In the left colon, tumor growth was undifferentiated (100%), while it was moderately differentiated in the right colon (83%). In right colon tumors, MMP2, p53, and β-catenin gene expressions were higher than compared to left colon (p = 4.59354E-05, p = 0.0035179, p = 0.00093798, respectively, for MMP2, p53 and β-catenin). β-catenin and p53 results obtained by real-time polymerase chain reaction were confirmed by immunohistochemistry assay (p = 0.01 and p = 0.001, respectively, for β-catenin and p53). CONCLUSION. Left and right human colon adenocarcinomas developed in animal models have distinct phenotypes even when they have the same clonal origin. Microenvironment has influenced p53, β-catenin, and MMP2 expression in animal models of colon cancer.

  6. Sertoli-Leydig cell tumor

    Sertoli-stromal cell tumor; Arrhenoblastoma; Androblastoma; Ovarian cancer - Sertoli-Leydig cell tumor ... The exact cause of this tumor is not known. Changes (mutations) in genes may play a role. SLCT occur most often in young women 20 to 30 ...

  7. The effect of vitamin A on the migration and DNA synthesis of rat bladder tumor cell line NBT II in culture.

    Tchao, R; Leighton, J


    In the presence of vitamin A, NBT II cells, derived from a carcinoma of rat bladder, grew as a monolayer with diminished piling up. Keratinization, which normally appeared within stratified cells in postconfluent cultures, was inhibited. A "wounding" technique suitable for quantitative analysis of cell migration was developed for confluent cultures grown on glass coverslips. Vitamin A treatment enhanced the migration of cells from the wound edge. In dense postconfluent monolayer cultures, vitamin A treatment maintained a higher percentage of cells in DNA synthesis than in the control cultures, as determined by 3H-TdR uptake and autoradiography. In contrast, in sparse cultures vitamin A did not stimulate DNA synthesis or increase the mitotic index. This stimulatory effect, limited to dense cultures, may be attributable to vitamin A causing viable cells to be shed into the medium, thereby maintaining the monolayer just at confluence. Thus vitamin A inhibits squamous cell differentiation, enhances migration, and maintains the culture in the proliferative phase. In a different system of high cell density, NBT II aggregates cultured in a combined matrix of chick plasma clot and collagen-coated sponge, vitamin A also enhanced the migration of cells. These results may explain, in part, the failure of vitamin A to inhibit completely the growth of some established tumors.

  8. Hydrogen sulfide induces hyperpolarization and decreases the exocytosis of secretory granules of rat GH3 pituitary tumor cells.

    Mustafina, Alsu N; Yakovlev, Aleksey V; Gaifullina, Aisylu Sh; Weiger, Thomas M; Hermann, Anton; Sitdikova, Guzel F


    The aim of the present study was to evaluate the effects of hydrogen sulfide (H2S) on the membrane potential, action potential discharge and exocytosis of secretory granules in neurosecretory pituitary tumor cells (GH3). The H2S donor - sodium hydrosulfide (NaHS) induced membrane hyperpolarization, followed by truncation of spontaneous electrical activity and decrease of the membrane resistance. The NaHS effect was dose-dependent with an EC50 of 152 μM (equals effective H2S of 16-19 μM). NaHS effects were not altered after inhibition of maxi conductance calcium-activated potassium (BK) channels by tetraethylammonium or paxilline, but were significantly reduced after inhibition or activation of ATP-dependent potassium channels (KATP) by glibenclamide or by diazoxide, respectively. In whole-cell recordings NaHS increased the amplitude of KATP currents, induced by hyperpolarizing pulses and subsequent application of glibenclamide decreased currents to control levels. Using the fluorescent dye FM 1-43 exocytosis of secretory granules was analyzed in basal and stimulated conditions (high K(+) external solution). Prior application of NaHS decreased the fluorescence of the cell membrane in both conditions which links with activation of KATP currents (basal secretion) and activation of KATP currents and BK-currents (stimulated exocytosis). We suggest that H2S induces hyperpolarization of GH3 cells by activation of KATP channels which results in a truncation of spontaneous action potentials and a decrease of hormone release.

  9. Ovarian Germ Cell Tumors Treatment

    ... ovarian germ cell tumor are swelling of the abdomen or vaginal bleeding after menopause. Ovarian germ cell ... if you have either of the following: Swollen abdomen without weight gain in other parts of the ...

  10. Relationship between immune state and tumor growth rate in rats bearing progressive and non-progressive mammary tumors.

    Remedi, M M; Hliba, E; Demarchi, M; Depiante-Depaoli, M


    Impaired immune responses occur frequently in cancer patients or in tumor-bearing animals, but the mechanisms of the tumor-induced immune defects remain poorly understood. The aim of the present study was to determine the relevance of the immune system in the control of tumor growth. We have developed a model of progressive and non-progressive mammary tumor, chemically induced in female Wistar rats. In this model we evaluated the development of an immune response after immunization of rats bearing progressive and non-progressive tumors with a non-related antigen, such as sheep red blood cells. We also studied the activation state of peritoneal macrophages from animals bearing tumors by evaluating the production of free radicals. Our findings indicated that the cell-mediated immunity in rats bearing progressive tumors fails to respond to heterologous antigen in vivo, as demonstrated by a negative delayed-type hypersensitivity reaction, and is accompanied by minor nitric oxide production by peritoneal exudate cells as well as a lower capacity for macrophage activation. The study of non-progressive tumor-bearing rats indicated that the cell-mediated immune response was intact and an activated state of macrophages was found in vivo. The results described in this paper should be taken into account when therapies based on cancer vaccines are chosen for the treatment of cancer.

  11. Cyclosporin safety in a simplified rat brain tumor implantation model

    Francisco H. C. Felix


    Full Text Available Brain cancer is the second neurological cause of death. A simplified animal brain tumor model using W256 (carcinoma 256, Walker cell line was developed to permit the testing of novel treatment modalities. Wistar rats had a cell tumor solution inoculated stereotactically in the basal ganglia (right subfrontal caudate. This model yielded tumor growth in 95% of the animals, and showed absence of extracranial metastasis and systemic infection. Survival median was 10 days. Estimated tumor volume was 17.08±6.7 mm³ on the 7th day and 67.25±19.8 mm³ on 9th day post-inoculation. Doubling time was 24.25 h. Tumor growth induced cachexia, but no hematological or biochemical alterations. This model behaved as an undifferentiated tumor and can be promising for studying tumor cell migration in the central nervous system. Dexamethasone 3.0 mg/kg/day diminished significantly survival in this model. Cyclosporine 10 mg/kg/day administration was safely tolerated.

  12. The morphological changes in transplanted tumors in rats at plasmonic photothermal therapy

    Bucharskaya, Alla B.; Maslyakova, Galina N.; Navolokin, Nikita A.; Dikht, Nataliya I.; Terentyuk, Georgy S.; Bashkatov, Alexey N.; Genina, Elina A.; Khlebtsov, Boris N.; Khlebtsov, Nikolai G.; Tuchin, Valery V.


    The aim of work was to study the morphological changes in transplanted liver tumors of rats after plasmonic photothermal therapy (PPTT). The gold nanorods functionalized with thiolated polyethylene glycol were injected intravenously to rats with transplanted liver cancer PC-1. A day after injection the tumors were irradiated by the infrared 808-nm diode laser. The withdrawal of the animals from the experiment and sampling of tumor tissue for morphological study were performed 24 hours after the laser exposure. The standard histological and immunohistochemical staining with antibodies to proliferation marker Ki-67 and apoptosis marker BAX were used for morphological study of transplanted tumors. The plasmonic photothermal therapy had pronounced damaging effect in rats with transplanted liver tumors expressed in degenerative and necrotic changes in the tumor cells. The decrease of proliferation marker Ki-67 and increase of expression of apoptosis marker BAX were observed in tumor cells after PPTT.

  13. The relationship between sirtuin 1 (SIRT1 expression and tumor size, Proliferating Cell Nuclear Antigen (PCNA expression and histological grading in rat breast carcinoma induced by dimethylbenz(anthracene (DMBA

    Novrita Padauleng Dewajani Purnomosari, Sri Herwiyanti Harjadi, Irianiwati, Sitarina Widyarini


    Full Text Available Controversy regarding the role of SIRT1 in pathology of cancers exists and is still under debate.SIRT1 could act as either a tumor supressor or tumor promotor. This study was conducted toevaluate the relationship between SIRT1 expression and tumor size, Proliferating Cell NuclearAntigen (PCNA expression and histological grading in rat breast carcinoma induced bydimethylbenz(áanthracene (DMBA. Thirty female Sprague Dawley rats were randomly allocatedinto three groups with 10 rats in each group. Group 1 as negative control was just fed thestandard food. Group 2 as vehicle control was fed the standard food and corn oil. Group 3 asinduction group was fed the standard food and induced with DMBA at dose of 20 mg/kg bodyweight (BW in corn oil twice a week for five weeks. All rats were palpated weekly to determinethe appearance, size and location of tumors. Sixteen weeks after DMBA induction rats weresacrified and histological preparations of the breast carcinoma tissue were then processed forSIRT1 and PCNA expression examination as well as histological grading. The result showed thatSIRT1 expression was significantly higher in breast carcinoma tissue compared to normal gland(26.12 vs 0.05; p = 0.004. SIRT1-positive was observed mostly in poor histological gradecarcinomas (56.2%, and it was not observed in good histological grade carcinomas. However,there was no significantly difference between SIRT1 and histological grading (p = 0.097; r =0.285. A significant correlation between SIRT1 expression and the tumor size (p =0.009; r=0.877, as well as PCNA expression (p =0.000; r =0.790 was observed. In conclusion, thereis relationship between SIRT1 expression and tumor size as well as PCNA expression in rat breastcarcinoma induced by DMBA.

  14. Augmentation of anti-tumor activity by immunization with Mycobacterium tuberculosis (Tbc and tuberculin-coupled tumor cells.



    Full Text Available The anti-tumor effect of immunization with heat-killed Mycobacterium tuberculosis (Tbc and Tuberculin (PPD-coupled syngeneic tumor cells was examined in vivo. Three tumor cell lines were employed. Immunization of Tbc-primed BALB/c mice with PPD-coupled syngeneic Meth-A tumor cells displayed a potent anti-tumor effect on viable Meth-A cells inoculated subcutaneously. Neither PPD-coupled LLC (Lewis Lung Carcinoma cells nor sonicated PPD-coupled Meth-A cells were capable of immunizing these mice. PPD-coupled syngeneic whole tumor cells were indispensable for induction of this tumor-specific resistance. Immunization of Tbc-primed C3H/He mice with PPD-coupled syngeneic MH134 tumor cells did not elicit anti-tumor activity against MH134, but additional pretreatment of mice with cyclophosphamide brought on an anti-tumor effect. Antimetastatic reactivity was investigated in C57BL/6 mice bearing LLC, with a reduction in metastases noted. This antimetastatic effect was observed even when the mice were immunized with PPD-coupled LLC cells three days after removal of the initial tumor. Immunization with Tbc and PPD-coupled Meth-A cells together with intraperitoneal administration of murine or rat interleukin 2 (IL 2 further augmented anti-Meth-A resistance. Murine IL 2 further inhibited tumor growth during the early stage, while rat IL 2 showed an anti-tumor effect throughout the course of tumor growth.

  15. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) accelerates expression of differentiation markers in cultures of rat palatal epithelial cells

    Arenholt, D; Dabelsteen, Erik


    Cultures of rat palatal epithelium grown on collagen rafts were treated with different doses of the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Sections from biopsies taken 1, 6, 24, and 48 hr after the addition of TPA were examined for the localization of staining by blood...

  16. Infantile pericardial round cell tumor

    K H Sridevi


    Full Text Available Cardiac malignancies presenting in infancy are rare. Desmoplastic small round cell tumor (DSRCT is a rare occurrence in this age group. No case of intrapericardial DSRCT has been reported in the literature in infants.

  17. Radiation immunomodulatory gene tumor therapy of rats with intracerebral glioma tumors

    Persson, Bertil R R; Koch, Catrin Bauréus; Grafström, Gustav


    Single-fraction radiation therapy with 5 or 15 Gy (60)Co gamma radiation was combined with intraperitoneal injections of syngeneic interferon gamma (IFN-gamma)-transfected cells in rats with intracerebral N29 or N32 glioma tumors at days 7, 21 and 35 after inoculation. For intracerebral N29 tumors......, single-fraction radiation therapy with 5 or 15 Gy had no significant effect on the survival time. Immunization with IFN-gamma-transfected N29 cells significantly increased the survival time by 61%. Single-fraction radiation therapy with 5 Gy combined with immunization increased the survival time...... significantly by 87% and complete remissions by 75% while with 15 Gy the survival time increased 45% with 38% complete remissions. For intracerebral N32 tumors, single-fraction radiation therapy with 15 Gy increased the survival time significantly by 20%. Immunization by itself had no significant effect...

  18. Elevated levels of mitochonrial respiratory complexes activities and ATP production in 17-β-estradiol-induced prolactin-secretory tumor cells in male rats are inhibited by melatonin in vivo and in vitro

    WANG Bao-qiang; YANG Quan-hui; XU Rong-kun; XU Jian-ning


    Background Our earlier studies indicate that melatonin inhibits the proliferation of prolactinoma and induces apoptosis of pituitary prolactin-secreting tumor in rats.Melatonin has also been shown to induce apoptosis and to reduce the production of ATP in breast tumor cells.This study analyzed the levels of the four mitochondrial respiratory complexes and the production of ATP and also the effects of melatonin treatment of prolactinoma.Methods In the in vivo study,mitochondria were harvested from control pituitaries or prolactinoma collected from the pituitaries of melatonin-and 17-β-estradiol (E2)-treated male rats.In the in vitro study,prolactinoma cells mitochondria were harvested.Activities of the four mitochondrial respiratory complexes were assayed using fluorometer.ATP production of prolactinoma cells was estimated using bioluminescent methods.Results Elevated levels of four mitochondrial respiratory complexes activities and ATP production were recorded in prolactinoma cells.Moreover,in both in vivo and in vitro studies,melatonin inhibited the activities of mitochondrial respiratory complexes and the production of ATP in prolactinoma cells.Conclusions There is a link between mitochondrial function increase and tumorigenesis.Melatonin induces apoptosis of pituitary prolactin-secreting tumor of rats via the induction of mitochondrial dysfunction and inhibition of energy metabolism.

  19. Modelo de tumor experimental em rim de ratos Experimental tumor model in rats kidney

    Lúcio Flávio Gonzaga Silva


    Full Text Available O carcinossarcoma 256 de Walker tem despertado o interesse de muitos pesquisadores como modelo experimental para estudo da biologia tumoral. OBJETIVO: estabelecer um modelo de tumor renal que possa ser usado para estudar in vivo e in vitro, as alterações impostas pelas neoplasias. MÉTODOS: utilizados vinte ratos Wistar, machos, adultos, pesando entre 250-300 g, oriundos do Laboratório de Cirurgia Experimental da Universidade Federal do Ceará. Sob anestesia inalatória procedia-se uma pequena incisão supraumbilical, e com manobra delicada fazia-se a exposição do rim direito. Neste órgão eram inoculadas 3x10(5 células tumorais viáveis. Os animais então eram mantidos em gaiolas individuais com as mesmas condições ambientais e com água e dieta ad libitum. RESULTADOS: o Carcinossarcoma 256 de Walker, implantado no parênquima do rim direito de ratos Wistar apresentou índice de pega de 100%, e crescimento rápido, invadiu por contiguidade as estruturas vizinhas, porém sem apresentar metástases, no entanto, levando os animais a óbito no curso médio de 14 dias. CONCLUSÃO: o modelo de implante de tumor de Walker no parênquima do rim direito de ratos Wistar é eficiente, tem reprodutibilidade, apresentando um índice de pega de 100%, e permitindo seu uso em linhas de pesquisa.Walker carcinossarcoma 256 has a great interest as experimental model for studies on tumoral biology. OBJECTIVE: develop a kidney tumor model to be used in the evaluation of the biological behavior of neoplasms in vitro and in vivo environments. METHODS: twenty adult male Wistar rats weighting between 250-300 g were obtained from the Federal University of the Ceará Experimental Surgery Laboratory. Upon ether anesthesia, the right kidney of each animal was accessed through a supraumbelical incision and inoculated with a solution containing 3 x 10(5 tumor cells (Walker 256 carcinossarcoma tumor cells. Following anesthetic recovery the rats were returned to their

  20. Tumor-protective and tumor-promoting actions of dietary whey proteins in an N-methyl-N-nitrosourea model of rat mammary carcinogenesis.

    Eason, Renea R; Till, S Reneé; Frank, Julie A; Badger, Thomas M; Korourian, Sohelia; Simmen, Frank A; Simmen, Rosalia C M


    The mammary tumor-protective effects of dietary factors are considered to be mediated by multiple signaling pathways, consistent with the heterogeneous nature of the disease and the distinct genetic profiles of tumors arising from diverse mammary cell populations. In a 7,12-dimethylbenz(a)anthracene-induced model of carcinogenesis, we showed previously that female Sprague-Dawley rats exposed to AIN-93G diet containing whey protein hydrolysate (WPH) beginning at gestation Day 4 had reduced tumor incidence than those exposed to diet containing casein (CAS), due partly to increased mammary differentiation and reduced activity of phase I metabolic enzymes. Here, we evaluated the tumor-protective effects of these same dietary proteins to the direct-acting carcinogen N-methyl-N-nitrosourea (NMU). We found that lifetime exposure to WPH, relative to CAS, decreased mammary tumor incidence and prolonged the appearance of tumors in NMU-treated female rats, with no corresponding effects on tumor multiplicity. At 115 days post-NMU, histologically normal mammary glands from WPH-fed tumor-bearing rats had increased gene expression for the tumor suppressor BRCA1 and the differentiation marker kappa-casein than those of CAS-fed tumor-bearing rats. Tumor-bearing rats from the WPH group had more advanced tumors, with a greater incidence of invasive ductal carcinoma than ductal carcinoma in situ and higher serum C-peptide levels than corresponding rats fed CAS. WPH-fed tumor-bearing rats were also heavier after NMU administration than CAS tumor-bearing rats, although no correlation was noted between body weight and C-peptide levels for either diet group. Results demonstrate the context-dependent tumor-protective and tumor-promoting effects of WPH; provide support for distinct signaling pathways underlying dietary effects on development of mammary carcinoma; and raise provocative questions on the role of diet in altering the prognosis of existing breast tumors.

  1. SCA-1 Identifies the Tumor-Initiating Cells in Mammary Tumors of BALB-neuT Transgenic Mice

    Cristina Grange


    Full Text Available Cancer stem cells, initiating and sustaining the tumor process, have been isolated in human and murine breast cancer using different cell markers. In the present study, we aimed to evaluate the presence and characteristics of stem/tumor-initiating cells in the model of the mouse mammary neoplasia driven by the activated form of rat Her-2/neu oncogene (BALB-neuT mice. For this purpose, we generated tumor spheres from primary spontaneous BALB-neuT tumors. Tumor sphere cultures were characterized for clonogenicity, self-renewal, and ability to differentiate in epithelial/myoepithelial cells of the mammary gland expressing basal and luminal cytokeratins and alpha-smooth muscle actin. In addition, tumor spheres were more resistant to doxorubicin compared with parental tumor cells. In the attempt to identify a selected marker for the sphere-generating cells, we found that Sca-1+ cells, present in tumors or enriched in mammospheres, and not CD24+ or CD29+ cells, were responsible for the sphere generation in vitro. Moreover, cells from the tumor spheres showed an increased tumor-generating ability in respect to the epithelial tumor cells. Sca-1+ sorted cells or clonal mammospheres derived from a Sca-1+ cell showed a superimposable tumor-initiating ability. The data of the present study indicate that a Sca-1+ population derived from mammary BALB-neuT tumors is responsible for sphere generation in culture and for initiating tumors in vivo.

  2. Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model

    Ong John M


    Full Text Available Abstract Background The blood-brain tumor barrier (BTB impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases. Results In this study, we examined the function and regulation of calcium-activated potassium (KCa channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain, human brain microvessel endothelial cells (HBMEC and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening. Conclusion These findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.

  3. Inhibition of hippocampal cell proliferation by methotrexate in rats is not potentiated by the presence of a tumor

    Seigers, Riejanne; Pourtau, Line; Schagen, Sanne B.; van Dam, Frits S. A. M.; Koolhaas, Jaap M.; Konsman, Jan Pieter; Buwalda, Bauke


    Methotrexate is a widely used cytostatic in chemotherapy cocktails for the treatment of cancer but is associated with cognitive impairment. Previous animal studies indicated that methorexate decreases hippocampal cell proliferation, which might contribute to the observed cognitive impairment.

  4. Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

    Martín-Rodríguez, Juan F; Muñoz-Bravo, Jose L; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M; Castaño, Justo P; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A


    Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

  5. Disruptive cell cycle regulation involving epigenetic downregulation of Cdkn2a (p16(Ink4a)) in early-stage liver tumor-promotion facilitating liver cell regeneration in rats.

    Tsuchiya, Takuma; Wang, Liyun; Yafune, Atsunori; Kimura, Masayuki; Ohishi, Takumi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto


    Cell cycle aberration was immunohistochemically examined in relation to preneoplastic liver cell foci expressing glutathione S-transferase placental form (GST-P) at early stages of tumor-promotion in rats with thioacetamide (TAA), a hepatocarcinogen facilitating liver cell regeneration. Immunoexpression of p16(Ink4a) following exposure to other hepatocarcinogens/promoters and its DNA methylation status were also analyzed during early and late tumor-promotion stages. GST-P(+) liver cell foci increased cell proliferation and decreased apoptosis when compared with surrounding liver cells. In concordance with GST-P(+) foci, checkpoint proteins at G(1)/S (p21(Cip1), p27(Kip1) and p16(Ink4a)) and G(2)/M (phospho-checkpoint kinase 1, Cdc25c and phospho-Wee1) were either up- or downregulated. Cellular distribution within GST-P(+) foci was either increased or decreased with proteins related to G(2)-M phase or DNA damage (topoisomerase IIα, phospho-histone H2AX, phospho-histone H3 and Cdc2). In particular, p16(Ink4a) typically downregulated in GST-P(+) foci and regenerative nodules at early tumor-promotion stage with hepatocarcinogens facilitating liver cell regeneration and in neoplastic lesions at late tumor-promotion stage with hepatocarcinogens/promoters irrespective of regenerating potential. Hypermethylation at exon 2 of Cdkn2a was detected at both early- and late-stages. Thus, diverse disruptive expression of G(1)/S and G(2)/M proteins, which allows for clonal selection of GST-P(+) foci, results in the acquisition of multiple aberrant phenotypes to disrupt checkpoint function. Moreover, increased DNA-damage responses within GST-P(+) foci may be the signature of genetic alterations. Intraexonic hypermethylation may be responsible for p16(Ink4a)-downregulation, which facilitates cell cycle progression in early preneoplastic lesions produced by repeated cell regeneration and late-stage neoplastic lesions irrespective of the carcinogenic mechanism. Copyright © 2012

  6. Defensive nature of Sargassum polycystum (Brown alga)against acetaminophen-induced toxic hepatitis in rats: Role of drug metabolizing microsomal enzyme system, tumor necrosis factor-α and fate of liver cell structural integrity

    H Balaji raghavendran; A Sathivel; T Devaki


    AIM: To assess the defensive nature of Sargassum polycystum (S. Polycystum) (Brown alga) against acetaminophen (AAP)-induced changes in drug metabolizing microsomal enzyme system, tumor necrosis factor (TNF-α)and fine structural features of the liver during toxic hepatitis in rats.METHODS: Male albino Wistar strain rats used for the study were randomly categorized into 4 groups. Group Ⅰ consisted of normal control rats fed with standard diet.Group Ⅱ rats were administered with acetaminophen (800 mg/kg body weight, intraperitoneally). Group Ⅲ rats were pre-treated with S. Polycystum extract alone.Group Ⅳ rats were orally pre-treated with S. Polycystum extract (200 mg/kg body weight for 21 d) prior to acetaminophen induction (800 mg/kg body weight,intraperitoneally). Serum separated and liver was excised and microsomal fraction was isolated for assaying cytochrome P450, NADPH Cyt P450 reductase and b5.Serum TNF-α was detected using ELISA. Fine structural features of liver were examined by transmission electron microscopy.RESULTS: Rats intoxicated with acetaminophen showed considerable impairment in the activities of drug metabolizing microsomal enzymes, such as cytochrome P450, NADPH Cyt P450 reductase and b5 when compared with the control rats. The rats intoxicated with acetaminophen also significantly triggered serum TNF-α when compared with the control rats. These severe alterations in the drug metabolizing enzymes were appreciably prevented in the rats pretreated with S. Polycystum. The rats pretreated with S. Polycystum showed considerable inhibition in the elevation of TNF-α compared to the rats intoxicated with acetaminophen. The electron microscopic observation showed considerable loss of structural integrity of the endoplasmic reticulum, lipid infiltration and ballooning of mitochondria in the acetaminophen-intoxicated rats,whereas the rats treated with S. Polycystum showed considerable protection against acetaminophen-induced alterations in

  7. Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α, prevents retinal ganglion cell loss in a rat model of glaucoma.

    Miin Roh

    Full Text Available BACKGROUND: Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor-α (TNF-α as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF-α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death. METHODOLOGY/PRINCIPAL FINDINGS: Episcleral vein cauterization (EVC caused intraocular pressure (IOP to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH. Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs. CONCLUSIONS/SIGNIFICANCE: Ocular hypertension (OHT triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF-α antagonists or suppressors of inflammation.

  8. Microenvironments Dictating Tumor Cell Dormancy

    Bragado, Paloma; Sosa, Maria Soledad; Keely, Patricia; Condeelis, John


    The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support three potential scenarios contributing to tumor cell dormancy. The first scenario proposes that DTCs from invasive cancers activate stress signals in response to the dissemination process and/or a growth suppressive target organ microenvironment inducing dormancy. The second scenario asks whether therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying specific gene signatures prime new DTCs to enter dormancy in a matching target organ microenvironment that can also control the timing of DTC dormancy. The third and final scenario proposes that early dissemination contributes a population of DTCs that are unfit for immediate expansion and survive mostly in an arrested state well after primary tumor surgery, until genetic and/or epigenetic mechanisms activate their proliferation. We propose that DTC dormancy is ultimately a survival strategy that when targeted will eradicate dormant DTCs preventing metastasis. For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support. PMID:22527492

  9. Mechanisms of tumor cell necrosis.

    Proskuryakov, Sergey Y; Gabai, Vladimir L


    Until recently, necrosis, unlike apoptosis, was considered as passive and unregulated form of cell death. However, during the last decade a number of experimental data demonstrated that, except under extreme conditions, necrosis may be a well-regulated process activated by rather specific physiological and pathological stimuli. In this review, we consider mechanisms and the role of necrosis in tumor cells. It became recently clear that the major player in necrotic cascade is a protein kinase RIP1, which can be activated by number of stumuli including TNF, TRAIL, and LPS, oxidative stress, or DNA damage (via poly-ADP-ribose polymerase). RIP1 kinase directly (or indirectly via another kinase JNK) transduces signal to mitochondria and causes specific damage (mitochondrial permeability transition). Mitochondrial collapse activates various proteases (e.g., calpains, cathepsin) and phospholipases, and eventually leads to plasma membrane destruction, a hallmark of necrotic cell death. Necrosis, in contrast to apoptosis, usually evokes powerful inflammatory response, which may participate in tumor regression during anticancer therapy. On the other hand, excessive spontaneous necrosis during tumor development may lead to more aggressive tumors due to stimulatory role of necrosis-induced inflammation on their growth.

  10. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

    Bojana Gligorijevic


    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  11. Palifosfamide in Treating Patients With Recurrent Germ Cell Tumors


    Adult Central Nervous System Germ Cell Tumor; Adult Teratoma; Malignant Extragonadal Germ Cell Tumor; Malignant Extragonadal Non-Seminomatous Germ Cell Tumor; Extragonadal Seminoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Seminoma; Stage IV Ovarian Germ Cell Tumor

  12. Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

    Acquaviva, Joseph T.; Hasanjee, Aamr M.; Bahavar, Cody F.; Zhou, Fefian; Liu, Hong; Howard, Eric W.; Bullen, Liz C.; Silvy, Ricardo P.; Chen, Wei R.


    Laser immunotherapy (LIT) is being developed as a treatment modality for metastatic cancer which can destroy primary tumors and induce effective systemic anti-tumor responses by using a targeted treatment approach in conjunction with the use of a novel immunoadjuvant, glycated chitosan (GC). In this study, Non-invasive Laser Immunotherapy (NLIT) was used as the primary treatment mode. We incorporated single-walled carbon nanotubes (SWNTs) into the treatment regimen to boost the tumor-killing effect of LIT. SWNTs and GC were conjugated to create a completely novel, immunologically modified carbon nanotube (SWNT-GC). To determine the efficacy of different laser irradiation durations, 5 minutes or 10 minutes, a series of experiments were performed. Rats were inoculated with DMBA-4 cancer cells, a highly aggressive metastatic cancer cell line. Half of the treatment group of rats receiving laser irradiation for 10 minutes survived without primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 minutes had no survivors. Thus, Laser+SWNT-GC treatment with 10 minutes of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

  13. Patient-Derived Antibody Targets Tumor Cells

    An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

  14. Treatment Option Overview (Extragonadal Germ Cell Tumors)

    ... Germ Cell Tumors Treatment Extragonadal Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Extragonadal Germ ... Certain factors affect prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment ...

  15. Dendritic cells are stressed out in tumor.

    Maj, Tomasz; Zou, Weiping


    A recently paper published in Cell reports that dendritic cells (DCs) are dysfunctional in the tumor environment. Tumor impairs DC function through induction of endoplasmic reticulum stress response and subsequent disruption of lipid metabolic homeostasis.

  16. In vivo tumor cell adhesion in the pulmonary microvasculature is exclusively mediated by tumor cell - endothelial cell interaction

    Mees Soeren T


    Full Text Available Abstract Background Metastasis formation is the leading cause of death among colon cancer patients. We established a new in-situ model of in vivo microscopy of the lung to analyse initiating events of metastatic tumor cell adhesion within this typical metastatic target of colon cancer. Methods Anaesthetized CD rats were mechanically ventilated and 106 human HT-29LMM and T84 colon cancer cells were injected intracardially as single cell suspensions. Quantitative in vivo microscopy of the lung was performed in 10 minute intervals for a total of 40 minutes beginning with the time of injection. Results After vehicle treatment of HT-29LMM controls 15.2 ± 5.3; 14.2 ± 7.5; 11.4 ± 5.5; and 15.4 ± 6.5 cells/20 microscopic fields were found adherent within the pulmonary microvasculature in each 10 minute interval. Similar numbers were found after injection of the lung metastasis derived T84 cell line and after treatment of HT-29LMM with unspecific mouse control-IgG. Subsequently, HT-29LMM cells were treated with function blocking antibodies against β1-, β4-, and αv-integrins wich also did not impair tumor cell adhesion in the lung. In contrast, after hydrolization of sialylated glycoproteins on the cells' surface by neuraminidase, we observed impairment of tumor cell adhesion by more than 50% (p Conclusions These results demonstrate that the initial colon cancer cell adhesion in the capillaries of the lung is predominantly mediated by tumor cell - endothelial cell interactions, possibly supported by platelets. In contrast to reports of earlier studies that metastatic tumor cell adhesion occurs through integrin mediated binding of extracellular matrix proteins in liver, in the lung, the continuously lined endothelium appears to be specifically targeted by circulating tumor cells.

  17. Human neutrophils facilitate tumor cell transendothelial migration.

    Wu, Q D


    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.

  18. Peripheral dentinogenic ghost cell tumor

    Sushant S Kamat


    Full Text Available Dentinogenic ghost cell tumors (DGCT are uncommon lesions mainly with rare peripheral types. This report presents a case of peripheral DGCT on the left side of the mandibular alveolar ridge of a heavy smoker, a 68-year-old man, with main presenting feature as a mild pain. Submandibular lymphadenopathy and radiological "saucerization" were evident. Differential diagnosis included fibroma, neurofibroma, peripheral ameloblastoma, peripheral odontogenic fibroma, and peripheral giant cell granuloma. Histologically, ameloblastoma-like epithelial elements were seen in association with grouped ghost cells. Proliferating polyhedral cells and stellate reticulum-like cells with various densities were spread over a wide range of the field. The lesion was curetted and after 2 years of follow up, it did not recur.

  19. Effects of leucine supplemented diet on intestinal absorption in tumor bearing pregnant rats

    de Mello Maria


    Full Text Available Abstract Background It is known that amino acid oxidation is increased in tumor-bearing rat muscles and that leucine is an important ketogenic amino acid that provides energy to the skeletal muscle. Methods To evaluate the effects of a leucine supplemented diet on the intestinal absorption alterations produced by Walker 256, growing pregnant rats were distributed into six groups. Three pregnant groups received a normal protein diet (18% protein: pregnant (N, tumor-bearing (WN, pair-fed rats (Np. Three other pregnant groups were fed a diet supplemented with 3% leucine (15% protein plus 3% leucine: leucine (L, tumor-bearing (WL and pair-fed with leucine (Lp. Non pregnant rats (C, which received a normal protein diet, were used as a control group. After 20 days, the animals were submitted to intestinal perfusion to measure leucine, methionine and glucose absorption. Results Tumor-bearing pregnant rats showed impairment in food intake, body weight gain and muscle protein content, which were less accentuated in WL than in WN rats. These metabolic changes led to reduction in both fetal and tumor development. Leucine absorption slightly increased in WN group. In spite of having a significant decrease in leucine and methionine absorption compared to L, the WL group has shown a higher absorption rate of methionine than WN group, probably due to the ingestion of the leucine supplemented diet inducing this amino acid uptake. Glucose absorption was reduced in both tumor-bearing groups. Conclusions Leucine supplementation during pregnancy in tumor-bearing rats promoted high leucine absorption, increasing the availability of the amino acid for neoplasic cells and, mainly, for fetus and host utilization. This may have contributed to the better preservation of body weight gain, food intake and muscle protein observed in the supplemented rats in relation to the non-supplemented ones.

  20. Angiogenesis-independent tumor growth mediated by stem-like cancer cells.

    Sakariassen, P.; Prestegarden, L.; Wang, J.; Skaftnesmo, K.O.; Mahesparan, R.; Molthoff, C.F.M.; Sminia, P.; Sundlisaeter, E.; Misra, A.; Tysnes, B.B.; Chekenya, M.; Peters, H.; Lende, G.; Kalland, K.H.; Oyan, A.M.; Petersen, K.; Jonassen, I.; Kogel, A.J. van der; Feuerstein, B.G.; Terzis, A.J.; Bjerkvig, R.; Enger, P.O.


    In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells ex

  1. A Survey of Mesenchyme-related Tumors of the Rat Kidney in the National Toxicology Program Archives, with Particular Reference to Renal Mesenchymal Tumor.

    Hard, Gordon C; Seely, John Curtis; Betz, Laura J


    In order to harmonize diagnostic terminology, confirm diagnostic criteria, and describe aspects of tumor biology characteristic of different tumor types, a total of 165 cases of mesenchyme-related tumors and nephroblastomas of the rat kidney were reexamined from the National Toxicology Program (NTP) Archives. This survey demonstrated that renal mesenchymal tumor (RMT) was the most common spontaneous nonepithelial tumor in the rat kidney, also occurring more frequently in the NTP studies than nephroblastoma. Renal sarcoma was a distinct but very rare tumor entity, representing a malignant, monomorphous population of densely crowded, fibroblast-like cells, in which, unlike RMT, preexisting tubules did not persist. Nephroblastoma was characterized by early death of affected animals, suggesting an embryonal origin for this tumor type. Male and female rats were equally disposed to developing RMT, but most of the cases of nephroblastoma occurred in female rats and liposarcoma occurred mostly in male rats. This survey confirmed discrete histopathological and biological differences between the mesenchyme-related renal tumor types and between RMT and nephroblastoma. Statistical analysis also demonstrated a lack of any relationship of these renal tumor types to test article administration in the NTP data bank.

  2. NK cells in the tumor microenvironment

    Larsen, Stine K; Gao, Yanhua; Basse, Per H


    The presence of natural killer (NK) cells in the tumor microenvironment correlates with outcome in a variety of cancers. However, the role of intratumoral NK cells is unclear. Preclinical studies have shown that, while NK cells efficiently kill circulating tumor cells of almost any origin...

  3. Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).

    Hallgren, Oskar; Aits, Sonja; Brest, Patrick; Gustafsson, Lotta; Mossberg, Ann-Kristin; Wullt, Björn; Svanborg, Catharina


    HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.

  4. Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinases (MMPs) as regulators of tumor-host interaction in a spontaneous metastasis model in rats.

    Donadio, Ana Carolina; Remedi, María Mónica; Susperreguy, Sebastián; Frede, Silvia; Gilardoni, Mónica Beatriz; Tang, Yi; Pellizas, Claudia Gabriela; Yan, Li


    EMMPRIN has a role in invasion and metastasis through the induction of MMPs and the consequent modulation of cell-substrate and cell-cell adhesion processes. The present study evaluates the expression of EMMPRIN protein and MMP-2/9 activity in tumor and parenchymal cells in a spontaneous metastasis model in rats. Moreover, we explore the regulation of EMMPRIN and MMP-9 by tumor-epithelial cell interactions in vitro. By zymography, we observed an increased proMMP-9 expression in both metastasized liver and spleen samples from tumor bearing rats. Immunohistochemical studies showed EMMPRIN-positive tumor cells in tumor biopsies as well as in spleen and liver samples from tumor bearing rats. Interestingly, a significant increase in EMMPRIN expression in hepatic cells was also detected. The regulation of EMMPRIN expression in tumor and liver cells in response to tumor-host interaction was investigated in vitro through a tumor cell line culture on extracellular matrix (ECM) molecules or in co-culture with normal rat liver cells (BRL3A cells). No significant changes in EMMPRIN expression were detected in tumor cells cultured on ECM molecules. On the other hand, EMMPRIN protein and MMP-9 mRNA expression were induced in BRL3A cells. The increase in EMMPRIN expression in BRL3A cells was inhibited by an anti-EMMPRIN antibody. These results reinforce the main role of EMMPRIN mediating tumor-host interactions that may evolve new opportunities for therapeutic interventions.

  5. Molecular characterization of radon-induced rat lung tumors; Caracterisation moleculaire de tumeurs pulmonaires radon-induites chez le rat

    Guillet Bastide, K


    The radon gas is a well known lung carcinogenic factor in human at high doses but the cancer risk at low doses is not established. Indeed, epidemiological studies at low doses are difficult to conduct because of the human exposure to other lung carcinogenic factors. These data underlined the necessity to conduct experiments on lung tumors developed on animal model. The aim of this work was to characterize rat lung tumors by working on a series of radon-induced tumors that included adenocarcinomas (A.C.), squamous cell carcinomas (S.C.C.) and adeno-squamous carcinomas (A.S.C.), that are mixed tumors with both A.C. and S.C.C. cellular components. A C.G.H. analysis of the three types of tumors allowed us to define chromosomal recurrent unbalances and to target candidate genes potentially implicated in lung carcinogenesis, as p16Ink4a, p19Arf, Rb1, K-Ras or c-Myc. A more precise analysis of the p16Ink4a/Cdk4/Rb1 and p19Arf/Mdm2/Tp53 pathways was performed and indicated that the Rb1 pathway was frequently inactivated through an absence of p16{sup Ink4a} protein expression, indicating that it has a major role in rat lung carcinogenesis. Finally, a comparative transcriptomic analysis of the three types of tumors allowed us to show for the first time that the complex tumors A.S.C. have a transcriptomic profile in accordance with their mixed nature but that they also display their own expression profiles specificities. This work allowed us to find molecular characteristics common to murine and human lung tumors, indicating that the model of lung tumors in rat is pertinent to search for radiation-induced lung tumors specificities and to help for a better molecular identification of this type of tumors in human. (author)

  6. Occurrence of Pineal Gland Tumors in Combined Chronic Toxicity/Carcinogenicity Studies in Wistar Rats.

    Treumann, Silke; Buesen, Roland; Gröters, Sibylle; Eichler, Jens-Olaf; van Ravenzwaay, Bennard


    Pineal gland tumors are very rare brain lesions in rats as well as in other species including humans. A total of 8 (out of 1,360 examined) Wistar rats from 3 different combined chronic toxicity/carcinogenicity or mere carcinogenicity studies revealed pineal gland tumors. The tumors were regarded to be spontaneous and unrelated to treatment. The morphology and immunohistochemical evaluation led to the diagnosis malignant pinealoma. The main characteristics that were variably developed within the tumors were the following: cellular atypia, high mitotic index, giant cells, necrosis, Homer Wright rosettes, Flexner-Wintersteiner rosettes and pseudorosettes, positive immunohistochemical reaction for synaptophysin, and neuron-specific enolase. The pineal gland is not a protocol organ for histopathological examination in carcinogenicity studies. Nevertheless, the pineal gland can occasionally be encountered on the routine brain section or if it is the origin of a tumor protruding into the brain, the finding will be recorded. Therefore, although known to be a rare tumor in rats, pineal neoplasms should be included in the list of possible differential diagnoses for brain tumors, especially when the tumor is located in the region of the pineal body.

  7. HAMLET kills tumor cells by apoptosis: structure, cellular mechanisms, and therapy.

    Gustafsson, Lotta; Hallgren, Oskar; Mossberg, Ann-Kristin; Pettersson, Jenny; Fischer, Walter; Aronsson, Annika; Svanborg, Catharina


    New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human alpha-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, alpha-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.

  8. Robo-Enabled Tumor Cell Extrusion.

    Richardson, Helena E; Portela, Marta


    How aberrant cells are removed from a tissue to prevent tumor formation is a key question in cancer biology. Reporting in this issue of Developmental Cell, Vaughen and Igaki (2016) show that a pathway with an important role in neural guidance also directs extrusion of tumor cells from epithelial tissues.

  9. Evolution of cooperation among tumor cells.

    Axelrod, Robert; Axelrod, David E; Pienta, Kenneth J


    The evolution of cooperation has a well established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the tissue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell-stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. Here, we add to this theory by regarding tumor cells as game players whose interactions help to determine their Darwinian fitness. We marshal evidence that tumor cells overcome certain host defenses by means of diffusible products. Our original contribution is to raise the possibility that two nearby cells can protect each other from a set of host defenses that neither could survive alone. Cooperation can evolve as by-product mutualism among genetically diverse tumor cells. Our hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.

  10. Renal cell carcinoma with areas mimicking renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma.

    Petersson, Fredrik; Grossmann, Petr; Hora, Milan; Sperga, Maris; Montiel, Delia Perez; Martinek, Petr; Gutierrez, Maria Evelyn Cortes; Bulimbasic, Stela; Michal, Michal; Branzovsky, Jindrich; Hes, Ondrej


    We present a cohort of 8 renal carcinomas that displayed a variable (5%-95% extent) light microscopic appearance of renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma (RAT/CCPRCC) without fulfilling the criteria for these tumors. All but 1 case predominantly (75%-95% extent) showed histopathologic features of conventional clear cell renal cell carcinoma. In 5 of 7 cases with mostly conventional clear renal cell carcinoma (CRCC) morphology, a diagnosis of CRCC was supported by the molecular genetic findings (presence of von Hippel-Lindau tumor suppressor [VHL] mutation and/or VHL promoter methylation and/or loss of heterozygosity [LOH] for 3p). Of the other 2 cases with predominantly characteristic CRCC morphology, 1 tumor did not reveal any VHL mutation, VHL promoter methylation, or LOH for 3p, and both chromosomes 7 and 17 were disomic, whereas the other tumor displayed polysomy for chromosomes 7 and 17 and no VHL mutation, VHL promoter methylation, or LOH for 3p. One tumor was composed primarily (95%) of distinctly RAT/CCPRCC-like morphology, and this tumor harbored a VHL mutation and displayed polysomy for chromosomes 7 and 17. Of the 5 cases with both histomorphologic features and molecular genetic findings of CRCC, we detected significant immunoreactivity for α-methylacyl-CoA racemase in 2 cases and strong diffuse immunopositivity for cytokeratin 7 in 3 cases. Despite the combination of positivity for α-methylacyl-CoA racemase and cytokeratin 7 in 2 cases, there was nothing to suggest of the possibility of a conventional papillary renal cell carcinoma with a predominance of clear cells.

  11. Effect of tumor cells and tumor microenvironment on NK-cell function.

    Vitale, Massimo; Cantoni, Claudia; Pietra, Gabriella; Mingari, Maria Cristina; Moretta, Lorenzo


    The ability of tumors to manage an immune-mediated attack has been recently included in the "next generation" of cancer hallmarks. In solid tumors, the microenvironment that is generated during the first steps of tumor development has a pivotal role in immune regulation. An intricate net of cross-interactions occurring between tumor components, stromal cells, and resident or recruited immune cells skews the possible acute inflammatory response toward an aberrant ineffective chronic inflammatory status that favors the evasion from the host's defenses. Natural killer (NK) cells have powerful cytotoxic activity, but their activity may be eluded by the tumor microenvironment. Immunosubversion, immunoediting or immunoselection of poorly immunogenic tumor cells and interference with tumor infiltration play a major role in evading NK-cell responses to tumors. Tumor cells, tumor-associated fibroblasts and tumor-induced aberrant immune cells (i.e. tolerogenic or suppressive macrophages, dendritic cells (DCs) and T cells) can interfere with NK-cell activation pathways or the complex receptor array that regulate NK-cell activation and antitumor activity. Thus, the definition of tumor microenvironment-related immunosuppressive factors, along with the identification of new classes of tissue-residing NK-like innate lymphoid cells, represent key issues to design effective NK-cell-based therapies of solid tumors.

  12. Cyclin D expression in plutonium-induced lung tumors in F344 rats

    Hahn, F.F.; Kelly, G. [SouthWest Scientific Resources, Inc., Albuquerque, NM (United States)


    The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

  13. Exercise training reduces PGE2 levels and induces recovery from steatosis in tumor-bearing rats.

    Lira, F S; Yamashita, A; Carnevali, L C; Gonçalves, D C; Lima, W P; Rosa, J C; Caperuto, E C; Rosa, L F C; Seelaender, M


    The effects of endurance training on PGE (2) levels and upon the maximal activity of hepatic carnitine palmitoyltransferase (CPT) system were studied in rats bearing the Walker 256 carciosarcoma. Animals were randomly assigned to a sedentary control (SC), sedentary tumor-bearing (ST), exercised control (EC), and as an exercised tumor-bearing (ET) group. Trained rats ran on a treadmill (60% VO (2) max) for 60 min/day, 5 days/week, for 8 weeks. We examined the mRNA expression (RT-PCR) and maximal activity (radioassay) of the carnitine palmitoyltransferase system enzymes (CPT I and CPT II), as well as the gene expression of fatty-acid-binding protein (L-FABP) in the liver. PGE (2) content was measured in the serum, in tumor cells, and in the liver (ELISA). CPT I and CPT II maximal activity were decreased (ptumor-bearing animals (ptumor-bearing training rats (ptumor (ptumor-bearing animals, preventing steatosis.

  14. Liver tumor promoting effects of fenbendazole in rats.

    Shoda, T; Onodera, H; Takeda, M; Uneyama, C; Imazawa, T; Takegawa, K; Yasuhara, K; Watanabe, T; Hirose, M; Mitsumori, K


    In order to examine whether fenbendazole has tumor-promoting activity, a total of 70 male Fischer 344 rats were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone; beginning 1 wk later, rats were given a diet containing 3,600; 1,800; 600; 200; 70; or 0 ppm of fenbendazole for 8 wk. Subgroups of 5 rats each from the DEN+ 1,800; DEN+0; 1,800; and 0 ppm groups were euthanatized after 1 wk of fenbendazole treatment, and the remaining animals were euthanatized at 8 wk. After 1 wk, relative liver weights (ratios to body weights) were significantly increased in the DEN+ 1,800 and 1,800 ppm groups, and based on light microscopy, periportal hepatocellular hypertrophy was evident in these groups. After 8 wk, relative liver weights were significantly increased in the groups given > or =600 ppm with or without DEN initiation. Periportal hepatocellular hypertrophy, characterized by a marked increase in smooth endoplasmic reticulum, was observed in the groups given > or =600 ppm with or without DEN initiation. Induction of cytochrome P-450 (CYP) 1A2, 2B1, or 4A1 was noted in the fenbendazole-treated groups with or without DEN initiation; that associated with CYP 1A2 was most marked. Positive immunostaining for anti-CYP 1A1/2 or CYP 2B1/2 was observed diffusely in the livers of animals in the DEN+1,800 and DEN+3,600 ppm groups. The numbers and areas of connexin 32 (Cx32)-positive spots per square centimeter in centrilobular hepatocytes were significantly decreased in an almost dose-dependent manner with fenbendazole treatment after DEN initiation. In situ hybridization for Cx32 mRNA revealed a remarkable decrease in its expression in the centrilobular hepatocytes in the DEN+70 ppm group. The numbers of glutathione S-transferase placental-form positive single cells (plus mini foci) were significantly increased in the DEN+ 1,800 and DEN+3,600 ppm groups. Since those agents that induce CYP 2B1/2 isozymes

  15. Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors


    Desmoplastic Small Round Cell Tumor; Ewing Sarcoma of Bone or Soft Tissue; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

  16. Cancer Stem Cells and Pediatric Solid Tumors

    Gregory K. Friedman


    Full Text Available Recently, a subpopulation of cells, termed tumor-initiating cells or tumor stem cells (TSC, has been identified in many different types of solid tumors. These TSC, which are typically more resistant to chemotherapy and radiation compared to other tumor cells, have properties similar to normal stem cells including multipotency and the ability to self-renew, proliferate, and maintain the neoplastic clone. Much of the research on TSC has focused on adult cancers. With considerable differences in tumor biology between adult and pediatric cancers, there may be significant differences in the presence, function and behavior of TSC in pediatric malignancies. We discuss what is currently known about pediatric solid TSC with specific focus on TSC markers, tumor microenvironment, signaling pathways, therapeutic resistance and potential future therapies to target pediatric TSC.


    Huggins, Charles; Torralba, Yolanda; Mainzer, Klaus


    A transplanted mammary fibroadenoma was found to grow in 95 per cent of intact adult female rats and the increment of tumor weights was progressive and logarithmic. The growth of the tumor was retarded by ovariectomy and still more when this was combined with adrenalectomy. In ovariectomized rats the growth of the tumor was stimulated by phenolic estrogens, this increase being enhanced when progesterone was added. In these responses to hormonal changes the mammary gland and the tumor resembled each other. Yet there are many differences between the growth of the fibroadenoma and that of the mammary gland. In contrast to the progressive growth which occurred in intact adult females there was a prolonged period of indolent growth of transplants in hypophysectomized rats; but after many weeks active growth began and the tumors eventually reached large size. During the period of quiescent growth the tumor was cytologically atrophic but after the growth spurt had started the microscopic appearance of the fibroadenoma resembled that of tumors growing in normal adult females. The mammary gland remained atrophic during both the slow and the accelerated phases of tumor growth, and so too with the other secondary sex expressions. In hypophysectomized rats estrone and progesterone, when combined, stimulated the growth of the tumor, and this growth was accelerated by the additional administration of lactogenic or growth hormones. None of these hormones, separately, stimulated the growth of the tumor. In ovariectomized rats other differences were demonstrated between the growth of the mammary gland and the fibroadenoma. Progesterone, injected alone, accelerated the growth of the tumor but not that of the mammary glands. The administration of phenolic estrogens exerted a biphasic effect on the growth of the tumor whilst that on the breast of its hosts was monophasic. With progressively increasing doses of these phenols there occurred primarily an augmentation of the rate of

  18. Introducing Cichorium Pumilum as a potential therapeutical agent against drug-induced benign breast tumor in rats.

    Al-Akhras, M-Ali H; Aljarrah, Khaled; Al-Khateeb, Hasan; Jaradat, Adnan; Al-Omari, Abdelkarim; Al-Nasser, Amjad; Masadeh, Majed M; Amin, Amr; Hamza, Alaaeldin; Mohammed, Karima; Al Olama, Mohammad; Daoud, Sayel


    Cichorium Pumilum (chicory) is could be a promising cancer treatment in which a photosensitizing drug concentrates in benign tumor cells and activated by quanta at certain wavelength. Such activated extracts could lead to cell death and tumor ablation. Previous studies have shown that Cichorium Pumilum (chicory) contains photosensitive compounds such as cichoriin, anthocyanins, lactucin, and Lactucopicrin. In the present study, the protective effect of sun light-activated Cichorium against the dimethylbenz[a]anthracene (DMBA) induced benign breast tumors to female Sprague-Dawley rats was investigated. Chicory's extract has significantly increase P.carbonyl (PC) and malondialdehyde (MDA) and decreases the hepatic levels of total antioxidant capacity (TAC) and superoxide dismutase (SOD) in benign breast tumors-induced group compared to control. It also significantly decrease the number of estrogen receptors ER-positive cells in tumor masses. These results suggest that chicory extracts could be used as herbal photosensitizing agent in treating benign breast tumor in rats.

  19. Laminin, a noncollagenous component of epithelial basement membranes synthesized by a rat yolk sac tumor

    Wewer, U; Albrechtsen, R; Ruoslahti, E


    Laminin, a glycoprotein antigenically similar or identical to a component of epithelial basement membranes, was identified as a major component of the abundant extracellular matrix synthesized by an experimentally induced rat yolk sac tumor. Immunocytochemical staining revealed laminin in cultured...... polypeptides with molecular weights of approximately 200,000 and 400,000. These comigrated with the polypeptides of mouse laminin isolated previously. The yolk sac tumor tissue grown in vivo contained laminin in the tumor cells and in the extracellular material as evidenced by immunofluorescence...... and in their basement membranes suggesting, but not proving, that both types of cells have ability to synthesize laminin. Production of laminin and the presence of laminin-containing basement membrane material may be important for the biological behavior of the yolk sac tumor. This tumor will also be a useful source...

  20. Morphogenesis of nasal tumors in rats exposed to hexamethylphosphoramide by inhalation

    Lee, K.P.; Trochimowicz, H.J.


    Hexamethylphosphoramide (HMPA) is used as a solvent, polymerization catalyst and, to some extent, as a deicing additive for jet fuels. Nasal tumors have been induced in rats by inhalation exposure to the compound for 6 to 24 months at concentrations of 50, 100, 400, and 4000 parts per billion (ppb), but not in rats exposed at 10 ppb for 24 months. Most nasal tumors were epidermoid carcinomas and developed from the respiratory epithelium or subepithelial nasal gland, both of which revealed squamous metaplasia or dysplasia in the anterior nasal cavity. The glandular cells appear to play an important role in developing epidermoid carcinomas in the nasal cavity. The ultrastructure of epidermoid carcinomas revealed abundant features of glandular differentiation in the neoplastic squamous cells. The morphological expression of glandular cell metamorphosis in the epidermoid carcinoma included intermediate cells showing both glandular and squamous differentiation, inter- or intracellular lumina, secretory vesicles, and mucus droplets in squamous cells and keratin plates.

  1. Metastasis and circulating tumor cells

    Dalum, van G.; Holland, L.; Terstappen, L.W.M.M.


    Cancer is a prominent cause of death worldwide. In most cases, it is not the primary tumor which causes death, but the metastases. Metastatic tumors are spread over the entire human body and are more difficult to remove or treat than the primary tumor. In a patient with metastatic disease, circulati

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

    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


    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

  3. Therapeutic Effect of Clarithromycin on a Transplanted Tumor in Rats

    Sassa, Kazuhiko; Mizushima, Yutaka; Fujishita, Takashi; Oosaki, Rokuo; Kobayashi, Masashi


    The therapeutic antitumor effect of clarithromycin (CAM) was examined with the 13762NF mammary adenocarcinoma and F-344 rat system. When CAM treatment at a dosage of 2 mg/kg of body weight orally for 21 days was commenced after inoculation of the tumor, no significant decrease in death rate was observed, although the loss in body weight was less than that in the untreated group. When tumor-bearing (TB) rats were treated with CAM in combination with carboplatin or cyclophosphamide, a significa...


    Abdalla, Rene Jorge; Cohen, Moisés; Nóbrega, Jezimar; Forgas, Andrea


    Synovial giant cell tumor is a benign neoplasm, rarely reported in the form of malignant metastasis. Synovial giant cell tumor most frequently occurs on the hand, and, most uncommon, on the ankle and knee. In the present study, the authors describe a rare case of synovial giant cell tumor on the knee as well as the treatment approach. Arthroscopy has been shown, in this case, to be the optimal method for treating this kind of lesion, once it allowed a less aggressive approach, while providing good visualization of all compartments of knee joint and full tumor resection.

  5. [Granular cell tumor of the larynx].

    Modrzyński, M; Wróbel, B; Zawisza, E; Drozd, K


    Granular cell tumor is an unusual growth of probably neuroectodermal histogenesis, first reported by Abrikossoff in 1926 with the name of myoblastenmyoma. Authors described a case of a 54 year man with laryngeal seat of granular-cell myoblastoma. In this case Abrikossoff tumor was located in the right vocal chord. The tumor was treated successfully surgically by microlaryngoscopy. The etiology, clinical features and diagnostic difficulties are discussed.

  6. Acidosis Promotes Metastasis Formation by Enhancing Tumor Cell Motility.

    Riemann, A; Schneider, B; Gündel, D; Stock, C; Gekle, M; Thews, O


    The tumor microenvironment is characterized by hypoxia, acidosis as well as other metabolic and biochemical alterations. Its role in cancer progression is increasingly appreciated especially on invasive capacity and the formation of metastasis. The effect of acidosis on metastasis formation of two rat carcinoma cell lines was studied in the animal model. In order to analyze the pH dependency of different steps of metastasis formation, invasiveness, cell adhesion and migration of AT-1 prostate cancer cells as well as possible underlying cell signaling pathways were studied in vitro. Acidosis significantly increased the formation of lung metastases of both tumor cell lines in vivo. In vitro, extracellular acidosis neither enhanced invasiveness nor affected cell adhesion to a plastic or to an endothelial layer. However, cellular motility was markedly elevated at pH 6.6 and this effect was sustained even when extracellular pH was switched back to pH 7.4. When analyzing the underlying mechanism, a prominent role of ROS in the induction of migration was observed. Signaling through the MAP kinases ERK1/2 and p38 as well as Src family kinases was not involved. Thus, cancer cells in an acidic microenvironment can acquire enhanced motility, which is sustained even if the tumor cells leave their acidic microenvironment e.g. by entering the blood stream. This increase depended on elevated ROS production and may contribute to the augmented formation of metastases of acidosis-primed tumor cells in vivo.

  7. Early treatment with metformin induces resistance against tumor growth in adult rats.

    Trombini, Amanda B; Franco, Claudinéia Cs; Miranda, Rosiane A; de Oliveira, Júlio C; Barella, Luiz F; Prates, Kelly V; de Souza, Aline A; Pavanello, Audrei; Malta, Ananda; Almeida, Douglas L; Tófolo, Laize P; Rigo, Kesia P; Ribeiro, Tatiane As; Fabricio, Gabriel S; de Sant'Anna, Juliane R; Castro-Prado, Marialba Aa; de Souza, Helenir Medri; de Morais, Hely; Mathias, Paulo Cf


    It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer.

  8. Granular cell tumors of the tracheobronchial tree.

    Maten, van der J; Blaauwgeers, JL; Sutedja, G.; Kwa, HB; Postmus, P.E.; Wagenaar, SS


    OBJECTIVE: To describe the population-based incidence and clinical characteristics of granular cell tumors of the tracheobronchial tree. METHODS: All newly registered tracheobronchial granular cell tumors in the Dutch Network and National Database for Pathology for 10 consecutive years (1990-1999) w

  9. Treatment Option Overview (Ovarian Germ Cell Tumors)

    ... ovarian germ cell tumor are swelling of the abdomen or vaginal bleeding after menopause. Ovarian germ cell ... if you have either of the following: Swollen abdomen without weight gain in other parts of the ...

  10. General Information about Ovarian Germ Cell Tumors

    ... ovarian germ cell tumor are swelling of the abdomen or vaginal bleeding after menopause. Ovarian germ cell ... if you have either of the following: Swollen abdomen without weight gain in other parts of the ...

  11. Immune Cells in Blood Recognize Tumors

    NCI scientists have developed a novel strategy for identifying immune cells circulating in the blood that recognize specific proteins on tumor cells, a finding they believe may have potential implications for immune-based therapies.

  12. Tumor Evasion from T Cell Surveillance

    Katrin Töpfer


    Full Text Available An intact immune system is essential to prevent the development and progression of neoplastic cells in a process termed immune surveillance. During this process the innate and the adaptive immune systems closely cooperate and especially T cells play an important role to detect and eliminate tumor cells. Due to the mechanism of central tolerance the frequency of T cells displaying appropriate arranged tumor-peptide-specific-T-cell receptors is very low and their activation by professional antigen-presenting cells, such as dendritic cells, is frequently hampered by insufficient costimulation resulting in peripheral tolerance. In addition, inhibitory immune circuits can impair an efficient antitumoral response of reactive T cells. It also has been demonstrated that large tumor burden can promote a state of immunosuppression that in turn can facilitate neoplastic progression. Moreover, tumor cells, which mostly are genetically instable, can gain rescue mechanisms which further impair immune surveillance by T cells. Herein, we summarize the data on how tumor cells evade T-cell immune surveillance with the focus on solid tumors and describe approaches to improve anticancer capacity of T cells.

  13. In vivo PET imaging and biodistribution of radiolabeled gold nanoshells in rats with tumor xenografts.

    Xie, Huan; Wang, Zheng Jim; Bao, Ande; Goins, Beth; Phillips, William T


    Here we report the radiolabeling of gold nanoshells (NSs) for PET imaging in rat tumor model. A conjugation method was developed to attach NSs with the radionuclide, (64)Cu. The resulting conjugates showed good labeling efficiency and stability in PBS and serum. The pharmacokinetics of (64)Cu-NS and the controls ((64)Cu-DOTA and (64)Cu-DOTA-PEG2K) were determined in nude rats with a head and neck squamous cell carcinoma xenograft by radioactive counting. Using PET/CT imaging, we monitored the in vivo distribution of (64)Cu-NS and the controls in the tumor-bearing rats at various time points after their intravenous injection. PET images of the rats showed accumulation of (64)Cu-NSs in the tumors and other organs with significant difference from the controls. The organ biodistribution of rats at 46h post-injection was analyzed by radioactive counting and compared between the (64)Cu-NS and the controls. Different clearance kinetics was indicated. Neutron activation analysis (NAA) of gold concentration was performed to quantify the amount of NSs in major tissues of the dosed rats and the results showed similar distribution. Overall, PET images with (64)Cu had good resolution and therefore can be further applied to guide photothermal treatment of cancer.

  14. Pathway-specific differences between tumor cell lines and normal and tumor tissue cells

    Tozeren Aydin


    Full Text Available Abstract Background Cell lines are used in experimental investigation of cancer but their capacity to represent tumor cells has yet to be quantified. The aim of the study was to identify significant alterations in pathway usage in cell lines in comparison with normal and tumor tissue. Methods This study utilized a pathway-specific enrichment analysis of publicly accessible microarray data and quantified the gene expression differences between cell lines, tumor, and normal tissue cells for six different tissue types. KEGG pathways that are significantly different between cell lines and tumors, cell lines and normal tissues and tumor and normal tissue were identified through enrichment tests on gene lists obtained using Significance Analysis of Microarrays (SAM. Results Cellular pathways that were significantly upregulated in cell lines compared to tumor cells and normal cells of the same tissue type included ATP synthesis, cell communication, cell cycle, oxidative phosphorylation, purine, pyrimidine and pyruvate metabolism, and proteasome. Results on metabolic pathways suggested an increase in the velocity nucleotide metabolism and RNA production. Pathways that were downregulated in cell lines compared to tumor and normal tissue included cell communication, cell adhesion molecules (CAMs, and ECM-receptor interaction. Only a fraction of the significantly altered genes in tumor-to-normal comparison had similar expressions in cancer cell lines and tumor cells. These genes were tissue-specific and were distributed sparsely among multiple pathways. Conclusion Significantly altered genes in tumors compared to normal tissue were largely tissue specific. Among these genes downregulation was a major trend. In contrast, cell lines contained large sets of significantly upregulated genes that were common to multiple tissue types. Pathway upregulation in cell lines was most pronounced over metabolic pathways including cell nucleotide metabolism and oxidative

  15. Tumor's other immune targets: dendritic cells.

    Esche, C; Lokshin, A; Shurin, G V; Gastman, B R; Rabinowich, H; Watkins, S C; Lotze, M T; Shurin, M R


    The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4-48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases.

  16. Development of a locally advanced orthotopic prostate tumor model in rats for assessment of combined modality therapy.

    Tumati, Vasu; Mathur, Sanjeev; Song, Kwang; Hsieh, Jer-Tsong; Zhao, Dawen; Takahashi, Masaya; Dobin, Timothy; Gandee, Leah; Solberg, Timothy D; Habib, Amyn A; Saha, Debabrata


    The purpose of this study was to develop an aggressive locally advanced orthotopic prostate cancer model for assessing high-dose image-guided radiation therapy combined with biological agents. For this study, we used a modified human prostate cancer (PCa) cell line, PC3, in which we knocked down a tumor suppressor protein, DAB2IP (PC3‑KD). These prostate cancer cells were implanted into the prostate of nude or Copenhagen rats using either open surgical implantation or a minimally invasive procedure under ultrasound guidance. We report that: i) these DAB2IP-deficient PCa cells form a single focus of locally advanced aggressive tumors in both nude and Copenhagen rats; ii) the resulting tumors are highly aggressive and are poorly controlled after treatment with radiation alone; iii) ultrasound-guided tumor cell implantation can be used successfully for tumor development in the rat prostate; iv) precise measurement of the tumor volume and the treatment planning for radiation therapy can be obtained from ultrasound and MRI, respectively; and v) the use of a fiducial marker for enhanced radiotherapy localization in the rat orthotopic tumor. This model recapitulates radiation-resistant prostate cancers which can be used to demonstrate and quantify therapeutic response to combined modality treatments.

  17. CellTracks cytometer for detection of circulating tumor cells

    Tibbe, A.G.J.; Kooi, van der A.; Groot, de M.R.; Vermes, I.


    Introduction: In patients with carcinomas, tumor cells are shed into the circulation. The number of the circulating tumor cells is low and technology is needed that has sufficient sensitivity and specificity to enumerate and characterize these cells. The CellTracks system was developed to provide an

  18. Similarity on neural stem cells and brain tumor stem cells in transgenic brain tumor mouse models

    Guanqun Qiao; Qingquan Li; Gang Peng; Jun Ma; Hongwei Fan; Yingbin Li


    Although it is believed that glioma is derived from brain tumor stem cells, the source and molecular signal pathways of these cells are stil unclear. In this study, we used stable doxycycline-inducible transgenic mouse brain tumor models (c-myc+/SV40Tag+/Tet-on+) to explore the malignant trans-formation potential of neural stem cells by observing the differences of neural stem cel s and brain tumor stem cells in the tumor models. Results showed that chromosome instability occurred in brain tumor stem cells. The numbers of cytolysosomes and autophagosomes in brain tumor stem cells and induced neural stem cel s were lower and the proliferative activity was obviously stronger than that in normal neural stem cells. Normal neural stem cells could differentiate into glial fibril ary acidic protein-positive and microtubule associated protein-2-positive cells, which were also negative for nestin. However, glial fibril ary acidic protein/nestin, microtubule associated protein-2/nestin, and glial fibril ary acidic protein/microtubule associated protein-2 double-positive cells were found in induced neural stem cells and brain tumor stem cel s. Results indicate that induced neural stem cells are similar to brain tumor stem cells, and are possibly the source of brain tumor stem cells.

  19. Giant cell tumor in adipose package Hoffa

    Etcheto, H. Rivarola; Escobar, G.; Blanchod, C. Collazo; Palanconi, M.; Zordan, J.; Salinas, E. Alvarez; Autorino₁, Carlos


    Tumors of adipose Hoffa package are very uncommon, with isolated cases reported in the literature. His presentation in pediatric patients knee is exceptional. The most frequently described tumors are benign including vellonodular synovitis. The extra-articular localized variant there of is known as giant cell tumor of the tendon sheath. It is characterized by locally aggressive nature, and has been described in reports of isolated cases. Objective: A case of giant cell tumor of the tendon sheath in adipose presentation package Hoffa in pediatric patients is presented in this paper. Methods: male patient eleven years with right knee pain after sports practice was evaluated. Physical examination, showed limited extension -30º, joint effusion, stable negative Lachman maneuver without peripheral knee laxity. MRI hyperintense on tumor is observed in T2 and hypointense on T1 homogeneous and defined edges content displayed prior to LCA related to adipose Hoffa package. Results: The tumor specimen was obtained and histopathology is defined as densely cellular tissue accumulation of xantomisados fibrocollagenous with histiocytes and multinucleated giant cells, compatible with giant cell tumor of tendon sheath. Conclusion: The presentation of giant cell tumors of the tendon sheath in Hoffa fat pad is exceptional. However, his suspicion allows adequate preoperative surgical planning, as a whole resection is the only procedure that has been shown to decrease the rate of recurrence of this disease.

  20. Herceptin conjugates linked by EDC boost direct tumor cell death via programmed tumor cell necrosis.

    Jiemiao Hu

    Full Text Available Tumor-targeted antibody therapy is one of the safest biological therapeutics for cancer patients, but it is often ineffective at inducing direct tumor cell death and is ineffective against resistant tumor cells. Currently, the antitumor efficacy of antibody therapy is primarily achieved by inducing indirect tumor cell death, such as antibody-dependent cell cytotoxicity. Our study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl carbodiimide hydrochloride, are capable of engendering human epidermal growth factor receptor 2 (Her2 positive tumor cells death. Using a high-performance liquid chromatography (HPLC system, three peaks with estimated molecular weights of antibody monomer, dimer, and trimer were isolated. Both Herceptin trimer and dimer separated by HPLC induced significant levels of necrotic tumor cell death, although the trimer was more effective than the dimer. Notably, the Herceptin trimer also induced Herceptin-resistant tumor cell death. Surprisingly different from the known cell death mechanism that often results from antibody treatment, the Herceptin trimer elicited effective and direct tumor cell death via a novel mechanism: programmed cell necrosis. In Her2-positive cells, inhibition of necrosis pathways significantly reversed Herceptin trimer-induced cell death. In summary, the Herceptin trimer reported herein harbors great potential for overcoming tumor cell resistance to Herceptin treatment.

  1. Esophageal carcinogenesis in the rat: zinc deficiency and alcohol effects on tumor induction.

    Newberne, P M; Schrager, T F; Broitman, S


    Sprague-Dawley male rats were fed zinc-deficient or supplemented diets for 2 weeks, administered a carcinogenic dose of methylbenzylnitrosamine and observed over 20 or more weeks for effects of superimposing excess zinc or alcohol on development of esophageal tumors. In three separate experiments it was shown that (1) excess zinc offered no protection, (2) switching diets during or after carcinogen exposure pointed toward involvement of zinc in both initiation and promotion, (3) neither ethanol nor 3-methyl butanol alone affected tumorigenesis but the two combined and superimposed on a zinc deficiency resulted in a significant enhancement of neoplasia. In one group of rats fed the zinc-deficient diet only, with no carcinogen, 4 rats developed neoplasms, one of which was malignant. Cell proliferation, an integral component of zinc deficiency, appears to be an important contribution to tumor induction in this model.

  2. Suprasellar/pineal bifocal germ cell tumors.

    Cuccia, Vicente; Alderete, Daniel


    Intracranial germ cell tumors (GCT) arise from embryonal rests of germinal cells. The aim of this report is to analyze a small group of GCT located simultaneously in the suprasellar and pineal regions without seeding either between both tumors or to other places. We named this group as suprasellar/pineal bifocal germ cell tumors (SPBT). A retrospective review of a series of 25 GCT showed a) 16 cases of unifocal non-disseminated pineal or sellar GCT, b) one case of unifocal disseminated pineal GCT, c) three cases with suprasellar and pineal double tumors with dissemination, and d) five cases with SPBT. The analysis is focused on the latter group. The series includes four pure germinomas and one germinal non-germinoma. MRI and endoscopic exploration were necessary to define SPBT. Endocrine, ocular, and increased intracranial pressure syndromes were identified and related to the size of the tumors. Chemotherapy and radiotherapy were performed in all SPBT. Radical or partial resection of SPBT offered no benefits over biopsy. Prognosis for bifocal groups was similar to unifocal tumors of the same histological type. Complete remission without recurrence and mortality were achieved in all cases. SPBT seem to be an entity defined by a) one tumor in the suprasellar and another in the pineal region, b) GCT with predominance of PG, but not exclusively, and c) MRI and endoscopy without any dissemination. The presence of two tumors does not indicate dissemination; SPBT were non-disseminated but focal tumors, and spinal radiotherapy was not necessary.

  3. Destruction of solid tumors by immune cells

    López, Álvaro G.; Seoane, Jesús M.; Sanjuán, Miguel A. F.


    The fractional cell kill is a mathematical expression describing the rate at which a certain population of cells is reduced to a fraction of itself. In order to investigate the fractional cell kill that governs the rate at which a solid tumor is lysed by a cell population of cytotoxic CD8+ T cells (CTLs), we present several in silico simulations and mathematical analyses. When the CTLs eradicate efficiently the tumor cells, the models predict a correlation between the morphology of the tumors and the rate at which they are lysed. However, when the effectiveness of the immune cells is decreased, the mathematical function fails to reproduce the process of lysis. This limit is thoroughly discussed and a new fractional cell kill is proposed.

  4. Harnessing Dendritic Cells for Tumor Antigen Presentation

    Nierkens, Stefan [Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, Nijmegen 6525 GA (Netherlands); Janssen, Edith M., E-mail: [Division of Molecular Immunology, Cincinnati Children' s Hospital Research Foundation, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229 (United States)


    Dendritic cells (DC) are professional antigen presenting cells that are crucial for the induction of anti-tumor T cell responses. As a consequence, research has focused on the harnessing of DCs for therapeutic interventions. Although current strategies employing ex vivo-generated and tumor-antigen loaded DCs have been proven feasible, there are still many obstacles to overcome in order to improve clinical trial successes and offset the cost and complexity of customized cell therapy. This review focuses on one of these obstacles and a pivotal step for the priming of tumor-specific CD8{sup +} and CD4{sup +} T cells; the in vitro loading of DCs with tumor antigens.

  5. Synchrotron microbeam radiation therapy for rat brain tumor palliation—influence of the microbeam width at constant valley dose

    Serduc, Raphaël; Bouchet, Audrey; Bräuer-Krisch, Elke; Laissue, Jean A.; Spiga, Jenny; Sarun, Sukhéna; Bravin, Alberto; Fonta, Caroline; Renaud, Luc; Boutonnat, Jean; Siegbahn, Erik Albert; Estève, François; Le Duc, Géraldine


    To analyze the effects of the microbeam width (25, 50 and 75 µm) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 µm wide microbeams, all spaced 211 µm on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 µm wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of ~50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 µm width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 µm or 25 µm widths when used with a 211 µm on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in all groups. The use of

  6. Synchrotron microbeam radiation therapy for rat brain tumor palliation-influence of the microbeam width at constant valley dose

    Serduc, Raphael; Fonta, Caroline; Renaud, Luc [Universite de Toulouse, UPS, Centre de Recherche Cerveau et Cognition (France); Bouchet, Audrey; Braeuer-Krisch, Elke; Sarun, Sukhena; Bravin, Alberto; Le Duc, Geraldine [European Synchrotron Radiation Facility, F38043 Grenoble (France); Laissue, Jean A [Institute of Pathology, University of Bern (Switzerland); Spiga, Jenny [Department of Physics, University of Cagliari, s.p. Monserrato-Sestu, Monserrato (Canada) 09042 (Italy); Boutonnat, Jean [TIMC lab, UMR CNRS 5525, Univ Joseph Fourier, CHU, Grenoble (France); Siegbahn, Erik Albert [Department of Medical Physics, Karolinska Universitetssjukhuset, 17176 Stockholm (Sweden); Esteve, Francois [INSERM U836, Equipe 6, Institut des Neurosciences de Grenoble, 38043 Grenoble Cedex (France)], E-mail:


    To analyze the effects of the microbeam width (25, 50 and 75 {mu}m) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 {mu}m wide microbeams, all spaced 211 {mu}m on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 {mu}m wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of {approx}50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 {mu}m width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 {mu}m or 25 {mu}m widths when used with a 211 {mu}m on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in

  7. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression

    Frohlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar


    Expression of ADAM12 is low in most normal tissues, but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In the present study, we found...... that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 appears to be dispensable for its tumor-promoting effect. Interestingly, we demonstrate that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence...... tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma ADAM12 is almost exclusively located in tumor cells and only rarely seen in the tumor-associated stroma. We...

  8. Tumor necrosis factor-α-mediated threonine 435 phosphorylation of p65 nuclear factor-κB subunit in endothelial cells induces vasogenic edema and neutrophil infiltration in the rat piriform cortex following status epilepticus

    Kim Ji-Eun


    Full Text Available Abstract Background Status epilepticus (SE induces severe vasogenic edema in the piriform cortex (PC accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF-α in blood-brain barrier (BBB disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE. Methods SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits. Results Following SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen. Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC. Conclusion These findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.

  9. Expression of thyroglobulin and calcitonin in spontaneous thyroid gland tumors in the Han Wistar rat.

    Pilling, Andrew M; Jones, Stewart A; Endersby-Wood, Helen J; McCormack, Nicola A M; Turton, John A


    Spontaneous follicular and C-cell tumors of the thyroid gland in the Han Wistar rat were examined using two morphologic procedures. Firstly, in situ hybridization (ISH) was used to localize thyroglobulin (TG) and calcitonin (CT) mRNAs. Secondly, the proteins for these markers were detected using immunohistochemistry (IHC). The aim was to study the morphology of the tumors and to examine the usefulness of TG and CT markers in the differential diagnosis of these lesions. Follicular tumors with cystic, papillary and follicular patterns showed relatively consistent expression of TG mRNA by ISH, thereby confirming the diagnostic value of this technique. However, no staining for TG markers was observed in solid lesions. In general, C-cell tumors comprised well-differentiated cells that continued to express CT mRNA and peptides even after embolic spread and metastasis. Therefore, the performance of either ISH or IHC for CT markers can be used for diagnostic confirmation. Additional features noted in C-cell tumors included the appearance of tumor emboli or metastases in association with small primary lesions (less than 5 average follicular diameters in size) and the presence of eosinophilic (amyloid-like) material showing immunopositivity for CT peptides. Finally, evidence is provided for the sequestration of TG protein by proliferating C-cells.

  10. Characterization of cell suspensions from solid tumors

    Pallavicini, M.


    The desirable features of cells in suspension will necessarily be dependent upon the use for which the cells were prepared. Adequate cell yield or recovery is defined by the measurement to be performed. Retention of cellular morphology is important for microscopic identification of cell types in a heterogenous cell suspension, and may be used to determine whether the cells in suspension are representative of those in the tumor in situ. Different dispersal protocols may yield cells with different degrees of clonogenicity, as well as altered biochemical features, such as loss of cellular proteins, surface antigens, nucleotide pools, etc. The quality of the cell suspension can be judged by the degree of cell clumping and level of cellular debris, both of which impact on flow cytometric measurements and studies in which the number of cells be known accurately. Finally, if the data measured on the cells in suspension are to be extrapolated to phenomena occurring in the tumor in situ, it is desirable that the cells in suspension are representative of those in the solid tumor in vivo. This report compares characteristics of tumor cell suspensions obtained by different types of selected disaggregation methods. 33 refs., 2 figs., 4 tabs.

  11. Ultrasound molecular imaging of VEGFR2 in a rat prostate tumor model using BR55.

    Tardy, Isabelle; Pochon, Sibylle; Theraulaz, Martine; Emmel, Patricia; Passantino, Lisa; Tranquart, François; Schneider, Michel


    To evaluate BR55, a new VEGFR2-specific ultrasound contrast agent, for imaging prostate tumors in an orthotopic model in the rat. Rat prostate adenocarcinoma were established by injection of G Dunning R-3327 tumor cells in one lobe of the prostate of Copenhagen rats. Imaging experiments were performed with BR55, SonoVue, and streptavidin-functionalized microbubbles coupled with an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody using a clinical ultrasound scanner. Contrast enhancement in the tumor and healthy prostate was followed over time by intermittent imaging at low acoustic power. Signal quantification and statistical analysis were performed in the tumor and healthy tissue to compare the behavior of the 3 contrast agents. Immunohistochemistry was performed on the prostate and tumor specimen to determine the expression of VEGFR2. Comparable contrast enhancement was observed in tumors at peak intensity for BR55 and SonoVue. Then, once unbound microbubbles had cleared from the circulation, a strong enhancement of the tumor was obtained with BR55, whereas no significant microbubble accumulation was detected in the healthy prostate tissue. SonoVue microbubbles were rapidly eliminated, and no significant binding was observed in the tumor. The tumor to prostate ratio calculated after signal quantification was about 20 for the 3 doses of BR55 tested. The enhancement obtained with BR55 in the tumor was not significantly different from the one observed with antibody-coupled streptavidin microbubbles. Intense staining for VEGFR2 was detected in the tumor vessels by immunohistochemistry. This study showed that BR55 binding to prostate tumors resulted in a strong enhancement of the lesions as early as a few minutes after contrast injection, whereas minimal nonspecific accumulation occurred in the healthy part of the gland. BR55, like SonoVue, provide information on tissue perfusion during the early vascular phase, but BR55 binding to the tumoral

  12. Stages of Childhood Extracranial Germ Cell Tumors

    ... tumors include the following: Having certain genetic syndromes : Klinefelter syndrome may increase the risk of germ cell ... and procedures may be used: Physical exam and history : An exam of the body to check general ...

  13. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer.

    Connolly, Nina P; Stokum, Jesse A; Schneider, Craig S; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J; Kim, Anthony J; Simard, J Marc; Winkles, Jeffrey A; Holland, Eric C; Woodworth, Graeme F


    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  14. Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats.

    Sun, K; Guo, X-L; Zhao, Q-d; Jing, Y-y; Kou, X-r; Xie, X-q; Zhou, Y; Cai, N; Gao, L; Zhao, X; Zhang, S-s; Song, J-r; Li, D; Deng, W-j; Li, R; Wu, M-c; Wei, L-x


    Many reports have shown that autophagy has a role as both a promoter and inhibitor in tumor development. However, the mechanism of this paradox is unknown. Tumor development is a multistep process. Therefore, we investigated whether the role of autophagy in hepatocarcinoma formation depended on the stage of tumor development. Based on our results, autophagy inhibition by chloroquine had a tumor-promotive effect in the rat model with N-diethylnitrosamine-induced hepatocarcinogenesis in its dysplastic stage (Ds) and a tumor-suppressive effect in its tumor-forming stage (Ts). In the Ds, autophagy inhibition enhanced cell proliferation, DNA damage and inflammatory cytokines expression in liver. These changes were dependent on the upregulation of reactive oxygen species (ROS) that was resulted from autophagy inhibition, and ultimately accelerated the process of hepatocarcinogenesis. However, in the Ts, autophagy inhibition restrained tumor formation by decreasing tumor cell survival and proliferation. In this stage, autophagy inhibition led to excessive ROS accumulation in the tumor, which promoted cell apoptosis, and prominently suppressed tumor cell metabolism. Taken together, our data suggested that autophagy suppressed hepatocarcinogenesis in the Ds by protecting normal cell stability and promoted hepatocarcinogenesis in the Ts by supporting tumor cells growth. Autophagy always had a role as a protector throughout the process of hepatocarcinoma development.

  15. Tumor hypoxia - A confounding or exploitable factor in interstitial brachytherapy? Effects of tissue trauma in an experimental rat tumor model

    van den Berg, AP; van Geel, CAJF; van Hooije, CMC; van der Kleij, AJ; Visser, AG


    Purpose: To evaluate the potential effects of tumor hypoxia induced by afterloading catheter implantation on the effectiveness of brachytherapy in a rat tumor model. Methods and Materials: Afterloading catheters (4) Here implanted in subcutaneously growing R1M rhabdomyosarcoma in female Wag/Rij rats

  16. Ovarian steroid cell tumors: sonographic characteristics.

    Monteagudo, A; Heller, D; Husami, N; Levine, R U; McCaffrey, R; Timor-Tritsch, I E


    The goal of the gynecologist is to detect ovarian tumors in their earliest stages. Small virilizing tumors, which barely affect the size of the ovaries, are such lesions. Since the introduction of transvaginal sonography it is technically possible to detect small intraovarian neoplasms. Three cases of virilizing steroid cell tumors in postmenopausal women with ovarian volumes just exceeding the normal sizes for age are presented. High-frequency transvaginal ultrasound and color Doppler studies to measure flow parameters were used. These small tumors had different echogenicity from the surrounding ovarian tissue and two had low impedance-to-flow values. Gray-scale transvaginal sonography combined with color Doppler studies can make the diagnosis of small steroid cell tumors easier and, at times, better than other, more costly imaging modalities.

  17. Energy and Redox Homeostasis in Tumor Cells

    Marcus Fernandes de Oliveira


    Full Text Available Cancer cells display abnormal morphology, chromosomes, and metabolism. This review will focus on the metabolism of tumor cells integrating the available data by way of a functional approach. The first part contains a comprehensive introduction to bioenergetics, mitochondria, and the mechanisms of production and degradation of reactive oxygen species. This will be followed by a discussion on the oxidative metabolism of tumor cells including the morphology, biogenesis, and networking of mitochondria. Tumor cells overexpress proteins that favor fission, such as GTPase dynamin-related protein 1 (Drp1. The interplay between proapoptotic members of the Bcl-2 family that promotes Drp 1-dependent mitochondrial fragmentation and fusogenic antiapoptotic proteins such as Opa-1 will be presented. It will be argued that contrary to the widespread belief that in cancer cells, aerobic glycolysis completely replaces oxidative metabolism, a misrepresentation of Warburg’s original results, mitochondria of tumor cells are fully viable and functional. Cancer cells also carry out oxidative metabolism and generally conform to the orthodox model of ATP production maintaining as well an intact electron transport system. Finally, data will be presented indicating that the key to tumor cell survival in an ROS rich environment depends on the overexpression of antioxidant enzymes and high levels of the nonenzymatic antioxidant scavengers.

  18. Escape from Tumor Cell Dormancy


    Pouliot, K. L. Stanley, J. Chia , J. M. Moseley, D. K. Hards and R. L. Anderson: Tumor-specific expression of alphavbeta3 integrin promotes...deep, measured by confocal imaging of microwells filled with 20-mm-diameter fluores - cent beads (Fig. 1). Evaluation of mechanical properties of PEG...

  19. [Sertoli cell tumor of the testis].

    Hita Rosino, E; López Hidalgo, J; Mellado Mesa, P; Olivar Buera, M


    Sertoli cell tumors (TCS) derivated from sex-cord estroma cells, are an uncommon variety of testicles neoplasms. A 66 year-old patient that came to the consultation for an increased scrotum of size present. Ultrasound viewed a hipoecoic nodule capable with testicular tumor, more secondary hidrocele. After undergoing the standard treatment, by means of groin radical orchiectomy, its pathologic analysis identified the lesion as Sertoli cell tumor conventional. The pathologic features that best correlate with a clinically benign course are as follows: a lower size tumor to 5 cm, mild nuclear atypia, a mitotic rate of less than 5 mitosis per 10 high power fields, and absent necrosis. Our case presented with these features. Follow-up of these neoplasms should be prolonged by the unusual of its presentation and a small percentage of cases are clinically malignant.

  20. Yersinia pestis YopJ suppresses tumor necrosis factor alpha induction and contributes to apoptosis of immune cells in the lymph node but is not required for virulence in a rat model of bubonic plague.

    Lemaître, Nadine; Sebbane, Florent; Long, Daniel; Hinnebusch, B Joseph


    The virulence of the pathogenic Yersinia species depends on a plasmid-encoded type III secretion system that transfers six Yop effector proteins into host cells. One of these proteins, YopJ, has been shown to disrupt host cell signaling pathways involved in proinflammatory cytokine production and to induce macrophage apoptosis in vitro. YopJ-dependent apoptosis in mesenteric lymph nodes has also been demonstrated in a mouse model of Yersinia pseudotuberculosis infection. These results suggest that YopJ attenuates the host innate and adaptive immune response during infection, but the role of YopJ during bubonic plague has not been completely established. We evaluated the role of Yersinia pestis YopJ in a rat model of bubonic plague following intradermal infection with a fully virulent Y. pestis strain and an isogenic yopJ mutant. Deletion of yopJ resulted in a twofold decrease in the number of apoptotic immune cells in the bubo and a threefold increase in serum tumor necrosis factor alpha levels but did not result in decreased virulence, systemic spread, or colonization levels in the spleen and blood. Our results indicate that YopJ is not essential for bubonic plague pathogenesis, even after peripheral inoculation of low doses of Y. pestis. Instead, the effects of YopJ appear to overlap and augment the immunomodulatory effects of other Y. pestis virulence factors.

  1. Identification of rat mammary tumor-1 gene (RMT-1), which is highly expressed in rat mammary tumors.

    Chiou, S; Yoo, J; Loh, K C; Guzman, R C; Gopinath, G R; Rajkumar, L; Chou, Y C; Yang, J; Popescu, N C; Nandi, S


    Full-term pregnancy early in life results in a permanent reduction in lifetime breast cancer risk in women. Parous rats and mice are also refractory to chemical carcinogenesis. Therefore, investigation of the differences between mammary glands from virgin and parous rats would provide valuable information regarding the protective effects of early full-term pregnancy. In this report, we examined the gene expression patterns in mammary glands from virgin and parous Lewis rats. Using differential display technology, a novel 4.2 kb cDNA, designated rat mammary tumor-1 (RMT-1) was isolated. Northern blot analysis of RMT-1 showed that RMT-1 expression was higher in the pre-pubertal and pubertal stages during rat mammary gland development while it was down-regulated in mammary glands from mature virgin and parous rats. RMT-1 expression was highest in rat mammary cancers compared with either the mammary glands of virgin or parous rats. At the Northern blot sensitivity level, RMT-1 expression was found only in the mammary gland. Northern blot analysis also showed that the expression of this gene was found in 74% of N-methyl-nitrosourea (MNU)-induced mammary cancers while it was not found in MNU-induced cancers from other organs. The examination of the RMT-1 gene structure revealed that it consists of five exons spanning 5.9 kb. Using fluorescence in situ hybridization, the gene was localized on rat chromosome 1 band q 43-51. The present data show that there is a correlation between high RMT-1 expression and rat mammary carcinogenesis or decreased RMT-1 expression and parity associated refractoriness to chemically induced mammary carcinogenesis. However, whether or not RMT-1 gene has a functional role in these processes remains to be investigated.

  2. Radiosensitivity of tumor cells. Oncogenes and apoptosis

    Peltenburg, L. T. C. [Leiden Univ., Leiden (Netherlands). Dept. of Clinical Oncology


    The success of treatment of cancer patients by radiotherapy largely depends on tumor radiosensitivity. Several molecular factors that determine the sensitivity of tumor cells to ionizing radiation have been identified during the last couple of years. Some of these factors are known as oncogenes and tumor suppressor genes. This review focuses on the influence of some of these molecular factors on a major determinant of radiosensitivity: i. e. programmed cell death or apoptosis. The crucial molecular step in ionizing radiation-induced apoptosis is the release of mitochondrial cytochrome c into the cell's cytosol. The ways the tumor suppressor protein p53, as well as the oncogenes ras and raf, c-myc and Bcl-2 can influence this process at different stages are presented. As will be discussed, the result of activation of an oncoprotein on tumor radiosensitivity depends on its mechanism of action and on the presence of other (oncogenic) factors, since complex interactions among many molecular factors determine the delicate balance between cell proliferation and cell death. The ongoing identification and characterization of factors influencing apoptosis will eventually make it possible to predict tumor radiosensitivity and thereby improve cancer treatment.

  3. Experimental nodel of C6 brain tumors in athymic rats Modelo experimental de tumor cerebral C6 em ratos atímicos

    Flávio K. Miura


    Full Text Available Malignant brain tumor experimental models tend to employ cells that are immunologically compatible with the receptor animal. In this study, we have proposed an experimental model of encephalic tumor development by injecting C6 cells into athymic Rowett rats, aiming at reaching a model which more closely resembles to the human glioma tumor. In our model, we observed micro-infiltration of tumor cell clusters in the vicinity of the main tumor mass, and of more distal isolated tumor cells immersed in normal encephalic parenchyma. This degree of infiltration is superior to that usually observed in other C6 models.Modelos experimentais de tumores cerebrais malignos geralmente utilizam células imunologicamente compatíveis com o animal receptor. Neste estudo apresentamos um modelo experimental baseado na inoculação de células C6 em ratos atímicos Rowett, visando obter um tumor que se assemelhe mais àqueles observados nos seres humanos. Neste modelo observamos microinfiltração de ilhotas de células na periferia da massa tumoral principal e nas áreas mais distantes, células tumorais isoladas no tecido cerebral normal. Este grau de infiltração é superior àquele observado em outros modelos utilizando as células C6.

  4. CD8+ Tumor-Infiltrating T Cells Are Trapped in the Tumor-Dendritic Cell Network

    Alexandre Boissonnas


    Full Text Available Chemotherapy enhances the antitumor adaptive immune T cell response, but the immunosuppressive tumor environment often dominates, resulting in cancer relapse. Antigen-presenting cells such as tumor-associated macrophages (TAMs and tumor dendritic cells (TuDCs are the main protagonists of tumor-infiltrating lymphocyte (TIL immuno-suppression. TAMs have been widely investigated and are associated with poor prognosis, but the immuno-suppressive activity of TuDCs is less well understood. We performed two-photon imaging of the tumor tissue to examine the spatiotemporal interactions between TILs and TuDCs after chemotherapy. In a strongly immuno-suppressive murine tumor model, cyclophosphamide-mediated chemotherapy transiently enhanced the antitumor activity of adoptively transferred ovalbumin-specific CD8+ T cell receptor transgenic T cells (OTI but barely affected TuDC compartment within the tumor. Time lapse imaging of living tumor tissue showed that TuDCs are organized as a mesh with dynamic interconnections. Once infiltrated into the tumor parenchyma, OTI T cells make antigen-specific and long-lasting contacts with TuDCs. Extensive analysis of TIL infiltration on histologic section revealed that after chemotherapy the majority of OTI T cells interact with TuDCs and that infiltration is restricted to TuDC-rich areas. We propose that the TuDC network exerts antigen-dependent unproductive retention that trap T cells and limit their antitumor effectiveness.

  5. Osteoclastic giant cell tumor of the pancreas: an immunohistochemical study

    Dizon, M A; Multhaupt, H A; Paskin, D L


    A case of an osteoclastic giant cell tumor of the pancreas is presented. Immunohistochemical studies were performed, which showed keratin (CAM, AE1) and epithelial membrane antigen positivity in the tumor cells. The findings support an epithelial origin for this tumor.......A case of an osteoclastic giant cell tumor of the pancreas is presented. Immunohistochemical studies were performed, which showed keratin (CAM, AE1) and epithelial membrane antigen positivity in the tumor cells. The findings support an epithelial origin for this tumor....

  6. Whole tumor antigen vaccination using dendritic cells: Comparison of RNA electroporation and pulsing with UV-irradiated tumor cells

    Benencia Fabian


    Full Text Available Abstract Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV B radiation using a convenient tumor model expressing human papilloma virus (HPV E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions.

  7. Molecular biology of testicular germ cell tumors.

    Gonzalez-Exposito, R; Merino, M; Aguayo, C


    Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies.

  8. Myeloid cells contribute to tumor lymphangiogenesis.

    Zumsteg, Adrian; Baeriswyl, Vanessa; Imaizumi, Natsuko; Schwendener, Reto; Rüegg, Curzio; Christofori, Gerhard


    The formation of new blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) promotes tumor outgrowth and metastasis. Previously, it has been demonstrated that bone marrow-derived cells (BMDC) can contribute to tumor angiogenesis. However, the role of BMDC in lymphangiogenesis has largely remained elusive. Here, we demonstrate by bone marrow transplantation/reconstitution and genetic lineage-tracing experiments that BMDC integrate into tumor-associated lymphatic vessels in the Rip1Tag2 mouse model of insulinoma and in the TRAMP-C1 prostate cancer transplantation model, and that the integrated BMDC originate from the myelomonocytic lineage. Conversely, pharmacological depletion of tumor-associated macrophages reduces lymphangiogenesis. No cell fusion events are detected by genetic tracing experiments. Rather, the phenotypical conversion of myeloid cells into lymphatic endothelial cells and their integration into lymphatic structures is recapitulated in two in vitro tube formation assays and is dependent on fibroblast growth factor-mediated signaling. Together, the results reveal that myeloid cells can contribute to tumor-associated lymphatic vessels, thus extending the findings on the previously reported role of hematopoietic cells in lymphatic vessel formation.

  9. Myeloid cells contribute to tumor lymphangiogenesis.

    Adrian Zumsteg

    Full Text Available The formation of new blood vessels (angiogenesis and lymphatic vessels (lymphangiogenesis promotes tumor outgrowth and metastasis. Previously, it has been demonstrated that bone marrow-derived cells (BMDC can contribute to tumor angiogenesis. However, the role of BMDC in lymphangiogenesis has largely remained elusive. Here, we demonstrate by bone marrow transplantation/reconstitution and genetic lineage-tracing experiments that BMDC integrate into tumor-associated lymphatic vessels in the Rip1Tag2 mouse model of insulinoma and in the TRAMP-C1 prostate cancer transplantation model, and that the integrated BMDC originate from the myelomonocytic lineage. Conversely, pharmacological depletion of tumor-associated macrophages reduces lymphangiogenesis. No cell fusion events are detected by genetic tracing experiments. Rather, the phenotypical conversion of myeloid cells into lymphatic endothelial cells and their integration into lymphatic structures is recapitulated in two in vitro tube formation assays and is dependent on fibroblast growth factor-mediated signaling. Together, the results reveal that myeloid cells can contribute to tumor-associated lymphatic vessels, thus extending the findings on the previously reported role of hematopoietic cells in lymphatic vessel formation.

  10. Correlation of MRI Biomarkers with Tumor Necrosis in Hras5 Tumor Xenograft in Athymic Rats

    Daniel P. Bradley


    Full Text Available Magnetic resonance imaging (MRI can measure the effects of therapies targeting the tumor vasculature and has demonstrated that vascular-damaging agents (VDA induce acute vascular shutdown in tumors in human and animal models. However, at subtherapeutic doses, blood flow may recover before the induction of significant levels of necrosis. We present the relationship between changes in MRI biomarkers and tumor necrosis. Multiple MRI measurements were taken at 4.7 T in athymic rats (n = 24 bearing 1.94 ± 0.2-cm3 subcutaneous Hras5 tumors (ATCC 41000 before and 24 hours after clinically relevant doses of the VDA, ZD6126 (0-10 mg/kg, i.v.. We measured effective transverse relaxation rate (R2*, initial area under the gadolinium concentration-time curve (IAUGC60/150, equivalent enhancing fractions (EHF60/150, time constant (Ktrans, proportion of hypoperfused voxels as estimated from fit failures in Ktrans analysis, and signal intensity (SI in T2-weighted MRI (T2W. ZD6126 treatment induced < 90% dose-dependent tumor necrosis at 10 mg/kg; correspondingly, SI changes were evident from T2W MRI. Although R2* did not correlate, other MRI biomarkers significantly correlated with necrosis at doses of ≥ 5 mg/kg ZD6126. These data on Hras5 tumors suggest that the quantification of hypoperfused voxels might provide a useful biomarker of tumor necrosis.

  11. Significance of rat mammary tumors for human risk assessment.

    Russo, Jose


    We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine the response of the tumors induced to chemotherapy. The utilization of experimental models of mammary carcinogenesis in risk assessment requires that the influence of ovarian, pituitary, and placental hormones, among others, as well as overall reproductive events are taken into consideration, since they are important modifiers of the susceptibility of the organ to neoplastic development. Several species, such as rodents, dogs, cats, and monkeys, have been evaluated for these purposes; however, none of them fulfills all the criteria specified previously. Rodents, however, are the most widely used models; therefore, this work will concentrate on discussing the rat rodent model of mammary carcinogenesis. © 2014 by The Author(s).

  12. VRP immunotherapy targeting neu: treatment efficacy and evidence for immunoediting in a stringent rat mammary tumor model.

    Laust, Amanda K; Sur, Brandon W; Wang, Kehui; Hubby, Bolyn; Smith, Jonathan F; Nelson, Edward L


    The ability to overcome intrinsic tolerance to a strict "self" tumor-associated antigen (TAA) and successfully treat pre-existing tumor is the most stringent test for anti-tumor immunotherapeutic strategies. Although this capacity has been demonstrated in various models using complicated strategies that may not be readily translated into the clinical arena, straightforward antigen-specific immunotherapeutic strategies in the most stringent models of common epithelial cancers have largely failed to meet this standard. We employed an immunotherapeutic strategy using an alphavirus-based, virus-like replicon particle (VRP), which has in vivo tropism for dendritic cells, to elicit immune responses to the non-mutated TAA rat neu in an aggressive rat mammary tumor model. Using this VRP-based immunotherapeutic strategy targeting a single TAA, we generated effective anti-tumor immunity in the setting of pre-existing tumor resulting in the cure of 36% of rats over multiple experiments, P = 0.002. We also observed down-regulation of rat neu expression in tumors that showed initial responses followed by tumor escape with resumption of rapid tumor growth. These responses were accompanied by significant anti-tumor proliferative responses and CD8+ cellular tumor infiltrates, all of which were restricted to animals receiving the anti-neu immunotherapy. Together these data, obtained in a stringent "self" TAA model, indicate that the VRP-based antigen-specific immunotherapy elicits sufficiently potent immune responses to exert immunologic pressure, selection, and editing of the growing tumors, thus supporting the activity of this straightforward immunotherapy and suggesting that it is a promising platform upon which to build even more potent strategies.

  13. In Vitro transformation of LW13 Rat liver epithelial Cells



    A rat liver epithelial cell line designated LW 13 was established using a sequential sedimentation method.The cell line retained many normal proerties of liver epithelial cells and showed some structural and functional features resembling those of liver parenchymal cells,LW13 cells became malignant after the intrduction of exogenous transforming EJ Ha ras gene,Tumors produced by inoculation of the transformed cells into baby rats contained areas of poorly differentialted hepatocellular carcinoma,In situ hybridization analysis confirmed the random rather than specific integration of exogenous ras gene into host chromosomes.Furthermore,an at least tenfold increase in the expression of the endogenous c mys gene was detected among transformed cell lines,suggesting the involvement of the c myc proto oncogene in the in vitro transformation of rat liver epithelial cells by EJ Ha ras oncogene.

  14. Cancer stem cell plasticity and tumor hierarchy

    Marina Carla Cabrera; Robert E Hollingsworth; Elaine M Hurt


    The origins of the complex process of intratumoralheterogeneity have been highly debated and differentcellular mechanisms have been hypothesized to accountfor the diversity within a tumor. The clonal evolution andcancer stem cell (CSC) models have been proposed asdrivers of this heterogeneity. However, the concept ofcancer stem cell plasticity and bidirectional conversionbetween stem and non-stem cells has added additionalcomplexity to these highly studied paradigms and may helpexplain the tumor heterogeneity observed in solid tumors.The process of cancer stem cell plasticity in which cancercells harbor the dynamic ability of shifting from a non-CSCstate to a CSC state and vice versa may be modulated byspecific microenvironmental signals and cellular interactionsarising in the tumor niche. In addition to promoting CSCplasticity, these interactions may contribute to the cellulartransformation of tumor cells and affect response tochemotherapeutic and radiation treatments by providingCSCs protection from these agents. Herein, we review theliterature in support of this dynamic CSC state, discussthe effectors of plasticity, and examine their role in thedevelopment and treatment of cancer.

  15. Gangliosides regulate tumor cell adhesion to collagen.

    Kazarian, Tamara; Jabbar, Adnan A; Wen, Fei-Qui; Patel, Dharmesh A; Valentino, Leonard A


    The ability of tumor cells to adhere to extracellular matrix proteins is critical for migration and invasion. The factors that regulate tumor cell adhesion are poorly characterized. Gangliosides promote platelet adhesion and may also play a role in the adhesion of other cell types. We hypothesized that pharmacological depletion of membrane gangliosides from adherent cells would abrogate adhesion to collagen and promote migration and invasion. To test these hypotheses, LA-N1 neuroblastoma cells, which avidly adhere to collagen and are rich with membrane gangliosides (43.69 nmol/10(8) cells), were cultured in the presence of D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol-HCl. Endogenous gangliosides were reduced by 98% (0.76 nmol/10(8) cells) and adhesion to collagen decreased by 67%. There were no changes in cell morphology, viability, proliferation rate or apoptosis. Pre-incubation of ganglioside-depleted cells in conditioned medium from control cells restored adhesion to collagen (0.45 +/- 0.002), comparable to that of control cells (0.49 +/- 0.035). Similarly, pre-incubation of ganglioside-depleted cells with purified GD2 completely restored adhesion in a concentration-dependent manner. When LA-N1 cells were cultured with retinoic acid, a biological response modifier known to increase endogenous gangliosides, adhesion to collagen increased. Next, we questioned whether changes in adhesion would be reflected as changes in migration and invasion. Cells depleted of endogenous cellular gangliosides migrated more than control cells. Finally, control cells replete with their endogenous gangliosides demonstrated less invasive potential than control cells. The data demonstrate that endogenous tumor gangliosides increase neuroblastoma cell adhesion to collagen and reduce migration and invasion in vitro.

  16. Giant cell tumor of bone: Multimodal approach

    Gupta A


    Full Text Available Background: The clinical behavior and treatment of giant cell tumor of bone is still perplexing. The aim of this study is to clarify the clinico-pathological correlation of tumor and its relevance in treatment and prognosis. Materials and Methods: Ninety -three cases of giant cell tumor were treated during 1980-1990 by different methods. The age of the patients varied from 18-58 yrs with male and female ratio as 5:4. The upper end of the tibia was most commonly involved (n=31, followed by the lower end of the femur(n=21, distal end of radius(n=14,upper end of fibula (n=9,proximal end of femur(n=5, upper end of the humerus(n=3, iliac bone(n=2,phalanx (n=2 and spine(n=1. The tumors were also encountered on uncommon sites like metacarpals (n=4 and metatarsal(n=1. Fifty four cases were treated by curettage and bone grafting. Wide excision and reconstruction was performed in twenty two cases . Nine cases were treated by wide excision while primary amputation was performed in four cases. One case required only curettage. Three inaccessible lesions of ilium and spine were treated by radiotherapy. Results: 19 of 54 treated by curettage and bone grafting showed a recurrence. The repeat curettage and bone grafting was performed in 18 cases while amputation was done in one. One each out of the cases treated by wide excision and reconstruction and wide excision alone recurred. In this study we observed that though curettage and bone grafting is still the most commonly adopted treatment, wide excision of tumor with reconstruction has shown lesser recurrence. Conclusion: For radiologically well-contained and histologically typical tumor, curettage and autogenous bone grafting is the treatment of choice . The typical tumors with radiologically deficient cortex, clinically aggressive tumors and tumors with histological Grade III should be treated by wide excision and reconstruction.

  17. Ultrasound features of orbital granular cell tumor.

    Ayres, Bernadete; Miller, Neil R; Eberhart, Charles G; Dibernardo, Cathy W


    The authors report the echographic characteristics of a rare orbital granular cell tumor and correlate these findings with histopathology. A 56-year-old woman presented with proptosis. Complete ophthalmic and ultrasound examinations were performed. Ultrasound revealed an oval, well-outlined orbital mass in the intraconal space with low-medium reflectivity and regular internal structure. An orbitotomy with complete excision of the tumor was performed. Histopathologic evaluation showed sheets and nests of cells with abundant eosinophilic and granular cytoplasm in a uniform distribution throughout the lesion. The echographic characteristics correlated well with the morphologic surgical findings and the histologic architecture. This is the first report describing the echographic characteristics of orbital granular cell tumor.

  18. In vivo photolabeling of tumor-infiltrating cells reveals highly regulated egress of T-cell subsets from tumors.

    Torcellan, Tommaso; Hampton, Henry R; Bailey, Jacqueline; Tomura, Michio; Brink, Robert; Chtanova, Tatyana


    Immune therapy is rapidly gaining prominence in the clinic as a major weapon against cancer. Whereas much attention has been focused on the infiltration of tumors by immune cells, the subsequent fate of these infiltrates remains largely unexplored. We therefore established a photoconversion-based model that allowed us to label tumor-infiltrating immune cells and follow their migration. Using this system, we identified a population of tumor-experienced cells that emigrate from primary tumors to draining lymph nodes via afferent lymphatic vessels. Although the majority of tumor-infiltrating cells were myeloid, T cells made up the largest population of tumor-egressing leukocytes. Strikingly, the subset composition of tumor-egressing T cells was greatly skewed compared with those that had infiltrated the tumor and those resident in the draining lymph node. Some T-cell subsets such as CD8(+) T cells emigrated more readily; others including CD4(-)CD8(-) T cells were preferentially retained, suggesting that specific mechanisms guide immune cell egress from tumors. Furthermore, tumor-egressing T cells were more activated and displayed enhanced effector function in comparison with their lymph node counterparts. Finally, we demonstrated that tumor-infiltrating T cells migrate to distant secondary tumors and draining lymph nodes, highlighting a mechanism whereby tumor-experienced effector T cells may mediate antitumor immunity at metastatic sites. Thus, our results provide insights into migration and function of tumor-infiltrating immune cells and the role of these cells in tumor immunity outside of primary tumor deposits.

  19. Immunosuppressive cells in tumor immune escape and metastasis.

    Liu, Yang; Cao, Xuetao


    Tumor immune escape and the initiation of metastasis are critical steps in malignant progression of tumors and have been implicated in the failure of some clinical cancer immunotherapy. Tumors develop numerous strategies to escape immune surveillance or metastasize: Tumors not only modulate the recruitment and expansion of immunosuppressive cell populations to develop the tumor microenvironment or pre-metastatic niche but also switch the phenotype and function of normal immune cells from a potentially tumor-reactive state to a tumor-promoting state. Immunosuppressive cells facilitate tumor immune escape by inhibiting antitumor immune responses and furthermore promote tumor metastasis by inducing immunosuppression, promoting tumor cell invasion and intravasation, establishing a pre-metastatic niche, facilitating epithelial-mesenchymal transition, and inducing angiogenesis at primary tumor or metastatic sites. Numerous translational studies indicate that it is possible to inhibit tumor immune escape and prevent tumor metastasis by blocking immunosuppressive cells and eliminating immunosuppressive mechanisms that are induced by either immunosuppressive cells or tumor cells. Furthermore, many clinical trials targeting immunosuppressive cells have also achieved good outcome. In this review, we focus on the underlying mechanisms of immunosuppressive cells in promoting tumor immune escape and metastasis, discuss our current understanding of the interactions between immunosuppressive cells and tumor cells in the tumor microenvironment, and suggest future research directions as well as potential clinical strategies in cancer immunotherapy.

  20. Oriented collagen fibers direct tumor cell intravasation

    Han, Weijing


    In this work, we constructed a Collagen I-Matrigel composite extracellular matrix (ECM). The composite ECM was used to determine the influence of the local collagen fiber orientation on the collective intravasation ability of tumor cells. We found that the local fiber alignment enhanced cell-ECM interactions. Specifically, metastatic MDA-MB-231 breast cancer cells followed the local fiber alignment direction during the intravasation into rigid Matrigel (∼10 mg/mL protein concentration).

  1. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors.

    Wyckoff, Jeffrey B; Wang, Yarong; Lin, Elaine Y; Li, Jiu-feng; Goswami, Sumanta; Stanley, E Richard; Segall, Jeffrey E; Pollard, Jeffrey W; Condeelis, John


    Although the presence of macrophages in tumors has been correlated with poor prognosis, until now there was no direct observation of how macrophages are involved in hematogenous metastasis. In this study, we use multiphoton microscopy to show, for the first time, that tumor cell intravasation occurs in association with perivascular macrophages in mammary tumors. Furthermore, we show that perivascular macrophages of the mammary tumor are associated with tumor cell intravasation in the absence of local angiogenesis. These results show that the interaction between macrophages and tumor cells lying in close proximity defines a microenvironment that is directly involved in the intravasation of cancer cells in mammary tumors.

  2. Management of desmoplastic small round cell tumor.

    Hayes-Jordan, Andrea; LaQuaglia, Michael P; Modak, Shakeel


    Desmoplastic small round cell tumor (DSRCT) is a soft tissue sarcoma of mesenchymal cell origin that typically presents with multiple intra-abdominal tumors and exhibits a multi-phenotypic pattern of immunohistochemical staining. The specific organ or tissue type of origin has yet to be identified. DSRCT rarely arises as a singular tumor in the abdomen; in most cases, there are dozens to hundreds of abdominal peritoneal tumors that are detected on diagnosis. One very large dominant mass is usually present in the omentum, with an additional one or two large conglomerates of tumors in the pelvis and right peritoneum, respectively. Despite an often overwhelmingly large number of abdominal tumors, symptoms of bowel obstruction are rare. Ascites may be present. In late stages, pleural effusions, pleural implants, mediastinal adenopathy, supraclavicular adenopathy, or bone metastasis may be present. With this challenging disease, multidisciplinary therapy, including aggressive surgery, is warranted. This review will address DSRCT biology and treatment options and discuss outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Establishment and Characterization of a Tumor Stem Cell-Based Glioblastoma Invasion Model

    Jensen, Stine Skov; Meyer, Morten; Petterson, Stine Asferg


    invasion and tumor stemness into account. METHODS: Glioblastoma stem cell-like containing spheroid (GSS) cultures derived from three different patients were established and characterized. The spheroids were implanted in vitro into rat brain slice cultures grown in stem cell medium and in vivo into brains......AIMS: Glioblastoma is the most frequent and malignant brain tumor. Recurrence is inevitable and most likely connected to tumor invasion and presence of therapy resistant stem-like tumor cells. The aim was therefore to establish and characterize a three-dimensional in vivo-like in vitro model taking...... of immuno-compromised mice. Invasion was followed in the slice cultures by confocal time-lapse microscopy. Using immunohistochemistry, we compared tumor cell invasion as well as expression of proliferation and stem cell markers between the models. RESULTS: We observed a pronounced invasion into brain slice...

  4. Management of nonfunctioning islet cell tumors

    Han Liang; Pu Wang; Xiao-Na Wang; Jia-Cang Wang; Xi-Shan Hao


    AIM: To more clearly define the clinical and pathological characteristics and appropriate diagnosis and treatment of nonfunctioning (NFICTs) islet cell tumors, and to review our institutional experience over the last 30 years.METHODS: The records of 43 patients confirmed to have nonfunctioning islet cell tumors of pancreas were retrospectively reviewed. Survival was estimated by the Kaplan-Meier methods and potential risk factors for survival were compared with the log-rank tests.RESULTS: The mean age was 31.63 years (range, 8 to 67 years). There were 7 men and 36 women. Twentyeight patients had a confirmed diagnosis of nonfunctioning islet cell carcinoma (NFICC) and benign islet cell tumors were found in 15 patients. The most common symptoms in patients with NFICTs were abdominal pain (55.8%),nausea and/or vomiting (32.6%), fatigue (25.6%) and abdominal mass (23.3%). Preoperative ultrasonic and computed tomography localized the tumors in all patients.Forty-three NFICTs were distributed throughout the pancreas, with 21 located to the right of the superior mesenteric vessels, 10 in the body of the pancreas, 6 in the tail of the pancreas, and multiple tumors were found in one patient. Thirty-nine of 43 patients (91%) underwent surgical resection. Surgical treatment was curative in 30patients (70%) and palliative in 9(21%). The resectability and curative resection rate in patients with NFICC of pancreas were 89% and 61%, respectively. The overall cumulative 5- and 10-year survival rates for patients with NFICC were 58.05% and 29.03%, respectively. Radical operation and diameter of cancer small than :10 cm were positive prognostic factors in females younger than 30years old. Multivariate Cox regression analysis indicated that radical operation was the only independent prognostic factor, P=0.007.CONCLUSION: Nonfunctioning islet cell tumors of pancreas are found mainly in young women. The long-term results for patients undergone surgery, especially curative resection are

  5. Neutrophil-tumor cell cannibalism in oral squamous cell carcinoma.

    Sarode, Sachin C; Sarode, Gargi S


    Cannibalism was recognized as a phenomenon seen mainly with the tumor cells ingesting other tumor cells. Recent reports have shown tumor cell engulfing other cells (xeno-cannibalism) as well, such as neutrophils, lymphocytes and erythrocytes. But no such finding has been reported in oral squamous cell carcinoma (OSCC) in the literature till date. Retrospective histopathological analysis of OSCC for identification of neutrophil-tumor cell cannibalism (NTCC) and its correlation with clinico-pathological parameters. The hematoxylin and eosin stained tissue sections of 500 OSCC cases were thoroughly screened at high power magnification (400X) for NTCC. Cases showing only frank NTCC were selected. Cases were subjected to immunohistochemical analysis using CD68 and lysozyme. Seven (1.4%) cases of OSCC which showed classical features of extreme NTCC on histopathological examination. Seventeen Cases (3.4%) showing occasional isolated NTCC were excluded. All the cases were poorly differentiated and showed cervical lymph node metastasis. Immunohistochemical analysis showed mild (+) to moderate (++) positivity in tumor cells for CD68 and lysozyme markers. NTCC in OSCC can predict the biological behavior and could serve as a useful prognostic marker in future. Tumor cell displaying macrophage phenotype and cell digestion could be mediated through lysosomal enzyme activity. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Benign and malignant mammary tumors induced by DMBA in female Wistar rats

    Dias, M.; Cabrita, S; Sousa, E.; França, B; Patrício, J; Oliveira, CF


    This study pretends to characterize 7, 12-dimetylbenz[a]anthracene-induced benign and malignant tumors. One hundred and twenty female Wistar rats were randomly allocated to two groups: Control Group and Induction Group; IG animals were given a single dose of DMBA and killed 24 weeks after. Other tumors besides breast tumors were diagnosed, mainly tumors of the salivary glands and ovarian benign epithelial tumors. Incidence of breast disorders was about 60%. Macroscopic mammary tumors varied i...

  7. The effects of topical instillation of adriamycin in bladder tumors of rats fed with FANFT.

    Pontes, J E; Izbicki, R; Silberberg, B; Baker, L; Pierce, J M


    Topical bladder instillation of adriamycin was evaluated in FANET produced rat tumors produced by diets containing (N-[4-(5-Nitro-2-Furyl)-2-Thiazolyl] Formamide). The drug was ineffective in either preventing or eradicating tumors. The failure of response in this animal model may be related to drug schedule, biological potential of this tumor, or ineffectiveness of Adriamycin in this tumor.

  8. Circulating Tumor Cells in Prostate Cancer

    Hu, Brian [Institute of Urology, University of Southern California, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA 90033 (United States); Rochefort, Holly [Department of Surgery, University of Southern California, 1520 San Pablo Street, HCT 4300, Los Angeles, CA 90033 (United States); Goldkorn, Amir, E-mail: [Department of Internal Medicine and Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Suite 3440, Los Angeles, CA 90033 (United States)


    Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management.

  9. Cyberknife radiosurgery for cranial plasma cell tumor.

    Alafaci, Cetty; Grasso, Giovanni; Conti, Alfredo; Caffo, Mariella; Salpietro, Francesco Maria; Tomasello, Francesco


    Cranial and intracranial involvement by myelomatous disease is relatively uncommon. Furthermore, systemic manifestations of multiple myeloma are present in the majority of these cases at the time of symptom onset. The authors report the case of a patient with serial appearance of multiple intracranial plasma cell tumor localizations as the first manifestations of a multiple myeloma. The patient was treated with CyberKnife radiosurgery for a lesion localized at the clivus and sella turcica with complete local control. With such a technique, based on high-dose conformality, the tumor was centered with an ablative dose of radiation and, at the same time, with a low dose spreading to the surrounding critical structures. The radiosensitivity of plasma cell tumors renders this treatment modality particularly advantageous for their localized manifestation. A technical description of this case is provided. To our knowledge, this is the first case of successful Cyberknife radiosurgery of multifocal intracranial plasmacytoma.

  10. Circulating tumor cells: utopia or reality?

    Conteduca, Vincenza; Zamarchi, Rita; Rossi, Elisabetta; Condelli, Valentina; Troiani, Laura; Aieta, Michele


    Circulating tumor cells (CTCs) could be considered a sign of tumor aggressiveness, but highly sensitive and specific methods of CTC detection are necessary owing to the rarity and heterogeneity of CTCs in peripheral blood. This review summarizes recent studies on tumor biology, with particular attention to the metastatic cascade, and the molecular characterization and clinical significance of CTCs. Recent technological approaches to enrich and detect these cells and challenges of CTCs for individualized cancer treatment are also discussed. This review also provides an insight into the positive and negative features of the future potential applications of CTC detection, which sometimes remains still a 'utopia', but its actual utility remains among the fastest growing research fields in oncology.

  11. Syndecans in tumor cell adhesion and signaling

    Rapraeger Alan C


    Full Text Available Abstract Anchorage of cells to "heparin" – binding domains that are prevalent in extracellular matrix (ECM components is thought to occur primarily through the syndecans, a four-member family of transmembrane heparan sulfate proteoglycans that communicate environmental cues from the ECM to the cytoskeleton and the signaling apparatus of the cell. Known activities of the syndecans trace to their highly conserved cytoplasmic domains and to their heparan sulfate chains, which can serve to regulate the signaling of growth factors and morphogens. However, several emerging studies point to critical roles for the syndecans' extracellular protein domains in tumor cell behavior to include cell adhesion and invasion. Although the mechanisms of these activities remain largely unknown, one possibility involves "co-receptor" interactions with integrins that may regulate integrin function and the cell adhesion-signaling phenotype. Thus, alterations in syndecan expression, leading to either overexpression or loss of expression, both of which take place in tumor cells, may have dramatic effects on tumor cell invasion.


    Gurudatta M, Deshmukh YA, Naikwadi A A


    Full Text Available Objective: To evaluate the anticancer effect of Carica papaya in DMBA induced mammary tumors in rats. Methods: Wistar rats were divided in to five groups (n=6, Group-I (Normal control administered vehicle olive oil, Group-II, Group-III ,Group-IV and V induced mammary tumors by administering single dose of DMBA (7,12 Dimethyl benz(Aanthracene orally 65 mg/kg. Group-III was administered aqueous leaf extract of Carica papaya (ALQECP in a dose of 200 mg/kg body wt for a period of 3 months, group-IV has given ALQECP 200 mg/kg body wt for a period of 21 days post 3 months of tumor induction, group-V rats were administered a small dose of Carica papaya extract intra tumor locally in the region of tumor. Results: Values of CA15-3 were increased in group-II rats (tumor control significantly, whereas in group-III (prevention group the levels of CA15-3 were found to be reduced substantially and the P value < 0.001. Similarly, CA-15-3 levels were reduced significantly in group-IV (treatment groupand P<0.005. The levels of LDH were seen to be increased in group-II, where as in group-III LDH levels were decreased and P<0.001.similarly group-IV LDH levels also reduced significantly but not to the level of group-III. Conclusion: Among the various markers for the detection of cancer antigen-15(CA15-3 and lactate dehydrogenase (LDH are important biochemical parameters that give a clear understanding of the progression and proliferation of cancer cells. In this study it was found that there is increase in the levels of markers such as CA15-3 and LDH and also the tumor volume in tumor control, these marker levels were decreased by the administration of aqueous leaf extract of Carica papaya in a dose of 200 mg/kg body wt. ALQECP not only prevented the progression of cancer growth but also has significant effect in reducing the both CA15-3 and LDH levels in treatment group.

  13. Redefining circulating tumor cells by image processing

    Ligthart, Sjoerd


    Circulating tumor cells (CTC) in the blood of patients with metastatic carcinomas are associated with poor survival and can be used to guide therapy. However, CTC are very heterogeneous in size and shape, and are present at very low frequencies. Missing or misjudging a few events may have great

  14. Multifunctional Nucleic Acids for Tumor Cell Treatment

    Pofahl, Monika; Wengel, Jesper; Mayer, Günter


    -proliferative and antimiR function in one 37-nucleotide nucleic acid molecule. It inhibits cancer cell growth and induces gene expression that is pathologically damped by an oncomir. These findings will have a strong impact on future developments regarding aptamer- and antimiR-related applications for tumor targeting...

  15. Redefining circulating tumor cells by image processing

    Ligthart, S.T.


    Circulating tumor cells (CTC) in the blood of patients with metastatic carcinomas are associated with poor survival and can be used to guide therapy. However, CTC are very heterogeneous in size and shape, and are present at very low frequencies. Missing or misjudging a few events may have great cons

  16. Redefining circulating tumor cells by image processing

    Ligthart, Sjoerd


    Circulating tumor cells (CTC) in the blood of patients with metastatic carcinomas are associated with poor survival and can be used to guide therapy. However, CTC are very heterogeneous in size and shape, and are present at very low frequencies. Missing or misjudging a few events may have great cons

  17. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

    Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E.; Geissler, Edward K.; Peter, Katrin; Siska, Peter J.; Kreutz, Marina


    Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy. PMID:28337200

  18. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment.

    Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E; Geissler, Edward K; Peter, Katrin; Siska, Peter J; Kreutz, Marina


    Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy.

  19. Granulocytic subset of myeloid derived suppressor cells in rats with mammary carcinoma

    Dolen, Y.; Gunaydin, G.; Esendagli, G.; Guc, D.


    Limited knowledge is available on myeloid derived suppressor cells (MDSCs) of rat origin. We examined the myeloid cells from peripheral blood, bone marrow and spleens of healthy and mammary tumor bearing rats employing a novel immunophenotyping strategy with CD172a, HIS48, and Rp-1 antibodies. We ad

  20. Growth hormone action in rat insulinoma cells expressing truncated growth hormone receptors

    Møldrup, Annette; Allevato, G; Dyrberg, Thomas


    Transfection of the insulin-producing rat islet tumor cell line RIN-5AH with a full length cDNA of the rat hepatic growth hormone (GH) receptor (GH-R1-638) augments the GH-responsive insulin synthesis in these cells. Using this functional system we analyzed the effect of COOH-terminal truncation...

  1. Clear-cell variant of calcifying epithelial odontogenic tumor (Pindborg tumor) in the mandible

    Ching-Yi Chen; Chung-Wei Wu; Wen-Chen Wang; Li-Min Lin; Yuk-Kwan Chen


    We present an uncommon case (female patient aged 59 years) of the clear-cell variant of calcifying epithelial odontogenic tumor (CEOT) (also known as Pindborg tumor) in the mandible. The clinical characteristics and probable origins of the clear tumor cells of previously reported cases of clear-cell variant of intraosseous CEOT are also summarized and discussed.

  2. In Vitro Efficient Expansion of Tumor Cells Deriving from Different Types of Human Tumor Samples

    Ilaria Turin


    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.

  3. Vascular Imaging of Solid Tumors in Rats with a Radioactive Arsenic-Labeled Antibody that Binds Exposed Phosphatidylserine

    Jennewein, Marc; Lewis, Matthew A.; Zhao, Dawen; Tsyganov, Edward; Slavine, Nikolai; He, Jin; Watkins, Linda; Kodibagkar, Vikram D.; O'Kelly, Sean; Kulkarni, Padmakar; Antich, Peter P.; Hermanne, Alex; Roösch, Frank; Mason, Ralph P.; Thorpe, Philip E.


    Purpose We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of vascular endothelial cells in tumors, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a chimeric monoclonal antibody that binds phosphatidylserine could be labeled with radioactive arsenic isotopes and used for molecular imaging of solid tumors in rats. Experimental Design Bavituximab was labeled with 74As (β+,T1/2 17.8 days) or 77As (β−,T1/2 1.6 days) using a novel procedure. The radionuclides of arsenic were selected because their long half-lives are consistent with the long biological half lives of antibodies in vivo and because their chemistry permits stable attachment to antibodies. The radiolabeled antibodies were tested for the ability to image subcutaneous Dunning prostate R3227-AT1 tumors in rats. Results Clear images of the tumors were obtained using planar γ-scintigraphy and positron emission tomography. Biodistribution studies confirmed the specific localization of bavituximab to the tumors. The tumor-to-liver ratio 72 h after injection was 22 for bavituximab compared with 1.5 for an isotype-matched control chimeric antibody of irrelevant specificity. Immunohistochemical studies showed that the bavituximab was labeling the tumor vascular endothelium. Conclusions These results show that radioarsenic-labeled bavituximab has potential as a new tool for imaging the vasculature of solid tumors. PMID:18316558

  4. Lung metastasis of benign giant cell tumor: a case report

    Bosi, Thiago Carneiro da Cunha; Andrade, Fernando Coelho Goulart de; Turtelli, Celso Montenegro; Ribeiro Junior, Helio Antonio [Universidade Federal do Triangulo Mineiro (UFMT), Uberaba, MG (Brazil). Dept. of Radiology and Imaging Diagnosis]. E-mail:; Fatureto, Marcelo Cunha [Universidade Federal do Triangulo Mineiro (UFMT), Uberaba, MG (Brazil). Dept. of Thoracic Surgery; Etchebehere, Renata Margarida [Universidade Federal do Triangulo Mineiro (UFMT), Uberaba, MG (Brazil). Dept. of Pathology


    Giant cell tumor is the sixth most frequent primary bone neoplasm, affecting long bone metaphysis, most frequently in young adults. On radiological images, this tumor appears as a lytic, well-defined, eccentric lesion. The authors report a case of benign giant cell tumor in a patient who presented with lung metastases five years after undergoing resection of the primary tumor. (author)

  5. The biology of circulating tumor cells.

    Pantel, K; Speicher, M R


    Metastasis is a biologically complex process consisting of numerous stochastic events which may tremendously differ across various cancer types. Circulating tumor cells (CTCs) are cells that are shed from primary tumors and metastatic deposits into the blood stream. CTCs bear a tremendous potential to improve our understanding of steps involved in the metastatic cascade, starting from intravasation of tumor cells into the circulation until the formation of clinically detectable metastasis. These efforts were propelled by novel high-resolution approaches to dissect the genomes and transcriptomes of CTCs. Furthermore, capturing of viable CTCs has paved the way for innovative culturing technologies to study fundamental characteristics of CTCs such as invasiveness, their kinetics and responses to selection barriers, such as given therapies. Hence the study of CTCs is not only instrumental as a basic research tool, but also allows the serial monitoring of tumor genotypes and may therefore provide predictive and prognostic biomarkers for clinicians. Here, we review how CTCs have contributed to significant insights into the metastatic process and how they may be utilized in clinical practice.

  6. Ambiguous effect of signals transmitted by the vagus nerve on fibrosarcoma incidence and survival of tumor-bearing rats.

    Mikova, Lucia; Horvathova, Lubica; Ondicova, Katarina; Tillinger, Andrej; Vannucci, Luca E; Bizik, Jozef; Gidron, Yori; Mravec, Boris


    While the parasympathetic nervous system appears to be involved in the regulation of tumor progression, its exact role is still unclear. Therefore, using a rat BP6-TU2 fibrosarcoma tumor model, we investigated the effect of (1) reduction of vagal activity produced by subdiaphragmatic vagotomy; and (2) enhancement of vagal activity produced by continuous delivery of electric impulses to the cervical part of the vagus nerve on tumor development and survival of tumor-bearing rats. We also evaluated the expression of cholinergic receptors within in vitro cultivated BP6-TU2 cells. Interestingly, we found that both, vagal stimulation and subdiaphragmatic vagotomy slightly reduced tumor incidence. However, survival of tumor-bearing rats was not affected by any of the experimental approaches. Additionally, we detected mRNA expression of the α1, α2, α5, α7, and α10 subunits of nicotinic receptors and the M1, M3, M4, and M5 subtypes of muscarinic receptors within in vitro cultivated BP6-TU2 cells. Our data indicate that the role of the vagus nerve in modulation of fibrosarcoma development is ambiguous and uncertain and requires further investigation.

  7. NMR exposure sensitizes tumor cells to apoptosis.

    Ghibelli, L; Cerella, C; Cordisco, S; Clavarino, G; Marazzi, S; De Nicola, M; Nuccitelli, S; D'Alessio, M; Magrini, A; Bergamaschi, A; Guerrisi, V; Porfiri, L M


    NMR technology has dramatically contributed to the revolution of image diagnostic. NMR apparatuses use combinations of microwaves over a homogeneous strong (1 Tesla) static magnetic field. We had previously shown that low intensity (0.3-66 mT) static magnetic fields deeply affect apoptosis in a Ca2+ dependent fashion (Fanelli et al., 1999 FASEBJ., 13;95-102). The rationale of the present study is to examine whether exposure to the static magnetic fields of NMR can affect apoptosis induced on reporter tumor cells of haematopoietic origin. The impressive result was the strong increase (1.8-2.5 fold) of damage-induced apoptosis by NMR. This potentiation is due to cytosolic Ca2+ overload consequent to NMR-promoted Ca2+ influx, since it is prevented by intracellular (BAPTA-AM) and extracellular (EGTA) Ca2+ chelation or by inhibition of plasma membrane L-type Ca2+ channels. Three-days follow up of treated cultures shows that NMR decrease long term cell survival, thus increasing the efficiency of cytocidal treatments. Importantly, mononuclear white blood cells are not sensitised to apoptosis by NMR, showing that NMR may increase the differential cytotoxicity of antitumor drugs on tumor vs normal cells. This strong, differential potentiating effect of NMR on tumor cell apoptosis may have important implications, being in fact a possible adjuvant for antitumor therapies.

  8. Tumor xenotransplantation in Wistar rats after treatment with cyclophosphamide and total lymphoid irradiation. [X-ray

    Hoogenhout, J. (St. Radbond Academic Hospital, Nijmegen, Netherlands); Kazem, I.; Jerusalem, C.R.; Bakkeren, J.A.J.; de Jong, J.; Kal, H.B.; van Munster, P.J.J.


    Three-month-old male Wistar rats were treated with cyclophosphamide and total lymphoid irradiation, and C22LR mouse osteosarcoma was transplanted into the rats. The effects of immunosuppression were monitored by lymphocyte counts, serum IgG determinations, phytohemagglutinin (PHA) and concanavalin A (Con A) responses, measurement of the proportion of B cells, and histopathological studies of the lymphoid organs. At eight days after treatment, the lymphocyte counts, IgG levels, and PHA and Con A values were decreased. Mitotic activity started in the depleted B and T cell areas of the peripheral lymphatic organs two weeks after treatment. There was a 94% graft take of the osteosarcoma. It was determined that the optimum time for tumor xenograft transplantation is 4 days after treatment. The duration of growth was 11 days, and this was followed by regression up to day 21.

  9. Tumor xenotransplantation in Wistar rats after treatment with cyclophosphamide and total lymphoid irradiation

    Hoogenhout, J.; Kazem, I.; Jerusalem, C.R.; Bakkeren, J.A.; de Jong, J.; Kal, H.B.; van Munster, P.J.


    Three-month-old male Wistar rats were treated with cyclophosphamide and total lymphoid irradiation, and C22LR mouse osteosarcoma was transplanted into the rats. The effects of immunosuppression were monitored by lymphocyte counts, serum IgG determinations, phytohemagglutinin (PHA) and concanavalin A (Con A) responses, measurement of the proportion of B cells, and histopathological studies of the lymphoid organs. At eight days after treatment, the lymphocyte counts, IgG levels, and PHA and Con A values were decreased. Mitotic activity started in the depleted B and T cell areas of the peripheral lymphatic organs two weeks after treatment. There was a 94% graft take of the osteosarcoma. It was determined that the optimum time for tumor xenograft transplantation is 4 days after treatment. The duration of growth was 11 days, and this was followed by regression up to day 21.

  10. Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin.

    Mamidi, Rao N V S; Proctor, Jim; De Jonghe, Sandra; Feyen, Bianca; Moesen, Esther; Vinken, Petra; Ma, Jing Ying; Bryant, Stewart; Snook, Sandra; Louden, Calvert; Lammens, Godelieve; Ways, Kirk; Kelley, Michael F; Johnson, Mark D


    Canagliflozin is an SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Studies were conducted to investigate the mechanism responsible for renal tubular tumors and pheochromocytomas observed at the high dose in a 2-year carcinogenicity study in rats. At the high dose (100mg/kg) in rats, canagliflozin caused carbohydrate malabsorption evidenced by inhibition of intestinal glucose uptake, decreased intestinal pH and increased urinary calcium excretion. In a 6-month mechanistic study utilization of a glucose-free diet prevented carbohydrate malabsorption and its sequelae, including increased calcium absorption and urinary calcium excretion, and hyperostosis. Cell proliferation in the kidney and adrenal medulla was increased in rats maintained on standard diet and administered canagliflozin (100mg/kg), and in addition an increase in the renal injury biomarker KIM-1 was observed. Increased cell proliferation is considered as a proximal event in carcinogenesis. Effects on cell proliferation, KIM-1 and calcium excretion were inhibited in rats maintained on the glucose-free diet, indicating they are secondary to carbohydrate malabsorption and are not direct effects of canagliflozin. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Effects of wall shear stress and its gradient on tumor cell adhesion in curved microvessels.

    Yan, W W; Cai, B; Liu, Y; Fu, B M


    Tumor cell adhesion to vessel walls in the microcirculation is one critical step in cancer metastasis. In this paper, the hypothesis that tumor cells prefer to adhere at the microvessels with localized shear stresses and their gradients, such as in the curved microvessels, was examined both experimentally and computationally. Our in vivo experiments were performed on the microvessels (post-capillary venules, 30-50 μm diameter) of rat mesentery. A straight or curved microvessel was cannulated and perfused with tumor cells by a glass micropipette at a velocity of ~1mm/s. At less than 10 min after perfusion, there was a significant difference in cell adhesion to the straight and curved vessel walls. In 60 min, the averaged adhesion rate in the curved vessels (n = 14) was ~1.5-fold of that in the straight vessels (n = 19). In 51 curved segments, 45% of cell adhesion was initiated at the inner side, 25% at outer side, and 30% at both sides of the curved vessels. To investigate the mechanical mechanism by which tumor cells prefer adhering at curved sites, we performed a computational study, in which the fluid dynamics was carried out by the lattice Boltzmann method , and the tumor cell dynamics was governed by the Newton's law of translation and rotation. A modified adhesive dynamics model that included the influence of wall shear stress/gradient on the association/dissociation rates of tumor cell adhesion was proposed, in which the positive wall shear stress/gradient jump would enhance tumor cell adhesion while the negative wall shear stress/gradient jump would weaken tumor cell adhesion. It was found that the wall shear stress/gradient, over a threshold, had significant contribution to tumor cell adhesion by activating or inactivating cell adhesion molecules. Our results elucidated why the tumor cell adhesion prefers to occur at the positive curvature of curved microvessels with very low Reynolds number (in the order of 10(-2)) laminar flow.

  12. Granular cell tumors of the urinary bladder

    Kayani Naila


    Full Text Available Abstract Background Granular cell tumors (GCTs are extremely rare lesions of the urinary bladder with only nine cases being reported in world literature of which one was malignant. Generally believed to be of neural origin based on histochemical, immunohistochemical, and ultrastructural studies; they mostly follow a clinically benign course but are commonly mistaken for malignant tumors since they are solid looking, ulcerated tumors with ill-defined margins. Materials and methods We herein report two cases of GCTs, one benign and one malignant, presenting with gross hematuria in a 14- and a 47-year-old female, respectively. Results Histopathology revealed characteristic GCTs with positive immunostaining for neural marker (S-100 and negative immunostaining for epithelial (cytokeratin, Cam 5.2, AE/A13, neuroendocrine (neuron specific enolase, chromogranin A, and synaptophysin and sarcoma (desmin, vimentin markers. The benign tumor was successfully managed conservatively with transurethral resection alone while for the malignant tumor, radical cystectomy, hysterectomy with bilateral salpingo-oophorectomy, anterior vaginectomy, plus lymph node dissection was done. Both cases show long-term disease free survival. Conclusion We recommend careful pathologic assessment for establishing the appropriate diagnosis and either a conservative or aggressive surgical treatment for benign or localized malignant GCT of the urinary bladder, respectively.

  13. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

    Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina


    HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

  14. Estimation of Tumor Volumes by 11C-MeAIB and 18F-FDG PET in an Orthotopic Glioblastoma Rat Model

    Halle, Bo; Thisgaard, Helge; Hvidsten, Svend


    UNLABELLED: Brain tumor volume assessment is a major challenge. Molecular imaging using PET may be a promising option because it reflects the biologically active cells. We compared the agreement between PET- and histology-derived tumor volumes in an orthotopic glioblastoma rat model with a noninf...




    In the WAG/Rij nude rat, subcutaneous (s.c.) and intracerebral (i.c.) xenografts of the human SCLC cell line GLC-28 were evaluated for their growth behavior, in vivo monoclonal antibody binding and presence of tumor infiltrating lymphocytes. For the i.c. xenografts, two models of cerebral tumor grow

  16. Does Royal jelly affect tumor cells?

    Shirzad Maryam


    Full Text Available Introduction: Royal jelly is a substance that appears to be effective on immune system and it appears to be effective on both prevention and growth of cancer cells. In this study, we aimed to carry out a research to investigate the effect of royal jelly on the growth of WEHI-164 fibrosarcoma cell in syngenic Balb/c mice. Methods: In an experimental study, 28 male Balb/c mice were designated into four equal groups. The mice were subcutaneously injected with 5x105 WEHI-164 tumor cells on the day zero in the chest area of the animal. Animals in groups 1 to 4 were orally given 100, 200, 300 mg/kg of royal jelly or vehicle, respectively. In every individual mouse, the tumour size was measured every 2 days from day 5 (days 5, 7, 9, 11, 13, 15 and 17. Data were statistically analyzed using Kruskal-Wallis and Mann Whitney-U tests. Result: Our results showed that the mean size of tumor in case group was significantly smaller than the control group in days 11, 13, 15 and 17 (P<0.05. No metastasis was seen in test and control groups. Conclusion: With emphasize on antitumor effect of royal jelly, it seems that royal jelly has important role in control and regression of fibrosarcoma cells. Since royal jelly showed a delayed effect in control of fibrosarcoma, we suggest that royal jelly be used at least 10 days before tumor inoculation.

  17. Circulating Tumor Cells Measurements in Hepatocellular Carcinoma

    Franck Chiappini


    Full Text Available Liver cancer is the fifth most common cancer in men and the seventh in women. During the past 20 years, the incidence of HCC has tripled while the 5-year survival rate has remained below 12%. The presence of circulating tumor cells (CTC reflects the aggressiveness nature of a tumor. Many attempts have been made to develop assays that reliably detect and enumerate the CTC during the development of the HCC. In this case, the challenges are (1 there are few markers specific to the HCC (tumor cells versus nontumor cells and (2 they can be used to quantify the number of CTC in the bloodstream. Another technical challenge consists of finding few CTC mixed with million leukocytes and billion erythrocytes. CTC detection and identification can be used to estimate prognosis and may serve as an early marker to assess antitumor activity of treatment. CTC can also be used to predict progression-free survival and overall survival. CTC are an interesting source of biological information in order to understand dissemination, drug resistance, and treatment-induced cell death. Our aim is to review and analyze the different new methods existing to detect, enumerate, and characterize the CTC in the peripheral circulation of patients with HCC.

  18. Terahertz spectroscopy and detection of brain tumor in rat fresh-tissue samples

    Yamaguchi, S.; Fukushi, Y.; Kubota, O.; Itsuji, T.; Yamamoto, S.; Ouchi, T.


    Terahertz (THz) spectroscopy and imaging of biomedical samples is expected to be an important application of THz analysis techniques. Identification and localization of tumor tissue, imaging of biological samples, and analysis of DNA by THz spectroscopy have been reported. THz time-domain spectroscopy (TDS) is useful for obtaining the refractive index over a broad frequency range. However, THz-TDS spectra of fresh tissue samples are sensitive to procedures such as sample preparation, and a standardized measurement protocol is required. Therefore, in this work, we establish a protocol for measurements of THz spectra of fresh tissue and demonstrate reliable detection of rat brain tumor tissue. We use a reflection THz-TDS system to measure the refractive index spectra of the samples mounted on a quartz plate. The tissue samples were measured immediately after sectioning to avoid sample denaturalization during storage. Special care was taken in THz data processing to eliminate parasitic reflections and reduce noise. The error level in our refractive index measurements was as low as 0.02 in the frequency range 0.8-1.5 THz. With increasing frequency, the refractive index in the tumor and normal regions monotonically decreased, similarly to water, and it was 0.02 higher in the tumor regions. The spectral data suggest that the tumor regions have higher water content. Hematoxylin-eosin stained images showed that increased cell density was also responsible for the observed spectral features. A set of samples from 10 rats showed consistent results. Our results suggest that reliable tumor detection in fresh tissue without pretreatment is possible with THz spectroscopy measurements. THz spectroscopy has the potential to become a real-time in vivo diagnostic method.

  19. Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy


    AD_________________ Award Number: W81XWH-14-1-0350 TITLE: Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy PRINCIPAL...30 Sep 2014 - 29 Sep 2016 4. TITLE AND SUBTILE Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy 5a. CONTRACT NUMBER... cancer . To eradicate chemoresistant tumor cells, it is important to identify the subset of tumor cells that can survive from chemotherapy and

  20. Stem Cells and the Origin and Propagation of Brain Tumors


    In recent years there has been a flood of interest in the relationship between brain tumors and stem cells. Some investigators have focused on the sensitivity of normal stem cells to transformation, others have described phenotypic or functional similarities between tumor cells and stem cells, and still others have suggested that tumors contain a subpopulation of “cancer stem cells” that is crucial for tumor maintenance or propagation. While all these concepts are interesting and provide insi...

  1. Consumption of hydrogen-rich water protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events in rats.

    Li, Fang-Yin; Zhu, Shao-Xing; Wang, Zong-Ping; Wang, Hua; Zhao, Yang; Chen, Gui-Ping


    The aim of this work was to test whether consumption with hydrogen-rich water (HW) alleviated renal injury and inhibited early tumor promotional events in Ferric nitrilotriacetate (Fe-NTA)-treated rats. Rats were injected with Fe-NTA solution (7.5mg Fe/kg body weight) intraperitoneally to induce renal injury and simultaneously treated with HW (1.3 ± 0.2mg/l). We found that consumption with HW ameliorated Fe-NTA-induced renal injuries including suppressing elevation of serum creatinine and blood urea nitrogen and inhibited early tumor promotional events including decreasing ornithine decarboxylase activity and incorporation of [3H]thymidine into renal DNA. Consumption with HW suppressed Fe-NTA-induced oxidative stress through decreasing formation of lipid peroxidation and peroxynitrite and activities of NADPH oxidase and xanthine oxidase, increasing activity of catalase, and restoring mitochondrial function in kidneys. Consumption with HW suppressed Fe-NTA-induced inflammation marked by reduced NF-κB, IL-6, and MCP-1 expression and macrophage accumulating in kidneys. In addition, consumption with HW suppressed VEGF expression, STAT3 phosphorylation and PCNA expression in kidneys of Fe-NTA-treated rats. Consumption with HW decreased the incidence of renal cell carcinoma and suppressed tumor growth in Fe-NTA-treated in rats. In conclusion, drinking with HW attenuated Fe-NTA-induced renal injury and inhibited early tumor promotional events in rats.

  2. Multicentric giant cell tumor around the knee

    Salgia Anil


    Full Text Available A case of multicentric giant cell tumor with synchronous occurrence in all three bones around the knee is reported here in view of its rarity. A 33-year-old average built male reported with complaints of severe pain, gradually increasing swelling around the right knee. A 3 x 2 cm swelling was present on the lateral aspect of the distal end of the right femur and a 3 x 3 cm swelling on the proximal part of the right tibia. Plain X-ray of right knee showed subarticular eccentrically located expansile lytic lesion in the lateral tibia condyle, lateral condyle of femur and patella. Fine needle aspiration cytology and subsequent histology ascertained the diagnosis of giant cell tumor of the bone. The patient was treated successfully with curettage, bone grafting and methyl methacrylate cementing (Sandwich technique.

  3. 异体大鼠骨肉瘤细胞RNA电转染树突状细胞瘤苗诱导的特异性抗骨肉瘤免疫学效应%Specific antitumor effects of tumor vaccine produced by autologous dendritic cells transfected of al-logeneie osteosarcoma total RNA through electroporation in rats

    于哲; 张婷; 张云飞; 马保安; 范清宇


    Objective To investigate the antitumor effects of tumor vaccine produced by autologous dendritic cells transfected of allogeneic osteosarcoma total RNA through electroporation in tumor-bearing rats model. Methods In the present study, the tumor vaccine was got by transfecting UMRI08 cells total RNA to SD rat bone marrow-derived DCs through electroporation, and was applied to in tumor-bearing rats model and the specific antitumor effects of the tumor vaccine were observed. Then CTL activity was evaluated one week after the first immunization of SD rats with electroporated DCs. Results The immunization using au-tologous DCs electrotransfected with allogeneic osteosarcoma total RNA induced UMRlO6-specific CTL re-sponses which were statistically significant. In in vivo experiments, 80% of the rats immunized with allo-geneic osteosarcoma RNA transfected to DCs were typically able to reject tumor challenge and remained tu-mor-free. Vaccinated survivors developed long immunological memory and were able to reject a subsequent rechallenge with the same tumor cells but not a syngeneic unrelated tumor line. Conclusion The present study provides valid evidence of integration of autologous rat DCs electroporated with allogeneie tumor cell derived total RNA and reveales the effective potential of activation of CTLs. The research also confirmes the therapeutic effectiveness of positive immunization through corresponding animal experiment. This technique and its products may thus represent a promising strategy for DC-based immunotherapy of patients with os-teosarcoma.%目的 本研究旨在探讨异体大鼠骨肉瘤细胞RNA电转染树突状细胞(dendritic cells,DC)瘤苗在大鼠肿瘤动物模型诱导的抗骨肉瘤免疫学效应.方法 本研究采用UMR108细胞RNA通过电穿孔的方法 转染至SD大鼠骨髓来源的DCs制备瘤苗.将该瘤苗应用于骨肉瘤荷瘤大鼠,观察其特异性抗肿瘤效应,并对瘤苗诱导的细胞毒性T淋巴细胞(cytotoxic T

  4. Salivary duct carcinoma with striking neutrophil-tumor cell cannibalism

    Payam Arya; Khalbuss, Walid E.; Monaco, Sara E.; Liron Pantanowitz


    Cannibalism of neutrophils by tumor cells has previously been reported in certain carcinomas, lymphoma and melanoma. Tumor cannibalism is believed to serve as a tumor-immune escape mechanism, associated with high-grade aggressive cancers with a significantly increased metastatic potential. This interesting phenomenon has not been previously documented in association with salivary gland tumors. We report, for the first time, striking neutrophil-tumor cell cannibalism associated with a high gra...

  5. Single-cell analyses of circulating tumor cells

    Xi-Xi Chen; Fan Bai


    Circulating tumor cells (CTCs) are a population of tumor cells mediating metastasis, which results in most of the cancer related deaths. hTe number of CTCs in the peripheral blood of patients is rare, and many platforms have been launched for detection and enrichment of CTCs. Enumeration of CTCs has already been used as a prognosis marker predicting the survival rate of cancer patients. Yet CTCs should be more potential. Studies on CTCs at single cell level may help revealing the underlying mechanism of tumorigenesis and metastasis. Though far from developed, this area of study holds much promise in providing new clinical application and deep understanding towards metastasis and cancer development.

  6. Dendritic cell-tumor cell hybrids and immunotherapy

    Cathelin, Dominique; Nicolas, Alexandra; Bouchot, André


    Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC-based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation...

  7. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses.

    Joshi, Nikhil S; Akama-Garren, Elliot H; Lu, Yisi; Lee, Da-Yae; Chang, Gregory P; Li, Amy; DuPage, Michel; Tammela, Tuomas; Kerper, Natanya R; Farago, Anna F; Robbins, Rebecca; Crowley, Denise M; Bronson, Roderick T; Jacks, Tyler


    Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients.

  8. An in vivo-like tumor stem cell-related glioblastoma in vitro model for drug discovery

    Jensen, Stine Skov; Aaberg-Jessen, Charlotte; Nørregaard, Annette

    the effects of new drugs on tumor cells including tumor stem cells. Implantation of glioblastoma cells into organotypic brain slice cultures has previously been published as a model system, but not using a stem cell favourable environment. Organotypic corticostriatal rat brain slice cultures were prepared......The discovery of tumor stem cells being highly resistant against therapy makes new demands to model systems suitable for evaluation of the effects of new drugs on tumor stem cells. The aim of the present study was therefore to develop an in vivo-like in vitro glioblastoma model for testing...... and cultured in a serum containing medium replaced after three days with a serum-free stem cell medium. Thereafter fluorescent DiI labelled glioblastoma spheroids from the cell line U87 and the tumor stem cell line SJ-1 established in our laboratory were implanted into the brain slices between cortex...

  9. The Effect of Dietary Glycine on the Hepatic Tumor Promoting Activity of Polychlorinated Biphenyls (PCBs) in Rats

    Bunaciu, Rodica Petruta; Tharappel, Job C.; Lehmler, Hans-Joachim; Korwel, Izabela; Robertson, Larry W.; Srinivasan, Cidambi; Spear, Brett T.; Glauert, Howard P.


    Polychlorinated biphenyls (PCBs) are ubiquitious lipophilic environmental pollutants. Some of the PCB congeners and mixtures of congeners have tumor promoting activity in rat liver. The mechanism of their activity is not fully understood and is likely to be multifactorial. The aim of this study was to investigate if the resident liver macrophages, Kupffer cells, are important in the promoting activity of PCBs. The hypothesis of this study was that the inhibition of Kupffer cell activity would...

  10. Pro-Tumor and Anti-Tumor Functions of IL-17 and of TH17 Cells in Tumor Microenvironment

    Gulubova M.


    Full Text Available The current review reveals the seven subclasses of CD4+ T helper cells, i.e. Th1, Th2, Th9, Th17, Th22, regulatory T cells and Tfh, the cytokines produced by them and their role in tumor microenvironment. Main attention was paid to IL-17 and Th17 cells. IL-17-producing cells were described, among which were Treg17 cells and Tc17 cells. The transcription factors, engaged in the activation of Th17 cell differentiation were reviewed. It was shown that Th17 cells might possess regulatory functions in tumor microenvironments that directs toward immunosuppression. The reciprocity between Treg and Th17 cells is realized when the production of a large amount of TGF-β in tumors causes Treg cell differentiation, and the addition of IL-6 shifts the differentiation of naïve T cells to Th17 cells. The main pro-tumor role of IL-17 is the promotion of tumor angiogenesis through stimulation of fibroblasts and endothelial cells. The antitumor functions of IL-17 are associated with enhancement of cytotoxic activity of tumor specific CTL cells and with angiogenesis that provide channels through which immune cells might invade tumor and promote antitumor immunity.

  11. Killer dendritic cells link innate and adaptive immunity against established osteosarcoma in rats.

    Chauvin, Camille; Philippeau, Jean-Marie; Hémont, Caroline; Hubert, Francois-Xavier; Wittrant, Yohann; Lamoureux, Francois; Trinité, Benjamin; Heymann, Dominique; Rédini, Françoise; Josien, Régis


    We have previously reported that a distinct subset of splenic CD4(-) rat dendritic cells (DC) induces a rapid and caspase-independent apoptosis-like cell death in a large number of tumor cells in vitro. The killing activity of these killer DC (KDC) was restricted to their immature state and was immediately followed by their engulfment of the apoptotic target cells, suggesting that these KDC could directly link innate and adaptive immunity to tumors. Here, we addressed this question using a transplantable model of rat osteosarcoma. First, we showed that rat KDC have an MHC II(+)CD103(+)CD11b(+)NKp46(-) phenotype and are therefore distinct from natural killer cells, which are MHC II(-)CD103(-)CD11b(-)NKp46(+). KDC numbers could be specifically and strongly (up to 10-fold) enhanced by Flt3L in vivo. The OSRGa cell line derived from the osteosarcoma tumor was killed and phagocytosed in vitro by both normal and Flt3L-induced splenic KDC. Such tumor antigen-loaded KDC were used to s.c. vaccinate progressive tumor-bearing rats. Vaccination with OSRGa-loaded KDC but not KDC loaded with irrelevant tumor cells (Jurkat) delayed tumor progression or even induced tumor regression. This vaccine effect was not observed in CD8 T cell-depleted animals and protective against tumor rechallenge. These results suggest that KDC possess the intrinsic capability not only to kill and then engulf tumor cells but also to efficiently cross-present tumor cell-derived antigen in vivo and subsequently induce an adaptive antitumor immune response.

  12. Photobiomodulation on tumor cells in vitro and tumor tissue in vivo

    Rong, Dong-Liang; Liu, Timon Cheng-Yi; Jin, Hua


    Background and Objective: There are many kinds of photobiomodulation (PBM) on tumor cells whereas PBM induced oncogenic transformation has not been found. These will be discussed in view of the anti-cancer efficacy of PBM. Study Design/Materials and Methods: The biological information model of PBM (BIMP) will be used to study PBM on tumor cells. Results: The PBM on tumor cells includes cell proliferation, cell cycle modulation, cell adhesion, cell differentiation and so on. The PBM on small tumor tissue in vivo may include the inhibition or promotion of tumor growth. The PBM can be designed to play an important role in anti-cancer treatments in terms of BIMP. Conclusions and discussion: PBM on tumor cells may develop into a novel anti-cancer therapeutic approach.

  13. Laparoscopic resection of a residual retroperitoneal tumor mass of nonseminomatous testicular germ cell tumors

    Ozturk, Cigdem; van Ginkel, Robert J.; Krol, Ruby M.; Gietema, Jourik A.; Hofker, Hendrik S.; Hoekstra, Harald J.

    Resection of a residual retroperitoneal tumor mass (RRRTM) is standard procedure after combination chemotherapy for metastatic nonseminomatous testicular germ cell tumors (NSTGCT). At the University Medical Center Groningen, 79 consecutive patients with disseminated NSTGCT were treated with

  14. Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells


    The biologically active lipopeptide kalkitoxin was previously isolated from the marine cyanobacterium Moorea producens (Lyngbya majuscula). Kalkitoxin exhibited N-methyl-d-aspartate (NMDA)-mediated neurotoxicity and acted as an inhibitory ligand for voltage-sensitive sodium channels in cultured rat cerebellar granule neurons. Subsequent studies revealed that kalkitoxin generated a delayed form of colon tumor cell cytotoxicity in 7-day clonogenic cell survival assays. Cell line- and exposure ...

  15. Giant cell tumor of the spine.

    Ozaki, Toshifumi; Liljenqvist, Ulf; Halm, Henry; Hillmann, Axel; Gosheger, Georg; Winkelmann, Winfried


    Six patients with giant cell tumor of the spine had surgery between 1981 and 1995. Three lesions were located in the scrum, two lesions were in the thoracic spine, and one lesion was in the lumbar spine. Preoperatively, all patients had local pain and neurologic symptoms. Two patients had cement implanted after curettage or intralesional excision of the sacral tumor; one patient had a local relapse. After the second curettage and cement implantation, the tumor was controlled. One patient with a sacral lesion had marginal excision and spondylodesis; no relapse developed. Two patients with thoracic lesions had planned marginal excision and spondylodesis; the margins finally became intralesional, but no relapse developed. One patient with a lumbar lesion had incomplete removal of the tumor and received postoperative irradiation. At the final followup (median, 69 months), five of six patients were disease-free and one patient died of disease progression. Two of the five surviving patients had pain after standing or neurologic problems. Although some contamination occurred, planning a marginal excision of the lesion seems beneficial for vertebral lesions above the sacrum. Total sacrectomy of a sacral lesion seems to be too invasive when cement implantation can control the lesion.

  16. Significance of Micrometastases: Circulating Tumor Cells and Disseminated Tumor Cells in Early Breast Cancer

    Catherine Oakman


    Full Text Available Adjuvant systemic therapy targets minimal residual disease. Our current clinical approach in the adjuvant setting is to presume, rather than confirm, the presence of minimal residual disease. Based on assessment of the primary tumor, we estimate an individual’s recurrence risk. Subsequent treatment decisions are based on characteristics of the primary tumor, with the presumption of consistent biology and treatment sensitivity between micrometastases and the primary lesion. An alternative approach is to identify micrometastatic disease. Detection of disseminated tumor cells (DTC in the bone marrow and circulating tumor cells (CTC from peripheral blood collection may offer quantification and biocharacterization of residual disease. This paper will review the prognostic and predictive potential of micrometastatic disease in early breast cancer.

  17. Induction of oxidative stress and oxidative damage in rat glial cells by acrylonitrile.

    Kamendulis, L M; Jiang, J; Xu, Y; Klaunig, J E


    Chronic treatment of rats with acrylonitrile (ACN) resulted in a dose-related increase in glial cell tumors (astrocytomas). While the exact mechanism(s) for ACN-induced carcinogenicity remains unresolved, non-genotoxic and possibly tumor promotion modes of action appear to be involved in the induction of glial tumors. Recent studies have shown that ACN induced oxidative stress selectively in rat brain in a dose-responsive manner. The present study examined the ability of ACN to induce oxidative stress in a rat glial cell line, a target tissue, and in cultured rat hepatocytes, a non-target tissue of ACN carcinogenicity. Glial cells and hepatocytes were treated for 1, 4 and 24 h with sublethal concentrations of ACN. ACN induced an increase in oxidative DNA damage, as evidenced by increased production of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in glial cells but not in rat hepatocytes. Hydroxyl radical formation following ACN treatment was also selectively increased in glial cells. Following 1 and 4 h of ACN exposure, the levels of the non-enzymatic antioxidant glutathione, as well as the activities of the enzymatic antioxidants catalase and superoxide dismutase were significantly decreased in the rat glial cells. Lipid peroxidation and the activity of glutathione peroxidase were not affected by ACN treatment in rat glial cells. No changes in any of these biomarkers of oxidative stress were observed in hepatocytes treated with ACN. These data indicate that ACN selectively induced oxidative stress in rat glial cells.

  18. Tumor growth reduction is regulated at the gene level in Walker 256 tumor-bearing rats supplemented with fish oil rich in EPA and DHA

    Borghetti, G.; Yamazaki, R.K.; Coelho, I.; Pequito, D.C.T.; Schiessel, D.L.; Kryczyk, M.; Mamus, R.; Naliwaiko, K.; Fernandes, L.C. [Departamento de Fisiologia, Setor de Ciências Biológicas, Universidade Federal do Paraná, Curitiba, PR (Brazil)


    We investigated the effect of fish oil (FO) supplementation on tumor growth, cyclooxygenase 2 (COX-2), peroxisome proliferator-activated receptor gamma (PPARγ), and RelA gene and protein expression in Walker 256 tumor-bearing rats. Male Wistar rats (70 days old) were fed with regular chow (group W) or chow supplemented with 1 g/kg body weight FO daily (group WFO) until they reached 100 days of age. Both groups were then inoculated with a suspension of Walker 256 ascitic tumor cells (3×10{sup 7} cells/mL). After 14 days the rats were killed, total RNA was isolated from the tumor tissue, and relative mRNA expression was measured using the 2{sup -ΔΔCT} method. FO significantly decreased tumor growth (W=13.18±1.58 vs WFO=5.40±0.88 g, P<0.05). FO supplementation also resulted in a significant decrease in COX-2 (W=100.1±1.62 vs WFO=59.39±5.53, P<0.001) and PPARγ (W=100.4±1.04 vs WFO=88.22±1.46, P<0.05) protein expression. Relative mRNA expression was W=1.06±0.022 vs WFO=0.31±0.04 (P<0.001) for COX-2, W=1.08±0.02 vs WFO=0.52±0.08 (P<0.001) for PPARγ, and W=1.04±0.02 vs WFO=0.82±0.04 (P<0.05) for RelA. FO reduced tumor growth by attenuating inflammatory gene expression associated with carcinogenesis.

  19. Tumor growth reduction is regulated at the gene level in Walker 256 tumor-bearing rats supplemented with fish oil rich in EPA and DHA.

    Borghetti, G; Yamazaki, R K; Coelho, I; Pequito, D C T; Schiessel, D L; Kryczyk, M; Mamus, R; Naliwaiko, K; Fernandes, L C


    We investigated the effect of fish oil (FO) supplementation on tumor growth, cyclooxygenase 2 (COX-2), peroxisome proliferator-activated receptor gamma (PPARγ), and RelA gene and protein expression in Walker 256 tumor-bearing rats. Male Wistar rats (70 days old) were fed with regular chow (group W) or chow supplemented with 1 g/kg body weight FO daily (group WFO) until they reached 100 days of age. Both groups were then inoculated with a suspension of Walker 256 ascitic tumor cells (3 × 10(7) cells/mL). After 14 days the rats were killed, total RNA was isolated from the tumor tissue, and relative mRNA expression was measured using the 2(-ΔΔCT) method. FO significantly decreased tumor growth (W=13.18 ± 1.58 vs WFO=5.40 ± 0.88 g, Psupplementation also resulted in a significant decrease in COX-2 (W=100.1 ± 1.62 vs WFO=59.39 ± 5.53, Pprotein expression. Relative mRNA expression was W=1.06 ± 0.022 vs WFO=0.31 ± 0.04 (P<0.001) for COX-2, W=1.08 ± 0.02 vs WFO=0.52 ± 0.08 (P<0.001) for PPARγ, and W=1.04 ± 0.02 vs WFO=0.82 ± 0.04 (P<0.05) for RelA. FO reduced tumor growth by attenuating inflammatory gene expression associated with carcinogenesis.

  20. Colon tumor cells grown in NASA Bioreactor


    These photos compare the results of colon carcinoma cells grown in a NASA Bioreactor flown on the STS-70 Space Shuttle in 1995 flight and ground control experiments. The cells grown in microgravity (left) have aggregated to form masses that are larger and more similar to tissue found in the body than the cells cultured on the ground (right). The principal investigator is Milburn Jessup of the University of Texas M. D. Anderson Cancer Center. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Cell constructs grown in a rotating bioreactor on Earth (left) eventually become too large to stay suspended in the nutrient media. In the microgravity of orbit, the cells stay suspended. Rotation then is needed for gentle stirring to replenish the media around the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). Credit: NASA and University of Texas M. D. Anderson Cancer Center.

  1. Oncogene amplification detected by in situ hybridization in radiation induced rat skin tumors. [C-myc:a3

    Yi Jin.


    Oncogene activation may play an important role in radiation induced carcinogenesis. C-myc oncogene amplification was detected by in situ hybridization in radiation-induced rat skin tumors, including squamous and basal cell carcinomas. In situ hybridization was performed with a biotinylated human c-myc third exon probe, visualized with an avidin-biotinylated alkaline phosphate detection system. No c-myc oncogene amplification was detected in normal rat skin at very early times after exposure to ionizing radiation, which is consistent with the view that c-myc amplification is more likely to be related to carcinogenesis than to normal cell proliferation. The incorporation of tritiated thymidine into the DNA of rat skin cells showed that the proliferation of epidermal cells reached a peak on the seventh day after exposure to ionizing radiation and then decreased. No connection between the proliferation of epidermal cell and c-myc oncogene amplification in normal or irradiated rat skin was found. The results indicated that c-myc amplification as measured by in situ hybridization was correlated with the Southern bolt results, but only some of the cancer cells were amplified. The c-myc positive cells were distributed randomly within regions of the tumor and exhibited a more uniform nuclear structure in comparison to the more vacuolated c-myc negative cells. No c-myc signal was detected in unirradiated normal skin or in irradiated skin cells near the tumors. C-myc amplification appears to be cell or cell cycle specific within radiation-induced carcinomas. 28 refs., 3 figs., 3 tabs.

  2. Photoacoustic endoscopic imaging study of melanoma tumor growth in a rat colorectum in vivo

    Li, Chiye; Yang, Joon-Mo; Chen, Ruimin; Zhang, Yu; Xia, Younan; Zhou, Qifa; Shung, K. Kirk; Wang, Lihong V.


    We performed a photoacoustic endoscopic imaging study of melanoma tumor growth in a nude rat in vivo. After inducing the tumor at the colorectal wall of the animal, we monitored the tumor development in situ by using a photoacoustic endoscopic system. This paper introduces our experimental method for tumor inoculation and presents imaging results showing the morphological changes of the blood vasculature near the tumor region according to the tumor progress. Our study could provide insights for future studies on tumor development in small animals.




    Full Text Available Granular cell tumor is a tumor derived from Schwann cells of peripheral nerves and it can occur throughout the body. About 5% of granular cell tumors occur in breast and are mostly benign in nature. We report a case of 30 year old female who presented with a swelling in right breast which on histo pathological examination revealed features consistent with granular cell tumor. This case is highlighted to reveal the importance of histopathology in differentiating granular cell tumor from carcinoma breast which is difficult based on clinical, radiological and cytological examination alone.

  4. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan


    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P tumors by a factor of two or more (2222  ±  784, 3687  ±  796 and 5658  ±  821 ng g-1) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement

  5. Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ.

    Hanibal Hani Adamo

    Full Text Available Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating changes in the tumor-bearing organ, for example growth of the vasculature, an altered extracellular matrix, and influx of inflammatory cells. To investigate this response further, we compared prostate morphology and the gene expression profile of tumor-bearing normal rat prostate tissue (termed tumor-instructed/indicating normal tissue (TINT with that of prostate tissue from controls. Dunning rat AT-1 prostate cancer cells were injected into rat prostate and tumors were established after 10 days. As controls we used intact animals, animals injected with heat-killed AT-1 cells or cell culture medium. None of the controls showed morphological TINT-changes. A rat Illumina whole-genome expression array was used to analyze gene expression in AT-1 tumors, TINT, and in medium injected prostate tissue. We identified 423 upregulated genes and 38 downregulated genes (p<0.05, ≥2-fold change in TINT relative to controls. Quantitative RT-PCR analysis verified key TINT-changes, and they were not detected in controls. Expression of some genes was changed in a manner similar to that in the tumor, whereas other changes were exclusive to TINT. Ontological analysis using GeneGo software showed that the TINT gene expression profile was coupled to processes such as inflammation, immune response, and wounding. Many of the genes whose expression is altered in TINT have well-established roles in tumor biology, and the present findings indicate that they may also function by adapting the surrounding tumor-bearing organ to the needs of the tumor. Even though a minor tumor cell contamination in TINT samples cannot be ruled out, our data suggest that there are tumor-induced changes in gene expression in the normal tumor-bearing organ which can probably not be explained by tumor cell contamination. It is important to validate these changes further, as they could

  6. Correlation of integrinα4β1 and its two ligands with mast cell recruitment in the surroundings of rat liver tumor%整合素α4β1及其配体与大鼠肝肿瘤周边肥大细胞募集的关系

    张志勇; 阮幼冰; 武忠弼


    目的:研究整合素α4β1(VLA-4)及其配体VCAM-1(vascular cell adhesion molecular-1)和FN(fibronectin)与肝肿瘤周边肥大细胞(mast cell, MC)募集的关系。方法:根据肝肿瘤周边肥大细胞数量,将18只雄性Wistar大鼠移植肝肿瘤模型进行分组,8只正常雄性Wistar大鼠作对照。用间接免疫荧光和流式细胞术检测各组大鼠腹腔肥大细胞整合素VLA-4分子的表达水平,同时用免疫组化研究肿瘤周边肝组织血管内皮细胞和肝窦内皮细胞表面VCAM-1和肿瘤周边FN的表达。结果:不同肝肿瘤大鼠肿瘤周边浸润肥大细胞数量有明显差异。各组大鼠腹腔MC表达整合素VLA-4分子均呈阳性,肿瘤周边肥大细胞浸润较多组,其整合素α4β1表达水平也较高。肿瘤周边血管内皮和窦内皮细胞表达VCAM-1阳性。肿瘤周边沉积大量呈阳性表达的FN与肥大细胞紧密相联。结论:整合素α4β1及其配体VCAM-1和FN在肝肿瘤周边肥大细胞募集中起重要作用;整合素α4β1的表达水平与肿瘤周边MC数呈平行关系。%Purpose To study the correlation of integrinα4β1 and its two ligands (vascular cell adhesion molecule-1 and fibronectin)with mast cell(MC)recruitment around the rat hepatocarcinoma. Methods Eighteen male Wistar rats with liver tumor were divided into three different groups in terms of mast cell numbers in the surroundings of liver tumor. Eight normal Wistar rats were used as control. Integrin VLA-4 expression in rat peritoneal mast cells was analyzed by indirect immunofluorescence and flow cytometry. Immunohistochemistry was also used to investigate whether endothelial cell VCAM-1 and fibronection were expressed positively. Results There were markedly different in mast cell numbers around rat liver tumor. Mast cells express high levels of integrin α4β1 on their surfaces. And the more mast cells around liver tumor, the higher levels of integrin VLA-4. We

  7. Tumor-altered dendritic cell function: implications for anti-tumor immunity

    Kristian Michael Hargadon


    Full Text Available Dendritic cells are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programming of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor

  8. Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis

    Merajver Sofia D


    Full Text Available Abstract Background The metastatic spread of solid tumors is directly or indirectly responsible for most cancer-related deaths. Tumor metastasis is very complex and this process requires a tumor cell to acquire enhanced motility, invasiveness and anoikis resistance to successfully establish a tumor at a distal site. Metastatic potential of tumor cells is directly correlated with the expression levels of several angiogenic cytokines. Copper is a mandatory cofactor for the function of many of these angiogenic mediators as well as other proteins that play an important role in tumor cell motility and invasiveness. We have previously shown that tetrathiomolybdate (TM is a potent chelator of copper and it mediates its anti-tumor effects by suppressing tumor angiogenesis. However, very little is known about the effect of TM on tumor cell function and tumor metastasis. In this study, we explored the mechanisms underlying TM-mediated inhibition of tumor metastasis. Results We used two in vivo models to examine the effects of TM on tumor metastasis. Animals treated with TM showed a significant decrease in lung metastasis in both in vivo models as compared to the control group. In addition, tumor cells from the lungs of TM treated animals developed significantly smaller colonies and these colonies had significantly fewer tumor cells. TM treatment significantly decreased tumor cell motility and invasiveness by inhibiting lysyl oxidase (LOX activity, FAK activation and MMP2 levels. Furthermore, TM treatment significantly enhanced tumor cell anoikis by activating p38 MAPK cell death pathway and by downregulating XIAP survival protein expression. Conclusions Taken together, these results suggest that TM is a potent suppressor of head and neck tumor metastasis by modulating key regulators of tumor cell motility, invasiveness and anoikis resistance.

  9. Circulating Tumor Cells, Enumeration and Beyond

    Jian-Mei Hou


    Full Text Available The detection and enumeration of circulating tumor cells (CTCs has shown significant clinical utility with respect to prognosis in breast, colorectal and prostate cancers. Emerging studies show that CTCs can provide pharmacodynamic information to aid therapy decision making. CTCs as a ‘virtual and real-time biopsy’ have clear potential to facilitate exploration of tumor biology, and in particular, the process of metastasis. The challenge of profiling CTC molecular characteristics and generating CTC signatures using current technologies is that they enrich rather than purify CTCs from whole blood; we face the problem of looking for the proverbial ‘needle in the haystack’. This review summarizes the current methods for CTC detection and enumeration, focuses on molecular characterization of CTCs, unveils some aspects of CTC heterogeneity, describes attempts to purify CTCs and scans the horizon for approaches leading to comprehensive dissection of CTC biology.

  10. [Precocious pseudopuberty secondary to granulosa cell tumor].

    Fernández, F; Jordán, J; Carmona, M; Oliver, A; Gracia, R; González, M; Peralta, A


    A case report of pseudoprecocity secondary to a unilateral ovarian tumor of granulosa cells is presented in a 13 month old female. Clinical manifestations appeared at two months of age as unilateral enlargement of the breast, development of pubic hair and vaginal discharge. Plasma estrogen levels were elevated, whereas there was no response of FSH and LH to LH-RH stimulation. The absence of a palpable abdominal mass and a normal ultrasound examination of the abdomen must be pointed out in our case. The suspected clinical and laboratory diagnosis was later confirmed by surgical abdominal examination and ovarian histopathology study. With the exception of a minimal breast enlargement which persists at two years of age, all other signs of pseudoprecocity have disappeared after the surgical removal of the neoplasm. The importance of surgical abdominal examination must be pointed out as a diagnostic method when clinical and laboratory findings suggest an ovarian tumor inspite of normal abdominal palpation, ultrasound and roentgenology.

  11. Isolation of Circulating Tumor Cells by Dielectrophoresis

    Gascoyne, Peter R. C., E-mail: [Department of Imaging Physics Research, The University of Texas M.D. Anderson Cancer Center Unit 951, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Shim, Sangjo [Department of Imaging Physics Research, The University of Texas M.D. Anderson Cancer Center Unit 951, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Department of Biomedical Engineering, The University of Texas at Austin, 1 University Station, C0800, Austin, TX 78712 (United States); Present address: Micro & Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, 208 North Wright Street, Urbana, IL 61801 (United States)


    Dielectrophoresis (DEP) is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs) from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a) the principles of DEP; (b) the biological basis for the dielectric differences between CTCs and blood cells; (c) why such differences are expected to be present for all types of tumors; and (d) instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF) is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies.

  12. Isolation of Circulating Tumor Cells by Dielectrophoresis

    Peter R. C. Gascoyne


    Full Text Available Dielectrophoresis (DEP is an electrokinetic method that allows intrinsic dielectric properties of suspended cells to be exploited for discrimination and separation. It has emerged as a promising method for isolating circulation tumor cells (CTCs from blood. DEP-isolation of CTCs is independent of cell surface markers. Furthermore, isolated CTCs are viable and can be maintained in culture, suggesting that DEP methods should be more generally applicable than antibody-based approaches. The aim of this article is to review and synthesize for both oncologists and biomedical engineers interested in CTC isolation the pertinent characteristics of DEP and CTCs. The aim is to promote an understanding of the factors involved in realizing DEP-based instruments having both sufficient discrimination and throughput to allow routine analysis of CTCs in clinical practice. The article brings together: (a the principles of DEP; (b the biological basis for the dielectric differences between CTCs and blood cells; (c why such differences are expected to be present for all types of tumors; and (d instrumentation requirements to process 10 mL blood specimens in less than 1 h to enable routine clinical analysis. The force equilibrium method of dielectrophoretic field-flow fractionation (DEP-FFF is shown to offer higher discrimination and throughput than earlier DEP trapping methods and to be applicable to clinical studies.

  13. Severe acute tumor lysis syndrome in patients with germ-cell tumors

    Guilherme Alvarenga Feres


    Full Text Available Germ-cell tumors are a high-proliferative type of cancer that may evolve to significant bulky disease. Tumor lysis syndrome is rarely reported in this setting. The reports of three patients with germ-cell tumors who developed severe acute tumor lysis syndrome following the start of their anticancer therapy are presented. All patients developed renal dysfunction and multiorgan failure. Patients with extensive germ-cell tumors should be kept on close clinical and laboratory monitoring. Physicians should be aware of this uncommon but severe complication and consider early admission to the intensive care unit for the institution of measures to prevent acute renal failure.

  14. Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells


    Award Number: W81XWH-13-1-0461 TITLE: Targeting Tumor Oct4 to Deplete Prostate Tumor - and Metastasis-Initiating Cells PRINCIPAL INVESTIGATOR: Daotai...29 2016 4. TITLE AND SUBTILE Targeting Tumor Oct4 to Deplete Prostate Tumor - and Metastasis-Initiating Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER...the c-MYC oncogene. POU5F1B is a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due

  15. Inhibitory effect of coffee on hepatoma proliferation and invasion in culture and on tumor growth, metastasis and abnormal lipoprotein profiles in hepatoma-bearing rats.

    Miura, Yutaka; Ono, Kanako; Okauchi, Rieko; Yagasaki, Kazumi


    We have already reported that instant coffee powder (ICP) and ICP-loaded rat sera could suppress proliferation and invasion of rat ascites hepatoma cell line of AH109A in vitro. In this report, we examined the mechanisms for suppression of tumor cell proliferation and invasion by ICP, and the effect of ICP on in vivo tumor growth, metastasis and abnormal lipoprotein profiles in hepatoma-bearing rats. ICP, when directly added to the culture media, induced cell cycle arrest (elongation of S phase) at a lower concentration (0.3 mg/mL) and apoptosis at a higher concentration (0.6-1.2 mg/mL). ICP and ICP-loaded rat sera showed reactive oxygen species (ROS)-scavenging property and canceled the enhancement of invasive activity of hepatoma cells induced by ROS in vitro. These results suggest that ICP suppresses the proliferation by inducing cell cycle arrest and apoptosis, and the invasion by scavenging ROS and that ICP could retain these properties after their gastrointestinal absorption. The hepatoma-bearing rats were fed with a 20% casein diet (20C) or 20C supplemented with 0.1%, ICP for 14 d. Dietary ICP significantly reduced solid tumor growth and tended to reduce hepatoma metastases to lung and lymphatic nodes, suggesting that ICP could suppress tumor cell proliferation and invasion in vivo. In addition, dietary ICP significantly increased serum high-density lipoprotein (HDL)-cholesterol and tended to reduce very low-density and low-density lipoprotein (VLDL+LDL)-cholesterol, resulting in amelioration of abnormal lipoprotein profiles occurred in hepatoma-bearing rats. In conclusion, ICP has the ability to induce cell cycle arrest and apoptosis in hepatoma cells and to suppress tumor cell invasion by reducing oxidative stresses in vitro, and it could also exhibit these effects in vivo, leading to the inhibition of tumor growth and metastases.

  16. The time-course of hindbrain neuronal activity varies according to location during either intraperitoneal or subcutaneous tumor growth in rats: single Fos and dual Fos/dopamine β-hydroxylase immunohistochemistry.

    Lackovicova, Lubica; Gaykema, Ronald P; Banovska, Lucia; Kiss, Alexander; Goehler, Lisa E; Mravec, Boris


    Neuronal activity in the nucleus of the solitary tract, ventrolateral medulla, area postrema, and parabrachial nucleus was studied in rats with intraperitoneal or subcutaneous tumors on the 7th, 14th, 21st, and 28th day after injection of fibrosarcoma tumor cells. We found that the number of Fos and dopamine β-hydroxylase immunopositive neurons differs between animals with intraperitoneal and subcutaneous tumors and also between tumor-bearing rats at different times following injection. Our data indicate that responses of the brainstem structures to peripheral tumor growth depend on the localization as well as the stage of the tumor growth.

  17. Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors


    Germ Cell Tumor; Teratoma; Choriocarcinoma; Germinoma; Mixed Germ Cell Tumor; Yolk Sac Tumor; Childhood Teratoma; Malignant Germ Cell Neoplasm; Extragonadal Seminoma; Non-seminomatous Germ Cell Tumor; Seminoma

  18. Circulating tumor cells: highlight on practical implications.

    Gazzaniga, Paola; Raimondi, Cristina; Gradilone, Angela; Naso, Giuseppe; Cortesi, Enrico; Frati, Luigi


    Circulating tumor cells (CTCs) are cells of presumed epithelial origin, whose prognostic and predictive value in metastatic cancer patients has recently been demonstrated. To date, the count of CTCs through the CellSearch® system represents a valid approach for monitoring disease status in patients with metastatic colorectal, breast, and prostate cancer; in these cancer types, a rise in the CTC count at any time during treatment predicts a poor outcome. Nevertheless, the clinical utility of monitoring CTC counts remains controversial, and what to do when CTC counts rise during therapy still remains an unanswered question. In this report, we suggest how to integrate CTC counts with their molecular characterization to better translate biologic information obtained on CTCs into daily clinical practice.

  19. 胶质瘤氩氦冻融产物负载树突状细胞对颅内胶质瘤大鼠的免疫治疗研究%Immunotherapy effect of dendritic cells pulsed by lysate of tumor cell Ar-He cryoablation on rat models of intracraniai gliomas

    苏道庆; 卢国辉; 胡丽娟; 王保安; 李明; 何骁征; 姜晓丹; 柯以铨; 张世忠


    Objective To investigate the role of C6 glioma cells mediated by rapid freezing and thawing ofAr-He cryoablation in the maturation of marrow-derived dendritic cells (BM-DCs) in Wistar rats,and the anti-tumor effect of these DCs on rat models of intracranial gliomas. Methods C6 glioma cells were routinely cultured in vitro; rapid freezing and thawing of Ar-He cryoablation was employed in C6 glioma cells of the experimental group, and C6 glioma cells of the negative control group were only performed insertion of the probe; blank control group (using rapid freezing and thawing of Ar-He cryoablation on the same amount of PBS) was also employed.Bone marrow-derived mononuclear cells (MNCs) were first prepared from tibia and femur bones of Wistar rats. These cells were cultured with such cytokines as recombinant granulocyte-macrophage colony-stimulating factor (rmGM-CSF),recombinant interleukin-4 (rmIL-4) and tumor necrosis factor-alpha (TNFα) to induce their maturation; BM-DCs were pulsed with or without tumor cell lysate obtained by rapid freezing and thawing of Ar-Hecryoablation at a ratio of (DC:tumor cells =1:3) 7 d after that.Morphological observation of BM-DCs was performed by light microscopy and the expression of DCs costimulatory molecules CD80 and CD86 were measured by flow cytometry 48 h after the addiction; the IL-12 level in the supematant of DCs was detected by ELISA. In order to determine whether or not vaccination with C6 TP DCs can induce the therapeutic potential in the established glioma-bearing models, the C6 cells cultured in vitro were stereotaxically implanted into the left caudate nucleus of Wistar rat brain; glioma-bearing rats were injected with vaccination with DCs,cells from the blank control group and negative control group on the 3rd and 10th d. Survival time was observed and determined using the method of Kaplan-Meier and Log-Rank analysis. Results DCs from rats' bone marrow cells cultured with cytokines and pulsed with tumor lysates

  20. Mixed germ cell tumors: Report of two cases

    Pradhan M Pagaro


    Full Text Available Germ cell tumors arise in the ovaries and testis and rarely in other tissues. Mixed germ cell tumors are rare. We report two cases of mixed germ cell tumors, one consisting of seminoma and immature teratoma in the testis of a 30-year-old male and second consisting of a yolk sac tumor and immature teratoma in the ovary of a 17-year-old female. Many combinations of mixed germ cell tumors have been reported but very few cases of the above-mentioned combinations have been reported in literature.

  1. Lack of major genome instability in tumors of p53 null rats.

    Roel Hermsen

    Full Text Available Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53, genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions.

  2. Lack of major genome instability in tumors of p53 null rats.

    Hermsen, Roel; Toonen, Pim; Kuijk, Ewart; Youssef, Sameh A; Kuiper, Raoul; van Heesch, Sebastiaan; de Bruin, Alain; Cuppen, Edwin; Simonis, Marieke


    Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53), genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT) activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions.

  3. Histopathology of a spontaneously developing mast cell sarcoma in a Wistar rat

    Baselmans, A.H.C.; Kuijpers, M.H.M.; Dijk, J.E. van


    A case report is given of a very rare spontaneous mast cell tumor in the eyelid of the left eye of a female Wistar rat used in a long-term oral toxicity study. Metastasis of the tumor had occurred in the mandibular lymph nodes and in the liver. Clinically, the animal showed blepharospasm,

  4. Histopathology of a spontaneously developing mast cell sarcoma in a Wistar rat

    Baselmans, A.H.C.; Kuijpers, M.H.M.; Dijk, J.E. van


    A case report is given of a very rare spontaneous mast cell tumor in the eyelid of the left eye of a female Wistar rat used in a long-term oral toxicity study. Metastasis of the tumor had occurred in the mandibular lymph nodes and in the liver. Clinically, the animal showed blepharospasm, dacryorrho

  5. Modelo de tumor de pulmão em rato com o carcinossarcoma de Walker Lung tumor model in rats with Walker’s carcinosarcoma

    Antero Gomes Neto


    Full Text Available OBJETIVO: Desenvolver um modelo de tumor pulmonar em ratos com o carcinossarcoma de Walker e verificar in vivo a presença de tumor por meio de tomografia computadorizada (TC. MÉTODOS: Ratos Wistar fêmeas (n=47 foram anestesiados com pentobarbital, intubados por traqueostomia e submetidos a toracotomia para injeção no parênquima pulmonar de células do tumor de Walker ou do veículo das mesmas. O estudo consistiu de duas etapas: na primeira desenvolveu-se a técnica de implante do tumor e estabeleceu-se o número de células necessário para um bom índice de pega tumoral. Na segunda etapa, determinou-se o volume do tumor em cm³ (Dxd²/2 através de TC e necropsia (6° dia do implante, e analizou-se a sobrevida dos animais. RESULTADOS: O índice de pega do tumor foi 93,3%, sendo 81,8% na primeira etapa e 100% na segunda. A mortalidade cirúrgica foi 17,0%. As medidas dos tumores foram semelhantes (0,099 vs. 0,111 cm³ na tomografia e na necropsia, respectivamente (r=0,993; pOBJECTIVE: To develop a lung tumor model in rats using Walker’s carcinosarcoma and to verify the presence in vivo of tumors using computerized tomography (CT. METHODS: Female Wistar rats (n=47 were anesthetized with pentobarbital, intubated through tracheostomy and submitted to thoracotomy; subsequently a 50-70 mu L volume containing Walker’s tumor cells, or the suspension of these same cells, was injected into the lung parenchyma. The study consisted of two phases: in the first a tumor implantation technique was developed and the number of cells required to attain a satisfactory tumor development rate was established. In the second phase, the tumor volume in cm³ (Dxd²/2 was determined through CT scan and necropsis, and the survival rates were analyzed. RESULTS: The overall tumor development rate was 93.3%, or rather, 81.1% in the first phase and 100% in the second. The surgical mortality rate was 17.0%. The average tumor volume was similar (0.099 vs. 0.111 cm

  6. [Circulating tumor cells and prostate cancer prognosis].

    Capoun, Otakar; Soukup, Viktor; Mikulová, Veronika; Jančíková, Markéta; Honová, Hana; Kološtová, Katarína; Zima, Tomáš; Hanuš, Tomáš


    Prostate cancer (PC) is the most common malignant disease in men. Prognosis of patients with metastatic PC is generally unfavourable; however there are significant differences in survival at this stage of the disease. The definition of prognosis is essential for the selection of therapy, respecting an individual risk. In recent years, the association between circulating tumor cells (CTC) detection and response to PC treatment has been widely investigated. Detection of CTC is based on a metastatic process theory and uses well-known tumor-specific antigens on the cell surface. Individual methods assess CTC with different sensitivity and are not yet efficient at the localised PC stage. Only the method of immunomagnetic separation and semi-automatic visualisation (CellSearchTM) has been validated and approved for the use in the PC management. Assessment of the CTC count directly correlates with the prognosis of patients with castration-resistant PC. Change in the CTC count during the therapy also considerably improves risk estimation and represents a marker of overall survival. New methods of CTC cultivation and gene profiling may contribute to individualisation of the treatment similarly to breast cancer. The authors present a review article about theory, methods of detection and clinical use of CTC in castration-resistant PC.

  7. Human primary brain tumor cell growth inhibition in serum-free medium optimized for neuron survival.

    Brewer, Gregory J; LeRoux, Peter D


    Glioblastoma is the most common primary brain tumor in adults from which about 15,000 patients die each year in the United States. Despite aggressive surgery, radiotherapy and chemotherapy, median survival remains only 1 year. Here we evaluate growth of primary human brain tumor cells in a defined nutrient culture medium (Neuregen) that was optimized for neuron regeneration. We hypothesized that Neuregen would inhibit tumor cell growth because of its ability to inhibit gliosis in rat brain. Tumor tissue was collected from 18 patients including 10 males and 8 females (mean age 60+/-12 years) who underwent craniotomy for newly diagnosed, histologically confirmed brain tumors. The tissue was shipped overnight in Hibernate transport medium. Tumor cells were isolated and plated in Neurobasal/serum or Neuregen on culture plastic. After 1 week, growth in Neuregen was significantly less in 9/10 glioblastoma multiforme cases, 5/5 meningioma cases and 3/3 cases of brain metastasis. Analysis of deficient formulations of Neuregen and formulations to which selected components were added back implicate no single active component. However, individual cases were sensitive to corticosterone, selenium, ethanolamine, fatty acids and/or antioxidants. Therefore, a defined culture medium that promotes neuron regeneration inhibits the growth of human primary glioblastoma, meningioma and metastatic tumor cells in culture. The possible in vivo efficacy of Neuregen for treatment of brain tumor resections remains to be determined.

  8. Tumor cell culture on collagen–chitosan scaffolds as three-dimensional tumor model: A suitable model for tumor studies

    Aziz Mahmoudzadeh


    Full Text Available Tumor cells naturally live in three-dimensional (3D microenvironments, while common laboratory tests and evaluations are done in two-dimensional (2D plates. This study examined the impact of cultured 4T1 cancer cells in a 3D collagen–chitosan scaffold compared with 2D plate cultures. Collagen–chitosan scaffolds were provided and passed confirmatory tests. 4T1 tumor cells were cultured on scaffolds and then tumor cells growth rate, resistance to X-ray radiation, and cyclophosphamide as a chemotherapy drug were analyzed. Furthermore, 4T1 cells were extracted from the scaffold model and were injected into the mice. Tumor growth rate, survival rate, and systemic immune responses were evaluated. Our results showed that 4T1 cells infiltrated the scaffolds pores and constructed a 3D microenvironment. Furthermore, 3D cultured tumor cells showed a slower proliferation rate, increased levels of survival to the X-ray irradiation, and enhanced resistance to chemotherapy drugs in comparison with 2D plate cultures. Transfer of extracted cells to the mice caused enhanced tumor volume and decreased life span. This study indicated that collagen–chitosan nanoscaffolds provide a suitable model of tumor that would be appropriate for tumor studies.

  9. Inositol hexaphosphate-induced enhancement of natural killer cell activity correlates with suppression of colon carcinogenesis in rats

    Zheng Zhang; Yang Song; Xiu-Li Wang


    AIM: To investigate the anti-neoplastic effect of inositol hexaphosphate (InsP6 or phytic acid) on dimethylhydrazine (DMH)-induced colon tumor in rats and its effect on blood natural killer (NK) cell activity.METHODS: Healthy Wistar rats, 4 wk old, were divided into control group (fed with common food) and TnsP6 group (fed with common food+2% sodium inositol hexaphosphate in the drinking water), 15 rats in each group. Both groups were injected with 1,2-dimethylhydrazine subcutaneously (20 mg/kg body weight) once a week for 20 wk. Rats were killed after 21 wk. The whole large intestine was isolated to determine the general condition of tumors and to test blood NK cell activity by lactate-dehydrogenaserelease assay.RESULTS: Administration of InsP6 significantly increased blood NK cell activity in DMH-induced colorectal tumor in rats. InsP6 group had a smaller tumor size on average and a smaller number of tumors than the control group. Its mortality was also higher than that in control. However, the variables of body weight and tumor incidence were not significantly different between the two groups.CONCLUSION: InsP6 can increase blood NK cell activity in DMH-induced colon tumor in rats and inhibit tumor growth and metastasis in rats.

  10. Naringin Inhibits Tumor Growth And Reduces Interleukin-6 And Tumor Necrosis Factor α Levels In Rats With Walker 256 Carcinosarcoma

    Camargo C.A.; Gomes-Marcondes M.C.C.; Wutzki N.C.; Aoyama H.


    The flavonoid naringin is a polyphenolic compound that naturally occurs in citrus. Patients with cancer generally present features of malnutrition and cachexia. Levels of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) are raised in patients with cancer. This study was designed to analyze the in vivo effect of naringin in the therapeutic treatment of rats bearing Walker 256 carcinosarcoma (W256). Rats were treated intraperitoneally with different doses o...

  11. Cancer stem cells in solid tumors: elusive or illusive?

    Lehrach Hans R


    Full Text Available Abstract During the past years in vivo transplantation experiments and in vitro colony-forming assays indicated that tumors arise only from rare cells. These cells were shown to bear self-renewal capacities and the ability to recapitulate all cell types within an individual tumor. Due to their phenotypic resemblance to normal stem cells, the term "cancer stem cells" is used. However, some pieces of the puzzle are missing: (a a stringent definition of cancer stem cells in solid tumors (b specific markers that only target cells that meet the criteria for a cancer stem cell in a certain type of tumor. These missing parts started an ongoing debate about which is the best method to identify and characterize cancer stem cells, or even if their mere existence is just an artifact caused by the experimental procedures. Recent findings query the cancer stem cell hypothesis for solid tumors itself since it was shown in xenograft transplantation experiments that under appropriate conditions tumor-initiating cells are not rare. In this review we critically discuss the challenges and prospects of the currently used major methods to identify cancer stem cells. Further on, we reflect the present discussion about the existence of cancer stem cells in solid tumors as well as the amount and characteristics of tumor-initiating cells and finally provide new perspectives like the correlation of cancer stem cells and induced pluripotent cells.

  12. Plexin D1 is ubiquitously expressed on tumor vessels and tumor cells in solid malignancies.

    Roodink, I.; Verrijp, K.; Raats, J.; Leenders, W.P.J.


    BACKGROUND: Plexin D1 is expressed on both tumor-associated endothelium and malignant cells in a number of clinical brain tumors. Recently we demonstrated that Plexin D1 expression is correlated with tumor invasion level and metastasis in a human melanoma progression series. The objective of this st

  13. Halofuginone Inhibits Angiogenesis and Growth in Implanted Metastatic Rat Brain Tumor Model-an MRI Study

    Rinat Abramovitch


    Full Text Available Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF is a potent inhibitor of collagen type α1(I. In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI, we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001. Treatment with HF significantly prolonged survival of treated animals (142%; P = .001. In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05. Additionally, HF treatment inhibited vessel maturation (P = .03. Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

  14. Establishment of a tumor sphere cell line from a metastatic brain neuroendocrine tumor.

    Iwata, Ryoichi; Maruyama, Masato; Ito, Tomoki; Nakano, Yosuke; Kanemura, Yonehiro; Koike, Taro; Oe, Souichi; Yoshimura, Kunikazu; Nonaka, Masahiro; Nomura, Shosaku; Sugimoto, Tetsuo; Yamada, Hisao; Asai, Akio


    Neuroendocrine tumors are rare, and little is known about the existence of cancer stem cells in this disease. Identification of the tumorigenic population will contribute to the development of effective therapies targeting neuroendocrine tumors. Surgically resected brain metastases from a primary neuroendocrine tumor of unknown origin were dissociated and cultured in serum-free neurosphere medium. Stem cell properties, including self-renewal, differentiation potential, and stem cell marker expression, were examined. Tumor formation was evaluated using intracranial xenograft models. The effect of temozolomide was measured in vitro by cell viability assays. We established the neuroendocrine tumor sphere cell line ANI-27S, which displayed stable exponential growth, virtually unlimited expansion in vitro, and expression of stem-cell markers such as CD133, nestin, Sox2, and aldehyde dehydrogenase. FBS-induced differentiation decreased Sox2 and nestin expression. On the basis of real-time PCR, ANI-27S cells expressed the neuroendocrine markers synaptophysin and chromogranin A. Intracranial xenotransplanted brain tumors recapitulated the original patient tumor and temozolomide exhibited cytotoxic effects on tumor sphere cells. For the first time, we demonstrated the presence of a sphere-forming, stem cell-like population in brain metastases from a primary neuroendocrine tumor. We also demonstrated the potential therapeutic effects of temozolomide for this disease.

  15. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis.

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M


    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology.

  16. A Think Tank of TINK/TANKs: Tumor-Infiltrating/Tumor-Associated Natural Killer Cells in Tumor Progression and Angiogenesis

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M.


    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This “polarization” has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as “TINKs”) and tumor-associated NK (altered peripheral NK cells, which here we call “TANKs”) are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  17. 裸大鼠人高转移肝癌皮下和原位移植模型的建立%Establishment of Subcutaneous and Orthotopic Transplant Tumor Model of Hepatocellar Carcinoma Cell Line with High Metastatic Potential in Nude Rat

    彭秀华; 沈艳; 徐春华; 周文江


    目的 探讨建立裸大鼠人高转移肝癌的皮下和原位移植模型的可行性,并观察其生物学特性.方法 体外培养人高转移肝癌株HCCLM3接种于裸大鼠皮下,建立皮下移植模型,然后用此移植瘤组织再接种于裸大鼠肝内,建立肝原位移植瘤模型.皮下移植的裸大鼠每周称重、测量瘤径,原位移植的裸大鼠每周称重,两组裸大鼠分别于移植8周后处死,通过巨检、镜检等观察移植肿瘤的生物学特性.结果 裸大鼠皮下均成瘤,未见肺转移,裸大鼠原位移植成瘤率90%,肺转移70%,腹水发生率50%,自发消退率0%.结论 裸大鼠人高转移肝癌HCCLM3移植瘤模型成功率高,原位移植有高转移,无自发消退现象,可作为研究肝癌转移和药物筛选的理想模型.%Objective To study the feasibility of the establishment of subcutaneous and orthotopic transplantation tumor model of hepatocellar carcinoma cell line with highly metastatic potential (HCCLM3) in nude rat, and its tumor biological characteristics.Methods HCCLM3 cell line was inoculated subcutaneously in nude rat to develop growing tumor.Orthotopic implant model was established by suturing histologically intact human tumor tissue on the liver of nude rat.Body weight of nude rat and diameter of tumor were measured weekly.The animals were then killed 8 weeks post transplantation, the biological characteristics of transplant tumor was observed by gross examination and microscopic examination.Results In subcutaneous transplant model, tumor formation rate was 100% and no lung metastasis.In orthotopic transplant model, tumor formation rate was 90%, metastasis rate of lung was 70%, the rate of mass ascites was 50% and the natural extinctive rate was 0%.Conclusion The orthotopic transplantation tumor model in nude rat is an ideal model for studying the metastatic mechanism and screening anti- tumor drugs for liver cancer, in view of its high successful rate and high spontaneous

  18. Lycopene in the prevention of renal cell cancer in the TSC2 mutant Eker rat model.

    Sahin, Kazim; Cross, Brian; Sahin, Nurhan; Ciccone, Karina; Suleiman, Shadeah; Osunkoya, Adeboye O; Master, Viraj; Harris, Wayne; Carthon, Bradley; Mohammad, Ramzi; Bilir, Birdal; Wertz, Karin; Moreno, Carlos S; Walker, Cheryl L; Kucuk, Omer


    Renal cell carcinoma (RCC) is the most frequent upper urinary tract cancer in humans and accounts for 80-85% of malignant renal tumors. Eker rat represents a unique animal model to study RCC since these rats develop spontaneous renal tumors and leiomyoma, which may be due to tuberous sclerosis 2 (TSC2) mutation resulting in the activation of the mammalian target of rapamycin (mTOR) pathway. This study examines the role of a lycopene-rich diet in the development of RCC in the TSC2 mutant Eker rat model. Ten-week old female Eker rats (n=90) were assigned in equal numbers to receive 0, 100 or 200mg/kg of lycopene as part of their daily diet. After 18 months the rats were sacrificed and the kidneys were removed. Immunohistochemical staining with antibodies against mTOR, phospho-S6 and EGFR were performed, as well as hematoxylin-eosin staining for histologic examination of the tumors. Tumors were counted and measured in individual kidneys. Presence of tumor decreased from 94% in control animals to 65% in the experimental group, but the difference was not statistically significant (Plycopene-treated rats (Plycopene group, tumor numbers decreased (Plycopene increased from 0 to 200. Control rats fed only basal diet had a greater length of tumors (23.98 mm) than rats fed lycopene supplement groups (12.90 mm and 11.07 mm) (Plycopene increased from 0 to 200mg/kg. All tumors showed strong staining with antibodies against mTOR, phospho-S6 and EGFR. In conclusion, dietary supplementation with lycopene attenuates the development of renal cell cancers in the predisposed TSC2 mutant Eker rat model. These results suggest that lycopene may play a role in the prevention of RCC.

  19. Circulating tumor cells in melanoma patients.

    Gary A Clawson

    Full Text Available Circulating tumor cells (CTCs are of recognized importance for diagnosis and prognosis of cancer patients. With melanoma, most studies do not show any clear relationship between CTC levels and stage of disease. Here, CTCs were enriched (∼400X from blood of melanoma patients using a simple centrifugation device (OncoQuick, and 4 melanocyte target RNAs (TYR, MLANA, MITF, and MIF were quantified using QPCR. Approximately one-third of melanoma patients had elevated MIF and MLANA transcripts (p<0.0001 and p<0.001, respectively compared with healthy controls. In contrast, healthy controls had uniformly higher levels of TYR and MITF than melanoma patients (p<0.0001. There was a marked shift of leukocytes into the CTC-enriched fractions (a 430% increase in RNA recovery, p<0.001, and no relationship between CTC levels and stage of disease was found. CTCs were captured on microfabricated filters and cultured. Captured melanoma CTCs were large cells, and consisted of 2 subpopulations, based on immunoreactivity. One subpopulation (∼50% stained for both pan-cytokeratin (KRT markers and the common leukocyte marker CD-45, whereas the second subpopulation stained for only KRT. Since similar cells are described in many cancers, we also examined blood from colorectal and pancreatic cancer patients. We observed analogous results, with most captured CTCs staining for both CD-45/KRT markers (and for the monocyte differentiation marker CD-14. Our results suggest that immature melanocyte-related cells (expressing TYR and MITF RNA may circulate in healthy controls, although they are not readily detectable without considerable enrichment. Further, as early-stage melanomas develop, immature melanocyte migration into the blood is somehow curtailed, whereas a significant proportion of patients develop elevated CTC levels (based on MIF and MLANA RNAs. The nature of the captured CTCs is consistent with literature describing leukocyte/macrophage-tumor cell fusion hybrids

  20. Tumor cell "dead or alive": caspase and survivin regulate cell death, cell cycle and cell survival.

    Suzuki, A; Shiraki, K


    Cell death and cell cycle progression are two sides of the same coin, and these two different phenomenons are regulated moderately to maintain the cellular homeostasis. Tumor is one of the disease states produced as a result of the disintegrated regulation and is characterized as cells showing an irreversible progression of cell cycle and a resistance to cell death signaling. Several investigations have been performed for the understanding of cell death or cell cycle, and cell death research has remarkably progressed in these 10 years. Caspase is a nomenclature referring to ICE/CED-3 cysteine proteinase family and plays a central role during cell death. Recently, several investigations raised some possible hypotheses that caspase is also involved in cell cycle regulation. In this issue, therefore, we review the molecular basis of cell death and cell cycle regulated by caspase in tumor, especially hepatocellular carcinoma cells.

  1. Growth delay effect of combined interstitial hyperthermia and brachytherapy in a rat solid tumor model.

    Papadopoulos, D; Kimler, B F; Estes, N C; Durham, F J


    The rat mammary AC33 solid tumor model was used to investigate the efficacy of interstitial hyperthermia and/or brachytherapy. Subcutaneous flank tumors were heated with an interstitial microwave (915 MHz) antenna to a temperature of 43 +/- 0.5 degrees C for 45 min for two treatments, three days apart, and/or implanted with Ir-192 seeds for three days (-25 Gy tumor dose). Following treatments, tumors were measured 2 to 3 times per week. Hyperthermia alone produced a modest delay in tumor volume regrowth, while brachytherapy was substantially more effective. The combination produced a improvement in tumor regrowth delay compared to brachytherapy alone.

  2. Photodynamic therapy for the treatment of induced mammary tumor in rats.

    Ferreira, Isabelle; Ferreira, Juliana; Vollet-Filho, José Dirceu; Moriyama, Lilian T; Bagnato, Vanderlei S; Salvadori, Daisy Maria Favero; Rocha, Noeme S


    The objective of this work was to evaluate photodynamic therapy (PDT) by using a hematoporphyrin derivative as a photosensitizer and light-emitting diodes (LEDs) as light source in induced mammary tumors of Sprague-Dawley (SD) rats. Twenty SD rats with mammary tumors induced by DMBA were used. Animals were divided into four groups: control (G1), PDT only (G2), surgical removal of tumor (G3), and submitted to PDT immediately after surgical removal of tumor (G4). Tumors were measured over 6 weeks. Lesions and surgical were LEDs lighted up (200 J/cm(2) dose). The light distribution in vivo study used two additional animals without mammary tumors. In the control group, the average growth of tumor diameter was approximately 0.40 cm/week. While for PDT group, a growth of less than 0.15 cm/week was observed, suggesting significant delay in tumor growth. Therefore, only partial irradiation of the tumors occurred with a reduction in development, but without elimination. Animals in G4 had no tumor recurrence during the 12 weeks, after chemical induction, when compared with G3 animals that showed 60 % recurrence rate after 12 weeks of chemical induction. PDT used in the experimental model of mammary tumor as a single therapy was effective in reducing tumor development, so the surgery associated with PDT is a safe and efficient destruction of residual tumor, preventing recurrence of the tumor.

  3. Administration of IκB-kinase inhibitor PS1145 enhances apoptosis in DMBA-induced tumor in male Wistar rats.

    Rajmani, R S; Gandham, Ravi Kumar; Gupta, Shishir Kumar; Sahoo, Aditya P; Singh, Prafull Kumar; Saxena, Shikha; Kumar, Rajiv; Chaturvedi, Uttara; Tiwari, Ashok K


    Nuclear factor kappa-B (NF-κB), a key anti-apoptotic factor, plays a critical role in tumor cell growth, metastasis, and angiogenesis. The transcriptional activity of NF-κB is normally suppressed in the cytoplasm due to its association with a natural inhibitor molecule IκB. Phosphorylation of the IκB at Ser 32 and Ser 36 by the IκB kinase complex (IKK) marks the degradation of the molecule by 26S proteasome. As NF-κB is constitutively activated in most of the tumor cells, inhibition of the activities of IKK may significantly sensitize the tumor cells to apoptosis. In the present study, we investigated the effect of IκB kinase-specific blocker PS1145 on DMBA-induced skin tumor of male Wistar rats. We examined the apoptotic effect of PS1145 on DMBA-induced tumor by various histopathological and molecular techniques. Our results demonstrate the significant expression of major pro-apoptotic genes like caspases 2, 3, 8, 9, and p53 in PS1145-treated tumor bearing group at mRNA levels as well as significant (P tumor progression, mitotic, AgNOR, and PCNA indices were significantly reduced in PS1145 treatment groups as compared to PBS control on day 28 of post-treatment. Furthermore, significant increase in TUNEL positive nuclei and observation of peculiar apoptotic nuclei in transmission electron microscopy were seen in PS1145 treatment group. We conclude that intravenous application of PS1145 promotes direct apoptosis in DMBA-induced skin tumor in male Wistar rats by blocking NF-κB and VEGF activities.

  4. Celecoxib and Ibuprofen Restore the ATP Content and the Gluconeogenesis Activity in the Liver of Walker-256 Tumor-Bearing Rats

    Camila Oliveira de Souza


    Full Text Available Background/Aims: The main purpose of this study was to investigate the effects of celecoxib and ibuprofen, both non-steroidal anti-inflammatory drugs (NSAIDs, on the decreased gluconeogenesis observed in liver of Walker-256 tumor-bearing rats. Methods: Celecoxib and ibuprofen (both at 25 mg/Kg were orally administered for 12 days, beginning on the same day when the rats were inoculated with Walker-256 tumor cells. Results: Celecoxib and ibuprofen treatment reversed the reduced production of glucose, pyruvate, lactate and urea from alanine as well as the reduced production of glucose from pyruvate and lactate in perfused liver from tumor-bearing rats. Besides, celecoxib and ibuprofen treatment restored the decreased ATP content, increased triacylglycerol levels and reduced mRNA expression of carnitine palmitoyl transferase 1 (CPT1, while ibuprofen treatment restored the reduced mRNA expression of peroxisome proliferator-activated receptor alpha (PPARα in the liver of tumor-bearing rats. Both treatments tended to decrease TNFα, IL6 and IL10 in the liver of tumor-bearing rats. Finally, the treatment with celecoxib, but not with ibuprofen, reduced the growth of Walker-256 tumor. Conclusion: Celecoxib and ibuprofen restored the decreased gluconeogenesis in the liver of Walker-256 tumor-bearing rats. These effects did not involve changes in tumor growth and probably occurred by anti-inflammatory properties of these NSAIDs, which increased expression of genes associated with fatty acid oxidation (PPARα and CPT1 and consequently the ATP production, normalizing the energy status in the liver of tumor-bearing rats.

  5. Identity and pathogenesis of stomach tumors in Sprague-Dawley rats associated with the dietary administration of butachlor.

    Hard, G C; Iatropoulos, M J; Thake, D C; Wheeler, D; Tatematsu, M; Hagiwara, A; Williams, G M; Wilson, A G


    Macroscopic stomach tumors induced in Sprague-Dawley rats during two chronic bioassays with the acetanilide herbicide butachlor at a dietary concentration of 3000 ppm, were evaluated histologically and immunohistochemically in order to determine their identity and pathogenesis. The tumors, which occurred primarily in female rats, were a heterogeneous series, including a few consisting wholly or partly of classic solid or anaplastic epithelium, but with the majority containing diffusely distributed primitive neoplastic cells. The latter had either the general appearance of undifferentiated epithelium or presented a more "mesenchyme-like" pattern where the cells were epithelioid, blastema-like, neuroendocrine-like or sarcoma-like with fascicular disposition. Gastric glandular profiles were also present, usually located near the periphery of the tumors, but in some cases extending into the diffuse tumor tissue. Most of the tumors displayed variable immunohistochemical reactivity for cytokeratin, vimentin and neuron-specific enolase but were negative for muscle-specific actin or desmin except in the stromal tracts. Detailed examination of all available gastric tissue revealed the presence of additional microscopic neoplasms and precursor hyperplastic lesions. All of these were typical gastric neuroendocrine cell lesions (gastric carcinoids) originating in the fundic mucosa but occasionally invading submucosally, and consisting of epithelial cells in organized clusters, rosettes or primitive tubules. The enterochromaffin-like (ECL) nature of these microscopic neoplasms and precursor lesions was substantiated by strong immunohistochemical reactivity for cytokeratin, neuron-specific enolase and chromogranin A, and a negative reaction for vimentin. One microscopic tumor showed a transition from differentiated neuroendocrine type in the fundic mucosa to a dispersed "mesenchyme-like" pattern in the submucosal extension. An additional finding in the butachlor-treated male and

  6. Effects of Parity and Serum Prolactin Levels on the Incidence and Regression of DMBA-Induced Tumors in OFA hr/hr Rats

    Corina V. Sasso


    Full Text Available Prolactin (PRL is a key player in the development of mammary cancer. We studied the effects of parity or hyperprolactinemia on mammary carcinogenesis in OFA hr/hr treated with 7,12-dimethylbenzanthracene. They were divided into three groups: nulliparous (Null, primiparous (PL, after pregnancy and lactation, and hyperprolactinemic rats (I, implanted in the arcuate nucleus with 17β-estradiol. The tumor incidence was similar in the three groups. However, a higher percentage of regressing tumors was evident in the PL group. Serum PRL, mammary development, and mammary β-casein content were higher in I rats compared to Null. The expression of hormone receptors was similar in the different groups. However, mammary tissue from PL rats bearing tumors had increased expression of PRL and estrogen alpha receptors compared to rats free of tumors. Our results suggest that serum PRL levels do not have relevance on the incidence of tumors, probably because the low levels of PRL in OFA rats are not further decreased by PL like in other strains. However, supraphysiological levels of PRL affect carcinogenesis. PL induces regression of the tumors due to the differentiation produced on the mammary cells. Alterations in the expression of hormonal receptors may be involved in progression and regression of tumors.

  7. Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer.

    Nurwidya, Fariz; Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal


    Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer.

  8. Delayed menopause due to granulosa cell tumor of the ovary

    Bhushan Murkey


    Full Text Available A 52-year-old patient presented with complaints of menorrhagia. Endometrial biopsy revealed simple hyperplasia of the endometrium. Total abdominal hysterectomy with bilateral oophorectomy was carried out. The ovaries looked grossly normal, but histopathology reported granulosa cell tumor of the right ovary. Granulosa cell tumors belong to the sexcord stromal category and account for approximately 2% of all ovarian tumors. We review the features and treatment of granulosa cell tumors and the importance of screening for ovarian tumors in a case of endometrial hyperplasia and delayed menopause.

  9. Tumor-Induced Myeloid-Derived Suppressor Cells.

    De Sanctis, Francesco; Bronte, Vincenzo; Ugel, Stefano


    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous, immune-suppressive leukocyte population that develops systemically and infiltrates tumors. MDSCs can restrain the immune response through different mechanisms including essential metabolite consumption, reactive oxygen and nitrogen species production, as well as display of inhibitory surface molecules that alter T-cell trafficking and viability. Moreover, MDSCs play a role in tumor progression, acting directly on tumor cells and promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. Many biological and pharmaceutical drugs affect MDSC expansion and functions in preclinical tumor models and patients, often reversing host immune dysfunctions and allowing a more effective tumor immunotherapy.

  10. Pharmacogenomics of Scopoletin in Tumor Cells

    Ean-Jeong Seo


    Full Text Available Drug resistance and the severe side effects of chemotherapy necessitate the development of novel anticancer drugs. Natural products are a valuable source for drug development. Scopoletin is a coumarin compound, which can be found in several Artemisia species and other plant genera. Microarray-based RNA expression profiling of the NCI cell line panel showed that cellular response of scopoletin did not correlate to the expression of ATP-binding cassette (ABC transporters as classical drug resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2. This was also true for the expression of the oncogene EGFR and the mutational status of the tumor suppressor gene, TP53. However, mutations in the RAS oncogenes and the slow proliferative activity in terms of cell doubling times significantly correlated with scopoletin resistance. COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression resulted in a set of 40 genes, which all harbored binding motifs in their promoter sequences for the transcription factor, NF-κB, which is known to be associated with drug resistance. RAS mutations, slow proliferative activity, and NF-κB may hamper its effectiveness. By in silico molecular docking studies, we found that scopoletin bound to NF-κB and its regulator IκB. Scopoletin activated NF-κB in a SEAP-driven NF-κB reporter cell line, indicating that NF-κB might be a resistance factor for scopoletin. In conclusion, scopoletin might serve as lead compound for drug development because of its favorable activity against tumor cells with ABC-transporter expression, although NF-κB activation may be considered as resistance factor for this compound. Further investigations are warranted to explore the full therapeutic potential of this natural product.

  11. Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats.

    Spielmann, J; Hanke, J; Knauf, D; Ben-Eliyahu, S; Jacobs, R; Stangl, G I; Bähr, I; Kielstein, H


    Obesity was identified as a major risk factor for malignant diseases, but underlying mechanisms remain unclear. Natural killer (NK) cells, a pivotal aspect of innate immunity, are capable of identifying and killing virally infected and tumor cells. Previous studies have shown altered NK cell functions in obesity, and the current study aimed to investigate the relationship between altered NK cell functions and increased cancer risk in obesity. To induce obesity male F344-rats received a high-fat diet (34% fat) or a control diet (4% fat). Thereafter, syngeneic mammary adenocarcinoma cells (MADB106) or a vehicle were intravenously (i.v.) injected. 15 min after injection, half of each group of rats were killed, lungs removed and immunohistochemically stained. Numbers of NK cells, MADB106 cells and NK cell-tumor cell interactions were quantified. Twenty-one days after tumor-cell injection the other half group of rats was killed and lung metastases were counted and relative mRNA concentrations of different NK cell receptors were determined. After short-term MADB106-challenge, DIO fed animals showed significantly decreased NK cell numbers in the blood and NK cell-tumor cell interactions in the lung as compared to their control littermates. Twenty-one days after MADB106 injection, the lungs of the DIO fed rats showed significantly more lung metastases compared to control animals, accompanied by reduced relative mRNA concentrations of the activating NK cell receptor NKG2D. We conclude that induction of obesity in F344-rats leads to reduced lung NK cell function against tumor cells and results in significantly enhanced lung metastasis as compared to lean animals. It can be hypothesized that obesity-induced altered NK cell functions play an important role in cancer growth and metastasis.

  12. Decreased expression of intercellular adhesion molecule-1 (ICAM-1) and urokinase-type plasminogen activator receptor (uPAR) is associated with tumor cell spreading in vivo.

    Donadio, Ana C; Remedi, María M; Frede, Silvia; Bonacci, Gustavo R; Chiabrando, Gustavo A; Pistoresi-Palencia, María C


    The development of an effective antitumor immune response to control tumor growth is influenced by the tumor cell itself and/or by the tumor microenvironment. Tumor invasion and tumor cell spreading require a finely tuned regulation of the formation and loosening of adhesive contacts of tumor cells with the extracellular matrix (ECM). In our laboratory, a rat tumor cell line derived from a spontaneous rat sarcoma revealed, by flow cytometry, a high frequency of intercellular adhesion molecule-1 (ICAM-1, 70.1 +/- 8.7%) and urokinase-type plaminogen activator receptor (uPAR, 51.2 +/- 5.2%) positive cells, while a weak expression of MHC class II (IA, 2.2 +/- 0.2% and IE, 17.4 +/- 3.7%) and B7 (12.1 +/- 2.2%) antigens was detected. In our tumor experimental model, after implantation of tumor cells, visible tumor masses were present at days 5-7 with a relatively fast tumor growth until day 15 (progressive phase) followed by a suppression of the tumor growth (regressive phase). Here we present data that correlates a significant decrease in the frequency of ICAM-1 and uPAR expressing tumor cells with the appearance of tumor cells in sites distant from that of the primary tumor. In addition we describe the development of a cellular immune response which controls the tumor progression and is associated with an increase in the expression of major histocompatibility complex (MHC) class II IA antigen during tumor development. The histological examination at tumor progressive and regressive time points revealed the relevant presence of polymorphonuclear neutrophils (PMNs) evidencing colliquative necrosis in tumor growth areas. Taken together, these results support the idea that the balance between adhesive interactions, proteolytic activity and tumorigenicity may lead to a tumor invasive phenotype.

  13. 17-beta-estradiol-dependent regulation of somatostatin receptor subtype expression in the 7315b prolactin secreting rat pituitary tumor in vitro and in vivo

    H.A. Visser-Wisselaar (Heleen); C.J. van Uffelen; P.M. van Koetsveld (Peter); E.G. Lichtenauer-Kaligis; A.M. Waaijers (Annet); P. Uitterlinden (Piet); D.M. Mooy; S.W.J. Lamberts (Steven); L.J. Hofland (Leo)


    textabstractIn the present study, we have investigated the role of estrogens in the regulation of somatostatin receptor subtype (sst) expression in 7315b PRL-secreting rat pituitary tumor cells in vitro and in vivo. sst were undetectable in freshly dispersed cells of the transplant

  14. Induction of mammary tumors in rat by intraperitoneal injection of NMU: histopathology and estral cycle influence.

    Rivera, E S; Andrade, N; Martin, G; Melito, G; Cricco, G; Mohamad, N; Davio, C; Caro, R; Bergoc, R M


    In order to obtain an experimental model we induced mammary tumors in female Sprague-Dawley rats. The carcinogen N-nitroso-N-methylurea (NMU) was injected intraperitoneally (i.p.) at doses of 50 mg/kg body weight when animals were 50, 80 and 110 days old. Tumor sizes were measured with a caliper and their growth parameters and histopathological properties were tested. For 100 rats, 88.4% of developed lesions were ductal carcinomas, histologically classified as 52.8% cribiform variety, 30.6% solid carcinoma. Metastases in liver, spleen and lung were present. Other primary tumors were detected with low incidence. The influence of the rat estrous cycle during the first exposure to intraperitoneal NMU injection was studied. The latency period in estrus, proestrus and diestrus was 82 +/- 15, 77 +/- 18 and 79 +/- 18 days, respectively. Tumor incidence was significantly higher in estrus (95.2%) than proestrus (71.4%) or diestrus (77.4), (P rats.

  15. Tumor infiltrating immune cells in gliomas and meningiomas.

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Miranda, David; Ruiz, Laura; Sousa, Pablo; Ciudad, Juana; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores


    Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control.

  16. Circulating tumor cells in oral squamous cell carcinoma: An insight

    B V Prakruthi


    Full Text Available Circulating tumor cells (CTCs are those cells present in the blood and have antigenic and/or genetic characteristics of a specific tumor type. CTCs can be detected in the peripheral blood of cancer patients. Various techniques are available for detection of CTCs, which provide evidence for future metastasis. CTCs may provide new insight into the biology of cancer and process of metastasis in oral squamous cell carcinoma (OSCC. The detection of CTCs may represent a new diagnostic tool for predicting the occurrence of metastatic disease in OSCC and endow with the treatment strategies to efficiently treat and prevent cancer metastasis. This review gives an insight into the significance of CTCs and different techniques for detection of CTCs.

  17. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance

    Felix Schmidt


    Full Text Available Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1 single cell isolation (e.g., by laser-capture microdissection, fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase, and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems. Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.

  18. Tumor-infiltrating B lymphocytes as an efficient source of highly specific immunoglobulins recognizing tumor cells

    Pelliccia Angela


    Full Text Available Abstract Background There is much evidence that tumor cells elicit a humoral immune response in patients. In most cases, the presence of antibodies in peripheral blood is detected only in small proportion of patients with tumors overexpressing the corresponding antigen. In the present study, we analyzed the significance of local humoral response provided by tumor-infiltrating lymphocytes in breast cancer patients. Methods The ability of a patient's immune system to produce specific antibodies inside tumor tissue, capable of recognizing tumor cells, was explored through analysis of the oligoclonality of antibodies derived from tumor-infiltrating lymphocytes and construction of a series of recombinant antibody libraries in scFv format, derived from breast tumor-infiltrating B lymphocytes. These libraries and one from peripheral blood lymphocytes of a single breast cancer patient were panned against three purified surface tumor antigens, such as CEA, MUC1 and ED-B domain, and against intact MCF7 breast carcinoma cells. Results Application of novel display vector, pKM19, allowed isolation of a large panel of breast cancer-specific antibodies against known tumor antigens, as well as against breast carcinoma cells. Reactivity of novel scFvs was confirmed by ELISA, immunohistochemistry, fluorescence staining and flow cytometry. We demonstrated that seven of ten primary breast tumor specimens, obtained using discarded surgical material, could be exploited as an appropriate source for generation of phage display libraries, giving highly specific antitumor antibodies which recognize heterologous tumor cells. Conclusion Local humoral immune response within tumor tissue in breast cancer patients frequently has an oligoclonal character. Efficient selection of specific antitumor antibodies from recombinant antibody libraries, derived from such oligoclonal tumor-infiltrated B lymphocytes, indicates the presence of natural immune response against tumor antigens

  19. Prognostic value of CD66b positive tumor-infiltrating neutrophils in testicular germ cell tumor


    Background Prognostic value of immune cells is not clear in testicular germ cell tumors (TGCTs). We aimed to investigate the prognostic value of tumor-infiltrating neutrophils in TGCTs. Methods A total of 102 patients who underwent orchiectomy for TGCT were investigated for CD66b positive tumor-infiltrating neutrophils (CD66b + TINs). Immmunostaining for CD66b was performed in 102 sections as described. Clinicopathological parameters as well as cancer specific survival and overall survival we...

  20. The metabolic advantage of tumor cells

    Schwartz Laurent


    Full Text Available Abstract 1- Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases. 2- Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas. Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases. 3- Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis. 4- The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase 5- IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability. 6- An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them...

  1. Internal radiotherapy of liver cancer with rat hepato-carcinoma-intestine-pancreas gene as a liver tumor-specific promoter

    Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J. [Hop Paul Brousse, INSERM, Hepatobiliary Ctr, U785, F-94800 Villejuif (France); Herve, J.; Cunha, A. Sa; Liu, B.; Valogne, Y.; Longuet, M.; Bregerie, O.; Guettier, C.; Samuel, D.; Brechot, C.; Faivre, J. [Univ Paris Sud, Fac Med, F-94800 Villejuif (France); Boisgard, R.; Tavitian, B. [INSERM, U803, F-91400 Orsay (France); Boisgard, R.; Tavitian, B. [CEA, Serv Hosp Frederic Joliot, Lab Imagerie Mol Expt, F-91400 Orsay (France); Roux, J.; Cales, P. [Univ Angers, UPRES EA 3859, Lab Hemodynam Interact Fibrose et Invas Tumorale H, Angers (France); Clerc, J. [Hop Cochin, AP HP, Dept Nucl Med, F-75014 Paris (France)


    The hepato-carcinoma-intestine-pancreas (HIP) gene, also called pancreatitis-associated protein-1 (PAP1) or Reg III {alpha}, is activated in most human hepatocellular carcinomas (HCCs) but not in normal liver, which suggests that HIP regulatory sequence could be used as efficient liver tumor-specific promoters to express a therapeutic polynucleotide in liver cancer. The sodium iodide sym-porter (NIS), which has recognized therapeutic and reporter gene properties, is appropriate to evaluate the transcriptional strength and specificity of the HIP promoter in HCC. For this purpose, we constructed a recombinant rat HIP-NIS adeno-viral vector (AdrHIP-NIS), and evaluated its performance as a mediator of selective radio-iodide uptake in tumor hepatocytes. Western blot, immunofluorescence, and iodide uptake assays were performed in AdrHIP-NIS-infected primary hepatocytes and transformed hepatic and non-hepatic cells. Nuclear imaging, tissue counting and immuno-histo-chemistry were performed in normal and HCC-bearing Wistar rats infected with AdrHIP-NIS intra-tumorally or via the hepatic artery. In AdrHIP-NIS-infected transformed hepatic cells, functional NIS was strongly expressed, as in cells infected with a cytomegalovirus-NIS vector. No NIS expression was found in AdrHIP-NIS-infected normal hepatocytes or transformed non-hepatic cells. In rats bearing multi-nodular HCC, AdrHIP-NIS triggered functional NIS expression that was preferential in tumor hepatocytes. Administration of 18 mCi of {sup 131}I resulted in the destruction of AdrHIP-NIS-injected nodules. This study has identified the rHIP regulatory sequence as a potent liver tumor-specific promoter for the transfer of therapeutic genes, and AdrHIP-NIS-mediated. {sup 131}I therapy as a valuable option for the treatment of multi-nodular HCC. (authors)


    G. Iravanlo Z. Nozarian


    Full Text Available Perivascular epithelioid cell tumor (PEComa is composed of HMB45+ epithelioid cells with clear to granular cytoplasm and perivascular distribution. We describe a uterine PEComa in a 33 years old woman where tumor cells were positive for HMB45 but negative for epithelial markers and negative or positive for smooth muscles markers.

  3. Experimental Study on Treatment of Glioma by Embyonic Neural Stem Cell Transplnation in Rats

    LUO Jie; ZHANG Li; TU Hanjun; HU Juntao; LI Xinjian; LI Dongsheng; LEI Ting


    The neural stem cells in Wistar rats were cultured in vitro, purified, and transplanted into C6 glioma model in order to observe their biological characters and provide a basic foundation for treatment of neurological diseases by neural stem cell transplantation. The cells at hippocampal area from gestation 15-day rats were cultured in vitro, and frozen and preserved in liquid nitrogen. C6 tu-mor-bearing models (n=25) and neural stem cells transplantation models (n=35) were established.When the tumor grew to 3 to 4 weeks,5 rats in each group were randomly selected for MRI examina-tion. At different intervals, the rats were perfused and sampled for HE staining, GFAP and BrdU im-munohistochemical staining. The results showed that after resuscitation of neural stem cells at 1-4 passages, the cell viability was 40%-63% with the difference being not significant. The cells could proliferate, passage, and most cells transplanted into glioma model survived. The mean survival time in neural stem cell transplantation group and control was 4.28 and 3.88 weeks respectively, and the average tumor size in the former was smaller than in the latter. It was concluded that embryonic neu- ral stem cells in rats could proliferate and differentiate, and after resuscitation the biological charac- teristic and viability of the cells were not influenced. Neural stem cells had inhibitory effects on the growth of glioma cells and could prolong the survival of rat model.

  4. The use of bispecific antibodies in tumor cell and tumor vasculature directed immunotherapy

    Molema, G; Kroesen, BJ; Helfrich, W; Meijer, DKF; de Leij, LFMH


    To overcome dose limiting toxicities and to increase efficacy of immunotherapy of cancer, a number of strategies are under development for selectively redirecting effector cells/molecules towards tumor cells. Many of these strategies exploit the specificity of tumor associated antigen recognition by

  5. 甲磺酸加贝酯对人胰腺癌BxPC-3细胞增殖及其裸鼠移植瘤生长的抑制作用%Inhibitory Effects of Gabexate Mesylate on the Proliferation of Human Pancreatic Cancer BxPC-3 Cells and the Growth of Transplantable Tumor in Nude Rats

    母齐鸣; 廖波


    OBJECTIVE:To study the inhibitory effects of gabexate mesylate (GM) on the proliferation of human pancreatic cancer BxPC-3 cells and the growth of transplantable tumor in nude rats.METHODS:The inhibitory rates of 0,0.01,0.1,0.25,0.5 and 1.0 mmol/L GM on the growth of BxPC-3 cells were detected by cytometry after treated for 24,48 and 72 h,respectively.Apoptosis rates of BxPC-3 cells were detected by flow cytometry after treated with 0,0.25,0.5 and 1.0 mmol/L GM for 24 h.The transplantable tumor model of nude rats was established and randomly divided into trial group (GM 5 mg/kg) and control group (0.9% sodium chloride) with 7 rats in each group.A day after inoculated with tumor tissues,both groups were given relevant medicines intraperitoneally twice a day for consecutive 14 days.The size of tumor in nude rats was determined in 2 groups each week,and anti-tumor rate was calculated after consecutive 6 weeks of measurement.RESULTS:Compared with non-administration,0.01and 0.1 mmol/L GM had no inhibitory effect on the growth of BxPC-3 cells (P>0.05) ; the inhibitory effect of 0.25,0.5 and 1.0 mmol/L GM on the growth of BxPC-3 cells were increased significantly (P<0.05),in dose-dependent and time-dependent manner.The apoptotic rates of BxPC-3 cells were 7%,15.2% and 21.4% after treated with 0.25,0.5,1.0 mmol/L GM,which were significant higher than 2% of BxPC-3 cells without treatment (P<0.05 or P<0.01).Compared with control group,there was no statistical significance in the tumor volume of rats in trial group within 2 weeks of treatment (P>0.05),but the tumor volume of rats decreased significantly since third week (P<0.05).Anti-tumor rate of GM in nude rats was 41.43%.CONCLUSIONS:GM can inhibit the growth of BxPC-3 cells and induce the apoptosis of the cells in dose-dependant and time-dependant manner.It also can inhibite the growth of trans plantable tumor in unde rats.%目的:研究甲磺酸加贝酯(GM)对人胰腺癌BxPC-3细胞增殖及其

  6. Flow cytometric DNA ploidy analysis of ovarian granulosa cell tumors

    D. Chadha; C.J. Cornelisse; A. Schabert (A.)


    textabstractAbstract The nuclear DNA content of 50 ovarian tumors initially diagnosed as granulosa cell tumors was measured by flow cytometry using paraffin-embedded archival material. The follow-up period of the patients ranged from 4 months to 19 years. Thirty-eight tumors were diploid or near-dip

  7. Tumor-derived circulating endothelial cell clusters in colorectal cancer.

    Cima, Igor


    Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease.

  8. Giant Cell Tumor of Tendon Sheath

    Jan Paul Briët


    Full Text Available Background:  Giant cell tumor of tendon sheath (GCTTS is often thought of as a volar finger mass. We hypothesized that GCTTS are equally common on the dorsal and volar aspects of the hand. In addition, we hypothesized that there are no factors associated with the location (volar versus dorsal and largest measured dimension of a GCTTS.  Methods:  A total of 126 patients with a pathological diagnosis of a GCTTS of the hand or finger were reviewed. Basic emographic and GCTTS specific information was obtained. Bivariable analyses were used to assess predicting factors for location (volar or dorsal side and largest measured diameter of a GCTTS.  Results:  Seventy-two tumors (57% were on the volar side of the hand, 47 (37% were dorsal, 6 (4.8% were both dorsal and volar, and one was midaxial (0.79%. The most common site of a GCTTS was the index finger (30%. There were no factors significantly associated with the location (volar or dorsal, n=119 of the GCTTS. There were also no factors significantly associated with a larger diameter of a GCTTS.  Conclusions:  A GCTTS was more frequently seen on the volar aspect of the hand. No significant factors associated with the location or an increased size of a GCTTS were found in this study.

  9. T cell avidity and tumor recognition: implications and therapeutic strategies

    Roszkowski Jeffrey J


    Full Text Available Abstract In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T celltumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T celltumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.

  10. Newcastle disease virus selectively kills human tumor cells.

    Reichard, K W; Lorence, R M; Cascino, C J; Peeples, M E; Walter, R J; Fernando, M B; Reyes, H M; Greager, J A


    Newcastle disease virus (NDV), strain 73-T, has previously been shown to be cytolytic to mouse tumor cells. In this study, we have evaluated the ability of NDV to replicate in and kill human tumor cells in culture and in athymic mice. Plaque assays were used to determine the cytolytic activity of NDV on six human tumor cell lines, fibrosarcoma (HT1080), osteosarcoma (KHOS), cervical carcinoma (KB8-5-11), bladder carcinoma (HCV29T), neuroblastoma (IMR32), and Wilm's tumor (G104), and on nine different normal human fibroblast lines. NDV formed plaques on all tumor cells tested as well as on chick embryo cells (CEC), the native host for NDV. Plaques did not form on any of the normal fibroblast lines. To detect NDV replication, virus yield assays were performed which measured virus particles in infected cell culture supernatants. Virus yield increased 10,000-fold within 24 hr in tumor and CEC supernatants. Titers remained near zero in normal fibroblast supernatants. In vivo tumoricidal activity was evaluated in athymic nude Balb-c mice by subcutaneous injection of 9 x 10(6) tumor cells followed by intralesional injection of either live or heat-killed NDV (1.0 x 10(6) plaque forming units [PFU]), or medium. After live NDV treatment, tumor regression occurred in 10 out of 11 mice bearing KB8-5-11 tumors, 8 out of 8 with HT-1080 tumors, and 6 out of 7 with IMR-32 tumors. After treatment with heat-killed NDV no regression occurred (P less than 0.01, Fisher's exact test). Nontumor-bearing mice injected with 1.0 x 10(8) PFU of NDV remained healthy. These results indicate that NDV efficiently and selectively replicates in and kills tumor cells, but not normal cells, and that intralesional NDV causes complete tumor regression in athymic mice with a high therapeutic index.

  11. Dendritic-tumor fusion cells in cancer immunotherapy.

    Takakura, Kazuki; Kajihara, Mikio; Ito, Zensho; Ohkusa, Toshifumi; Gong, Jianlin; Koido, Shigeo


    A promising area of clinical investigation is the use of cancer immunotherapy to treat cancer patients. Dendritic cells (DCs) operate as professional antigen-presenting cells (APCs) and play a critical role in the induction of antitumor immune responses. Thus, DC-based cancer immunotherapy represents a powerful strategy. One DC-based cancer immunotherapy strategy that has been investigated is the administration of fusion cells generated with DCs and whole tumor cells (DC-tumor fusion cells). The DC-tumor fusion cells can process a broad array of tumor-associated antigens (TAAs), including unidentified molecules, and present them through major histocompatibility complex (MHC) class I and II pathways in the context of co-stimulatory signals. Improving the therapeutic efficacy of DC-tumor fusion cell-based cancer immunotherapy requires increased immunogenicity of DCs and whole tumor cells. We discuss the potential ability of DC-tumor fusion cells to activate antigen-specific T cells and strategies to improve the immunogenicity of DC-tumor fusion cells as anticancer vaccines.

  12. Schwann cells: a new player in the tumor microenvironment.

    Bunimovich, Yuri L; Keskinov, Anton A; Shurin, Galina V; Shurin, Michael R


    Cancerous cells must cooperate with the surrounding stroma and non-malignant cells within the microenvironment to support the growth and invasion of the tumor. The nervous system is a component of every organ system of the body, and therefore, is invariably at the front line of the tumor invasion. Due to the complexity of the nervous system physiology, this review separately discusses the contributions of the central and peripheral nervous systems to the tumorigenesis and tumor progression. We further focus the discussion on the evidence that Schwann cells aid in tumor growth and invasion. Schwann cells, a largely unexplored element of the tumor microenvironment, may participate in the creation of tumor-favorable conditions through both bi-directional interaction with cancer cells and the facilitation of the immune-suppressive microenvironment through the mechanism of neural repair and immunomodulation.

  13. Characterization of the 9L gliosarcoma implanted in the Fischer rat: an orthotopic model for a grade IV brain tumor.

    Bouchet, Audrey; Bidart, Marie; Miladi, Imen; Le Clec'h, Céline; Serduc, Raphaël; Coutton, Charles; Regnard, Pierrick; Khalil, Enam; Dufort, Sandrine; Lemasson, Benjamin; Laissue, Jean; Pelletier, Laurent; Le Duc, Géraldine


    Among rodent models for brain tumors, the 9L gliosarcoma is one of the most widely used. Our 9L-European Synchrotron Radiation Facility (ESRF) model was developed from cells acquired at the Brookhaven National Laboratory (NY, USA) in 1997 and implanted in the right caudate nucleus of syngeneic Fisher rats. It has been largely used by the user community of the ESRF during the last decade, for imaging, radiotherapy, and chemotherapy, including innovative treatments based on particular irradiation techniques and/or use of new drugs. This work presents a detailed study of its characteristics, assessed by magnetic resonance imaging (MRI), histology, immunohistochemistry, and cytogenetic analysis. The data used for this work were from rats sampled in six experiments carried out over a 3-year period in our lab (total number of rats = 142). The 9L-ESRF tumors were induced by a stereotactic inoculation of 10(4) 9L cells in the right caudate nucleus of the brain. The assessment of vascular parameters was performed by MRI (blood volume fraction and vascular size index) and by immunostaining of vessels (rat endothelial cell antigen-1 and type IV collagen). Immunohistochemistry and regular histology were used to describe features such as tumor cell infiltration, necrosis area, nuclear pleomorphism, cellularity, mitotic characteristics, leukocytic infiltration, proliferation, and inflammation. Moreover, for each of the six experiments, the survival of the animals was assessed and related to the tumor growth observed by MRI or histology. Additionally, the cytogenetic status of the 9L cells used at ESRF lab was investigated by comparative genomics hybridization analysis. Finally, the response of the 9L-ESRF tumor to radiotherapy was estimated by plotting the survival curves after irradiation. The median survival time of 9L-ESRF tumor-bearing rats was highly reproducible (19-20 days). The 9L-ESRF tumors presented a quasi-exponential growth, were highly vascularized with a high

  14. Oral ingestion of Streptococcus thermophilus does not affect mucositis severity or tumor progression in the tumor-bearing rat.

    Tooley, Katie L; Howarth, Gordon S; Lymn, Kerry A; Lawrence, Andrew; Butler, Ross N


    Preventative or adjunctive agents for the amelioration of small intestinal chemotherapy-induced mucositis are not currently available for clinical use. We have previously demonstrated that oral ingestion of Streptococcus thermophilus (TH-4) partially attenuated chemotherapy-induced mucositis in the rat. Here we assess the effects of TH-4 on small intestinal damage and tumor progression in tumor-bearing rats with experimentally-induced mucositis. Female Dark Agouti tumor-bearing (mammary adenocarcinoma) rats (n = 36; 139 ± 1 g) had small intestinal damage induced via the administration of methotrexate (MTX). Rats were administered MTX; (1.5 mg/kg intramuscular) or saline at 0 and 24 h; with daily gavage administration of TH-4 (109 cfu/mL) or skim milk from -48 to +96 h post-MTX. Rats were allocated to groups (n=9): saline control, TH-4 control, MTX control or TH-4+MTX. The non-invasive ( 13) C-sucrose breath test (SBT) was conducted prior to tumor inoculation, pre-MTX (-24 h) and prior to sacrifice (96 h) to monitor gut function. At sacrifice small intestinal segments were excised and assessed for sucrase and myeloperoxidase activity as well as histological damage. Irrespective of TH-4 treatment, MTX-treated rats had a significant decrease in bodyweight, SBT levels, sucrase and myeloperoxidase activity, and histological damage score (p 0.05) but failed to alleviate mucositis indices. Although TH-4, at a dose of 109 cfu/mL, yielded neither protection nor amelioration of chemotherapy-induced mucositis, progression of mammary adenocarcinoma was unaffected.

  15. Immunohistochemical characterization of feline mast cell tumors.

    Mallett, C L; Northrup, N C; Saba, C F; Rodriguez, C O; Rassnick, K M; Gieger, T L; Childress, M O; Howerth, E W


    Expression of histamine, serotonin, and KIT was evaluated in 61 archived feline mast cell tumors (MCTs) from the skin (n = 29), spleen (n = 17), and gastrointestinal (GI) tract (n = 15) using immunohistochemistry. Twenty-eight percent of cutaneous MCTs, 18% of splenic MCTs, and 53% of GI MCTs displayed histamine immunoreactivity. Serotonin immunoreactivity was detected in 3 GI and 1 cutaneous MCT. Sixty-nine percent of cutaneous MCTs, 35% of splenic MCTs, and 33% of GI MCTs were positive for KIT. Expression of these biogenic amines and KIT was less common than expected. Results of this study suggest heterogeneity in feline MCTs based on anatomic location. Further studies are needed to explain the significance of these differences.

  16. Effects of combined selenium and vitamin E administration on DNA in Walker tumor bearing Wistar rat exposed to cytostatic acute treatment.

    Mihalache, Daria; Preoteasa, V; Barca, V


    Previous studies have showed that organic Se and Vitamin E have a significant protective effect when administered in combination with cytostatics. This paper reports the investigation on effects of mixed administration Orgasel 50 and Vitamin E in Wistar rat with experimentally induced Walker tumor under acute cytostatic treatment, with emphasis on two aspects: a) the influence of antioxidants upon liver unscheduled DNA biosynthesis under cytostatic (Lomustin) acute aggression; and b) the potential improvement of cytostatic effects by antioxidants treatment in tumor. Two lots of animals were used: lot 1 - Orgasel 50 and Vitamin E administered 7 days before the initiation of tumor induction and lot 2 - the antioxidants were concomitantly administered with tumor cell inoculation. The Walker tumor (an epithelial carcinoma) cells were subcutaneously injected (5 x 10(6) cells/0.5 ml in isotonic saline solution); the first tumor nodules appeared in 4 days; the tumor has reached the appropriate dimensions in 12 days. The unscheduled DNA biosynthesis caused by Lomustin in rat liver as well as the replicative DNA biosynthesis taking place in Walker tumor cells were assessed radioisotopically by measuring the uptake of 3H-Thymidine (200 microCi / 100 g.b.w.). Our observations regarding the role of antioxidant treatment suggest: 1) a benefic effect on DNA alkylant-induced lesions, expressed by a decrease in the level of 3H-Thymidine uptake in liver and, 2) an increase of the inhibitory activity of cytostatic on DNA replication biosynthesis in tumor cells, suggested by lower 3H-Thymidine incorporation in tumor cells. The most significant results were showed in both analyzed tissues, when the Orgasel 50 + Vitamin E administration begins at the same time with the tumor cell inoculation. These findings clearly show the organic Se salts and Vitamin E constitute a valuable adjuvant in anticancer medication, increasing the interest for the application of these antioxidants in cancer

  17. Tumor endothelial cells express high pentraxin 3 levels.

    Hida, Kyoko; Maishi, Nako; Kawamoto, Taisuke; Akiyama, Kosuke; Ohga, Noritaka; Hida, Yasuhiro; Yamada, Kenji; Hojo, Takayuki; Kikuchi, Hiroshi; Sato, Masumi; Torii, Chisaho; Shinohara, Nobuo; Shindoh, Masanobu


    It has been described that tumor progression has many similarities to inflammation and wound healing in terms of the signaling processes involved. Among biological responses, angiogenesis, which is necessary for tumor progression and metastasis, is a common hallmark; therefore, tumor blood vessels have been considered as important therapeutic targets in anticancer therapy. We focused on pentraxin 3 (PTX3), which is a marker of cancer-related inflammation, but we found no reports on its expression and function in tumor blood vessels. Here we showed that PTX3 is expressed in mouse and human tumor blood vessels based on immunohistochemical analysis. We found that PTX3 is upregulated in primary mouse and human tumor endothelial cells compared to normal endothelial cells. We also showed that PTX3 plays an important role in the proliferation of the tumor endothelial cells. These results suggest that PTX3 is an important target for antiangiogenic therapy.

  18. Soluble fibrin inhibits monocyte adherence and cytotoxicity against tumor cells: implications for cancer metastasis

    Patel Shonak


    Full Text Available Abstract Background Soluble fibrin (sFn is a marker for disseminated intravascular coagulation and may have prognostic significance, especially in metastasis. However, a role for sFn in the etiology of metastatic cancer growth has not been extensively studied. We have reported that sFn cross-linked platelet binding to tumor cells via the major platelet fibrin receptor αIIbβ3, and tumor cell CD54 (ICAM-1, which is the receptor for two of the leukocyte β2 integrins (αLβ2 and aMβ2. We hypothesized that sFn may also affect leukocyte adherence, recognition, and killing of tumor cells. Furthermore, in a rat experimental metastasis model sFn pre-treatment of tumor cells enhanced metastasis by over 60% compared to untreated cells. Other studies have shown that fibrin(ogen binds to the monocyte integrin αMβ2. This study therefore sought to investigate the effect of sFn on β2 integrin mediated monocyte adherence and killing of tumor cells. Methods The role of sFn in monocyte adherence and cytotoxicity against tumor cells was initially studied using static microplate adherence and cytotoxicity assays, and under physiologically relevant flow conditions in a microscope perfusion incubator system. Blocking studies were performed using monoclonal antibodies specific for β2 integrins and CD54, and specific peptides which inhibit sFn binding to these receptors. Results Enhancement of monocyte/tumor cell adherence was observed when only one cell type was bound to sFn, but profound inhibition was observed when sFn was bound to both monocytes and tumor cells. This effect was also reflected in the pattern of monocyte cytotoxicity. Studies using monoclonal blocking antibodies and specific blocking peptides (which did not affect normal coagulation showed that the predominant mechanism of fibrin inhibition is via its binding to αMβ2 on monocytes, and to CD54 on both leukocytes and tumor cells. Conclusion sFn inhibits monocyte adherence and cytotoxicity of

  19. Dielectrophoretic capture and genetic analysis of single neuroblastoma tumor cells

    Erica L Carpenter


    Full Text Available Our understanding of the diversity of cells that escape the primary tumor and seed micrometastases remains rudimentary, and approaches for studying circulating and disseminated tumor cells have been limited by low throughput and sensitivity, reliance on single parameter sorting, and a focus on enumeration rather than phenotypic and genetic characterization. Here we utilize a highly sensitive microfluidic and dielectrophoretic approach for the isolation and genetic analysis of individual tumor cells. We employed fluorescence labeling to isolate 208 single cells from spiking experiments conducted with 11 cell lines, including 8 neuroblastoma cell lines, and achieved a capture sensitivity of 1 tumor cell per 106 white blood cells. Sample fixation or freezing had no detectable effect on cell capture. Point mutations were accurately detected in the whole genome amplification product of captured single tumor cells but not in negative control white blood cells. We applied this approach to capture 144 single tumor cells from 10 bone marrow samples from patients suffering from neuroblastoma. In this pediatric malignancy, high-risk patients often exhibit wide-spread hematogenous metastasis, but access to primary tumor can be difficult or impossible. Here we used flow-based sorting to pre-enrich samples with tumor involvement below 0.02%. For all patients for whom a mutation in the Anaplastic Lymphoma Kinase gene had already been detected in their primary tumor, the same mutation was detected in single cells from their marrow. These findings demonstrate a novel, non-invasive, and adaptable method for the capture and genetic analysis of single tumor cells from cancer patients.

  20. Increased brain edema following 5-aminolevulinic acid mediated photodynamic in normal and tumor bearing rats

    Hirschberg, Henry; Angell-Petersen, Even; Spetalen, Signe; Mathews, Marlon; Madsen, Steen J.


    Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy, such as PDT, could be of benefit. PDT causes damage to both tumor cells as well as cerebral blood vessels leading to degradation of the blood brain barrier with subsequent increase of brain edema. The increase in brain edema following ALA-PDT was evaluated in terms of animal survival, histopatological changes in normal brain and tumor tissue and MRI scanning. The effect of steroid treatment, to reduce post-treatment PDT induced edema, was also examined. Methods:Tumors were established in the brains of inbred BD-IX and Fisher rats. At various times following tumor induction the animals were injected with ALA ip. and four hours later light treatment at escalating fluences and fluence rates were given. Nontumor bearing control animals were also exposed to ALA-PDT in a similar manner to evaluate damage to normal brain and degree of blood brain barrier (BBB) disruption. Results: Despite a very low level of PpIX production in normal brain, with a 200:1 tumor to normal tissue selectivity ratio measured at a distance of 2 mm from the tumor border, many animals succumbed shortly after treatment. A total radiant energy of 54 J to non-tumor bearing animals resulted in 50% mortality within 5 days of treatment. Treatment of tumor bearing animals with moderate fluence levels produced similar brain edema compared to higher fluence levels. ALA PDT in nontumor bearing animals produced edema that was light dose dependent. PDT appeared to open the BBB for a period of 24-48 hrs after which it was restored. The addition of post operative steroid treatment reduced the incident of post treatment morbidity and mortality. Conclusions: T2 and contrast enhanced T1 MRI scanning proved to be a highly effective and non-evasive modality in following the development of the edema reaction and the degree and time

  1. [The problems of yolk sac tumor morphogenesis in a light of the tumor stem cell theory].

    Karseladze, A I


    The analysis of possible morphogenesis of the different structures in human yolk sac tumor has been considered. The author has supposed that features of blood vessel microarchitecture formation and perpetual differentiation of tumor cells or theirs functional modification play a crucial role in the morphogenesis of YST. The immunohistochemical investigation of some stem cells markers has showed the necessity of accounting of their distribution pattern in various cellular structures for the differential diagnosis of morphogenetical steps of YST. The growth of tumor cells differentiation rate correlates with increasing of stem cells markers expression as well c-kit > OCT4 > CD30 > PLAP.

  2. Tumor-Initiating Cells and Methods of Use

    Hlatky, Lynn (Inventor)


    Provided herein are an isolated or enriched population of tumor initiating cells derived from normal cells, cells susceptible to neoplasia, or neoplastic cells. Methods of use of the cells for screening for anti-hyperproliferative agents, and use of the cells for animal models of hyperproliferative disorders including metastatic cancer, diagnostic methods, and therapeutic methods are provided.

  3. Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.

    Wang, Zhihui; Liu, Jin-Qing; Liu, Zhenzhen; Shen, Rulong; Zhang, Guoqiang; Xu, Jianping; Basu, Sujit; Feng, Youmei; Bai, Xue-Feng


    IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

  4. Targeted delivery of let-7b to reprogramme tumor-associated macrophages and tumor infiltrating dendritic cells for tumor rejection.

    Huang, Zhen; Gan, Jingjing; Long, Ziyan; Guo, Guangxing; Shi, Xiafei; Wang, Chunming; Zang, Yuhui; Ding, Zhi; Chen, Jiangning; Zhang, Junfeng; Dong, Lei


    Both tumor associated macrophages (TAMs) and tumor infiltrating dendritic cells (TIDCs) are important components in the tumor microenvironment that mediate tumor immunosuppression and promote cancer progression. Targeting these cells and altering their phenotypes may become a new strategy to recover their anti-tumor activities and thereby restore the local immune surveillance against tumor. In this study, we constructed a nucleic acid delivery system for the delivery of let-7b, a synthetic microRNA mimic. Our carrier has an affinity for the mannose receptors on TAMs/TIDCs and is responsive to the low-pH tumor microenvironment. The delivery of let-7b could reactivate TAMs/TIDCs by acting as a TLR-7 agonist and suppressing IL-10 production in vitro. In a breast cancer mouse model, let-7b delivered by this system efficiently reprogrammed the functions of TAMs/TIDCs, reversed the suppressive tumor microenvironment, and inhibited tumor growth. Taken together, this strategy, designed based upon TAMs/TIDCs-targeting delivery and the dual biological functions of let-7b (TLR-7 ligand and IL-10 inhibitor), may provide a new approach for cancer immunotherapy.

  5. Bone marrow-derived cells and tumor growth : Contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells

    Roorda, Berber D.; ter Elst, Arja; Kamps, Willem A.; de Bont, Eveline S. J. M.

    Research has provided evidence that tumor growth depends on the interaction of tumor cells with stromal cells, as already suggested in 1889 by Paget. Experimental and clinical studies have revealed that tumor stromal cells can be derived from bone marrow (BM)-derived progenitor cells, such as

  6. ALA-PDT of glioma cell micro-clusters in BD-IX rat brain

    Madsen, Steen J.; Angell-Petersen, Even; Spetalen, Signe; Carper, Stephen W.; Ziegler, Sarah A.; Hirschberg, Henry


    A significant contributory factor to the poor prognosis of patients with glioblastoma multiforme is the inability of conventional treatments to eradicate infiltrating glioma cells. A syngeneic rat brain tumor model is used to investigate the effects of aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) on small clusters of tumor cells sequestered in normal brain. The intrinsic sensitivity of rat glioma cells to PDT was investigated by exposing ALA-incubated cells to a range of radiant exposures and irradiances using 635 nm light. Biodistribution studies were undertaken on tumor-bearing animals in order to determine the tumor selectivity of the photosensitizer following systemic administration (i.p.) of ALA. Effects of ALA-PDT on normal brain and gross tumor were evaluated using histopathology. Effects of PDT on isolated glioma cells in normal brain were investigated by treating animals 48 h after tumor cell implantation: a time when the micro-clusters of cells are protected by an intact blood-brain-barrier (BBB). Rat glioma cells in monolayer are susceptible to ALA-PDT - lower irradiances are more effective than higher ones. Fluorescence microscopy of frozen tissue sections showed that photosensitizer is produced with better than 200:1 tumor-to-normal tissue selectivity following i.p. ALA administration. ALA-PDT resulted in significant damage to both gross tumor and normal brain, however, the treatment failed to prolong survival of animals with newly implanted glioma cells compared to non-treated controls if the drug was delivered either i.p. or directly into the brain. In contrast, animals inoculated with tumor cells pre-incubated in vitro with ALA showed a significant survival advantage in response to PDT.

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

    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


    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.

  8. Efficacy of Mesenchymal Stem Cells in Suppression of Hepatocarcinorigenesis in Rats: Possible Role of Wnt Signaling

    Abdel Aziz, Mohamed T


    Abstract Background The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs) in an experimental hepatocellular carcinoma (HCC) model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis. Methods Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA) and CCl 4 , rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR) in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups. Results Histopathological examination of liver tissue from animals which received DENA-CCl4 only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect. Conclusions Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell proliferation

  9. Efficacy of Mesenchymal Stem Cells in Suppression of Hepatocarcinorigenesis in Rats: Possible Role of Wnt Signaling

    Sabry Dina


    Full Text Available Abstract Background The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs in an experimental hepatocellular carcinoma (HCC model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis. Methods Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA and CCl4, rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups. Results Histopathological examination of liver tissue from animals which received DENA-CCl4 only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA, cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect. Conclusions Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell

  10. An unusual mixed germ cell tumor of the testis consisting of rhabdomyosarcoma, mature teratoma and yolk sac tumor

    Eva Lovri(c); Dubravka Bobonj Hi(z)ak; Melita Peri(c) Balja; Tanja Leni(c)ek; Bo(z)o Kru(s)lin


    @@ Dear Editor, We recently encountered a rare case of testicular mixed germ cell tumor (MGCT) in a 32-year-old man. The tumor was composed of a combination of a yolk sac tumor, teratoma and rhabdomyosarcomatous somatic type malignancy.

  11. Establishment and Characterization of a Tumor Stem Cell-Based Glioblastoma Invasion Model.

    Stine Skov Jensen

    Full Text Available Glioblastoma is the most frequent and malignant brain tumor. Recurrence is inevitable and most likely connected to tumor invasion and presence of therapy resistant stem-like tumor cells. The aim was therefore to establish and characterize a three-dimensional in vivo-like in vitro model taking invasion and tumor stemness into account.Glioblastoma stem cell-like containing spheroid (GSS cultures derived from three different patients were established and characterized. The spheroids were implanted in vitro into rat brain slice cultures grown in stem cell medium and in vivo into brains of immuno-compromised mice. Invasion was followed in the slice cultures by confocal time-lapse microscopy. Using immunohistochemistry, we compared tumor cell invasion as well as expression of proliferation and stem cell markers between the models.We observed a pronounced invasion into brain slice cultures both by confocal time-lapse microscopy and immunohistochemistry. This invasion closely resembled the invasion in vivo. The Ki-67 proliferation indexes in spheroids implanted into brain slices were lower than in free-floating spheroids. The expression of stem cell markers varied between free-floating spheroids, spheroids implanted into brain slices and tumors in vivo.The established invasion model kept in stem cell medium closely mimics tumor cell invasion into the brain in vivo preserving also to some extent the expression of stem cell markers. The model is feasible and robust and we suggest the model as an in vivo-like model with a great potential in glioma studies and drug discovery.

  12. Cell Mediated Photothermal Therapy of Brain Tumors.

    Hirschberg, Henry; Madsen, Steen J


    Gold based nanoparticles with strong near infra-red (NIR) absorption are ideally suited for photothermal therapy (PTT) of brain tumors. The goal of PTT is to induce rapid heating in tumor tissues while minimizing thermal diffusion to normal brain. PTT efficacy is sensitively dependent on both nanoparticle concentration and distribution in tumor tissues. Nanoparticle delivery via passive approaches such as the enhanced permeability and retention (EPR) effect is unlikely to achieve sufficient nanoparticle concentrations throughout tumor volumes required for effective PTT. A simple approach for improving tumor biodsitribution of nanoparticles is the use of cellular delivery vehicles. Specifically, this review focuses on the use of monocytes/macrophages (Mo/Ma) as gold nanoparticle delivery vectors for PTT of brain tumors. Although the efficacy of this delivery approach has been demonstrated in both in vitro and animal PTT studies, its clinical potential for the treatment of brain tumors remains uncertain.

  13. Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors

    Xiaonan Zhang


    Full Text Available The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an “Achilles heel” for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.

  14. Multiple skin tumors of indeterminate cells in an adult.

    Kolde, G; Bröcker, E B


    An adult patient with multiple unusual histiocytic tumors of the skin is described. As shown by immunohistologic study, electron microscopy, and immunoelectron microscopy, the tumors represent circumscribed proliferations of the Langerhans cell-related indeterminate dendritic cells of the skin. This distinct cutaneous histiocytosis may represent a paraneoplastic syndrome.

  15. [Clinical diagnosis and treatment of extragonadal germ cell tumors].

    Kakimoto, Kenichi


    Extragonadal germ cell tumors (EGGCT) are very rare and account for only 2% to 5% of all malignant germ cell neoplasms. Although multimodality treatment, including cisplatin-based chemotherapy and postchemotherapy surgery, has improved the prognosis of patients with EGGCT, few findings are available for these tumors. This article presents the clinical outcome and management of EGGCT patients.

  16. "Flagellated" cancer cells propel anti-tumor immunity.

    Garaude, Johan; Blander, J Magarian


    The use of innate immune receptor agonists in cancer therapies has suffered from many drawbacks. Our recent observations suggest that some of these hurdles can be overcome by introducing flagellin into tumor cells to promote tumor antigen presentation by dendritic cells (DCs) and simultaneously trigger two types of pattern recognition receptors (PRRs).

  17. Large mid-esophageal granular cell tumor: benign versus malignant

    Prarthana Roselil Christopher


    Full Text Available Granular cell tumors are rare soft tissue neoplasms, among which only 2% are malignant, arising from nervous tissue. Here we present a case of a large esophageal granular cell tumor with benign histopathological features which metastasized to the liver, but showing on positron emission tomography-computerized tomography standardized uptake value suggestive of a benign lesion.

  18. Cancer stem cells: a new approach to tumor development

    Natália Cristina Ciufa Kobayashi


    Full Text Available Many theories have been proposed to explain the origins of cancer. Currently, evidences show that not every tumor cell is capable of initiating a tumor. Only a small part of the cancer cells, called cancer stem cells (CSCs, can generate a tumor identical to the original one, when removed from human tumors and transplanted into immunosuppressed mice. The name given to these cells comes from the resemblance to normal stem cells, except for the fact that their ability to divide is infinite. These cells are also affected by their microenvironment. Many of the signaling pathways, such as Wnt, Notch and Hedgehog, are altered in this tumoral subpopulation, which also contributes to abnormal proliferation. Researchers have found several markers for CSCs; however, much remains to be studied, or perhaps a universal marker does not even exist, since they vary among tumor types and even from patient to patient. It was also found that cancer stem cells are resistant to radiotherapy and chemotherapy. This may explain the re-emergence of the disease, since they are not completely eliminated and minimal amounts of CSCs can repopulate a tumor. Once the diagnosis in the early stages greatly increases the chances of curing cancer, identifying CSCs in tumors is a goal for the development of more effective treatments. The objective of this article is to discuss the origin of cancer according to the theory of stem cell cancer, as well as its markers and therapies used for treatment.

  19. Intracellular particle tracking as a tool for tumor cell characterization

    Li, Yixuan; Duits, Michel H.G.; Schnekenburger, Jürgen


    We studied the dynamics of two types of intracellular probe particles, ballistically injected latex spheres and endogenous granules, in tumor cell lines of differerent metastatic potential: breast tumor cells (MCF-7 malignant, MCF-10A benign) and pancreas adenocarcinoma (PaTu8988T malignant, PaTu898

  20. Treatment Options By Stage (Ovarian Germ Cell Tumors)

    ... ovarian germ cell tumor are swelling of the abdomen or vaginal bleeding after menopause. Ovarian germ cell ... if you have either of the following: Swollen abdomen without weight gain in other parts of the ...

  1. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth

    Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make canc...

  2. Negligible Colon Cancer Risk from Food-Borne Acrylamide Exposure in Male F344 Rats and Nude (nu/nu) Mice-Bearing Human Colon Tumor Xenografts

    Raju, Jayadev; Roberts, Jennifer; Sondagar, Chandni; Kapal, Kamla; Aziz, Syed A.; Caldwell, Don; Mehta, Rekha


    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. PMID:24040114

  3. Cryo-ablation improves anti-tumor immunity through recovering tumor educated dendritic cells in tumor-draining lymph nodes

    He XZ


    Full Text Available Xiao-Zheng He,1,2 Qi-Fu Wang,1,2 Shuai Han,3 Hui-Qing Wang,1,2 Yong-Yi Ye,1,2 Zhi-Yuan Zhu,1,2 Shi-Zhong Zhang1,2 1Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China Background: In addition to minimally invasive destruction of tumors, cryo-ablation of tumors to some extent modulated anti-tumor immunity. Cryo-ablated tumors in glioma mice models induced anti-tumor cellular immunologic response which increases the percentage of CD3+ and CD4+T cells in blood as well as natural killer cells. As a crucial role in triggering anti-tumor immunity, dendritic cells (DCs were educated by tumors to adopt a tolerance phenotype which helps the tumor escape from immune monitoring. This study aims to study whether cryo-ablation could influence the tolerogenic DCs, and influence anti-tumor immunity in tumor-draining lymph nodes (TDLNs. Methods: Using the GL261 subcutaneous glioma mouse model, we created a tumor bearing group, cryo-ablation group, and surgery group. We analyzed alteration in phenotype and function of tolerogenic DCs, and evaluated the factors of anti-tumor immunity inhibition. Results: DCs in TDLNs in GL261 subcutaneous glioma mouse model expressed tolerogenic phenotype. In contrast to surgery, cryo-ablation improved the quantity and quality of these tolerogenic DCs. Moreover, the DCs decreased the expression of intracellular interleukin-10 (IL-10 and extra-cellular IL-10. In vitro, DCs from the cryo-ablation group recovered their specific function and induced potent anti-tumor immunity through triggering T cells. In vivo, cryo

  4. Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells

    J. Brian Morgan


    Full Text Available The biologically active lipopeptide kalkitoxin was previously isolated from the marine cyanobacterium Moorea producens (Lyngbya majuscula. Kalkitoxin exhibited N-methyl-d-aspartate (NMDA-mediated neurotoxicity and acted as an inhibitory ligand for voltage-sensitive sodium channels in cultured rat cerebellar granule neurons. Subsequent studies revealed that kalkitoxin generated a delayed form of colon tumor cell cytotoxicity in 7-day clonogenic cell survival assays. Cell line- and exposure time-dependent cytostatic/cytotoxic effects were previously observed with mitochondria-targeted inhibitors of hypoxia-inducible factor-1 (HIF-1. The transcription factor HIF-1 functions as a key regulator of oxygen homeostasis. Therefore, we investigated the ability of kalkitoxin to inhibit hypoxic signaling in human tumor cell lines. Kalkitoxin potently and selectively inhibited hypoxia-induced activation of HIF-1 in T47D breast tumor cells (IC50 5.6 nM. Mechanistic studies revealed that kalkitoxin inhibits HIF-1 activation by suppressing mitochondrial oxygen consumption at electron transport chain (ETC complex I (NADH-ubiquinone oxidoreductase. Further studies indicate that kalkitoxin targets tumor angiogenesis by blocking the induction of angiogenic factors (i.e., VEGF in tumor cells.

  5. Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study.

    De Jonghe, Sandra; Johnson, Mark D; Mamidi, Rao N V S; Vinken, Petra; Feyen, Bianca; Lammens, Godelieve; Proctor, Jim


    During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment-related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation. In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose-free diet. Canagliflozin-dosed rats on standard diet showed presence of basophilic renal tubular tumors (6/90) and an increased incidence of adrenal medullary hyperplasia (35/90), which was fully prevented by feeding a glucose-free diet (no RTT's; adrenal medullary hyperplasia in ≤5/90). These data further confirm that kidney and adrenal medullary tumors in the 2-year rat study were secondary to carbohydrate (glucose) malabsorption and were not due to a direct effect of canagliflozin on these target tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. A Study of CD45RA+ Depleted Haploidentical Stem Cell Transplantation in Children With Relapsed or Refractory Solid Tumors and Lymphomas


    Ewing Sarcoma; Gastrointestinal Tumor; Germ Cell Tumor; Hepatic Tumor; Lymphoma; Wilms Tumor; Rhabdoid Tumor; Clear Cell Carcinoma; Renal Cell Carcinoma; Melanoma; Neuroblastoma; Rhabdomyosarcoma; Non-rhabdomyosarcoma

  7. Internalization of NK cells into tumor cells requires ezrin and leads to programmed cell-in-cell death

    Shan Wang; Zhen Guo; Peng Xia; Tingting Liu; Jufang Wang; Shan Li; Lihua Sun; Jianxin Lu; Qian Wen; Mingqian Zhou; Li Ma; Xia Ding; Xiaoning Wang; Xuebiao Yao


    Cytotoxic lymphocytes are key players in the orchestration of immune response and elimination of defective cells. We have previously reported that natural killer (NK) cells enter target tumor cells, leading to either target cell death or self-destruction within tumor cells. However, it has remained elusive as to the fate of NK cells after internaliza-tion and whether the heterotypic cell-in-cell process is different from that of the homotypic cell-in-cell event recently named entosis. Here, we show that NK cells undergo a cell-in-cell process with the ultimate fate of apoptosis within tumor cells and reveal that the internalization process requires the actin cytoskeletal regulator, ezrin. To visualize how NK cells enter into tumor cells, we carried out real-time dual color imaging analyses of NK cell internalization into tumor cells. Surprisingly, most NK cells commit to programmed cell death after their entry into tumor cells, which is distinctively different from entosis observed in the homotypic cell-in-cell process. The apoptotic cell death of the internalized NK cells was evident by activation of caspase 3 and DNA fragmentation. Furthermore, NK cell death after internalization is attenuated by the caspase inhibitor, Z-VAD-FMK, confirming apoptosis as the mode of NK cell death within tumor cells. To determine protein factors essential for the entry of NK cells into tumor cells, we car-ried out siRNA-based knockdown analysis and discovered a critical role of ezrin in NK cell internalization. Impor-tantly, PKA-mediated phosphorylation of ezrin promotes the NK cell internalization process. Our findings suggest a novel regulatory mechanism by which ezrin governs NK cell internalization into tumor cells.

  8. Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

    Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang


    Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

  9. Solid tumor therapy by selectively targeting stromal endothelial cells.

    Liu, Shihui; Liu, Jie; Ma, Qian; Cao, Liu; Fattah, Rasem J; Yu, Zuxi; Bugge, Thomas H; Finkel, Toren; Leppla, Stephen H


    Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.

  10. Interleukin-2 inhibits proliferation of HPV-associated tumor cells and halts tumor growth in vivo.

    Casana, Patricia H; Hernandez, Hector; Arana, Manuel J


    Previous studies have shown inhibition of cervical cancer cell growth by treatment with high concentrations of IL-2. In the present study, we evaluated the in vitro and in vivo effects of recombinant human IL-2 on HPV-associated tumor cells (3T3-16). Treatment of 3T3-16 cells with rhIL-2 for 72 h inhibited cell growth in a dose-dependent manner and this effect was evidenced at nanomolar concentrations. These tumor cells expressed mRNA for beta and gamma subunits of the IL-2 receptor, which are required for signal transduction. In experiments to explore the effect of IL-2 on the growth of the HPV-associated tumor, mice received rhIL-2 through different routes: (i) intraperitoneal; (ii) subcutaneous, at the tumor inoculation site; or (iii) subcutaneous, distant from the tumor inoculation site. An effective antitumor response was observed only in those animals that received IL-2 at the tumor site (P<0.01). These results indicate the potential adequacy of therapeutic strategies based on local administration of rhIL-2 for cervical carcinoma, not only based on the ability of this cytokine to stimulate cellular-mediated immunity but also because of its direct effects on tumor cells.

  11. Tumor-stem cells interactions by fluorescence imaging

    Meleshina, Aleksandra V.; Cherkasova, Elena I.; Sergeeva, Ekaterina; Turchin, Ilya V.; Kiseleva, Ekaterina V.; Dashinimaev, Erdem B.; Shirmanova, Marina V.; Zagaynova, Elena V.


    Recently, great deal of interest is investigation the function of the stem cells (SC) in tumors. In this study, we studied «recipient-tumor- fluorescent stem cells » system using the methods of in vivo imaging and laser scanning microscopy (LSM). We used adipose-derived adult stem (ADAS) cells of human lentiviral transfected with the gene of fluorescent protein Turbo FP635. ADAS cells were administrated into nude mice with transplanted tumor HeLa Kyoto (human cervical carcinoma) at different stages of tumor growth (0-8 days) intravenously or into tumor. In vivo imaging was performed on the experimental setup for epi - luminescence bioimaging (IAP RAS, Nizhny Novgorod). The results of the imaging showed localization of fluorophore tagged stem cells in the spleen on day 5-9 after injection. The sensitivity of the technique may be improved by spectral separation autofluorescence and fluorescence of stem cells. We compared the results of in vivo imaging and confocal laser scanning microscopy (LSM 510 META, Carl Zeiss, Germany). Internal organs of the animals and tumor tissue were investigated. It was shown that with i.v. injection of ADAS, bright fluorescent structures with spectral characteristics corresponding to TurboFP635 protein are locally accumulated in the marrow, lungs and tumors of animals. These findings indicate that ADAS cells integrate in the animal body with transplanted tumor and can be identified by fluorescence bioimaging techniques in vivo and ex vivo.

  12. Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model.

    Jensen, Matthew B; Yan, Hongmei; Krishnaney-Davison, Rajeev; Al Sawaf, Abdullah; Zhang, Su-Chun


    Although administration of various stem cells has shown promise in stroke models, neural stem cells (NSCs) derived from human induced pluripotent stem cells (iPSCs) have advantages over other cell types. We studied whether these cells could survive, differentiate, and improve stroke recovery in an ischemic stroke model. Human iPSCs were induced in vitro to an early NSC stage. One week after focal cerebral ischemia, 20 rats received cells or vehicle by intracerebral injection. Graft cell fate, infarct volume, and behavioral deficits were assessed. Graft cells were found in 8 of the transplanted rats (80%), with estimated mean graft cell numbers nearly double the amount transplanted 1 month later. Graft cells also expressed markers of NSCs in 5 rats (63%), neurons in all 8 rats (100%), rare astrocytes in 4 rats (50%), and signs of proliferation in 4 rats (50%), but no tumor formation was observed. Stroke volume and behavioral recovery were similar between the groups. To our knowledge, this is the first report of transplantation of NSCs derived from human iPSCs in a stroke model. Human iPSC-derived NSCs survived in the postischemic rat brain and appeared to differentiate, primarily into neurons. This cell transplantation approach for stroke appears to be feasible, but further optimization is needed. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  13. Identification of a population of epidermal squamous cell carcinoma cells with enhanced potential for tumor formation.

    Gautam Adhikary

    Full Text Available Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation.

  14. A model of hemodynamic responses of rat tumors to hyperoxic gas challenge

    Xia, Mengna; Mason, Ralph P.; Liu, Hanli


    We measured the changes of oxy-hemoglobin (Δ[HbO2]) and deoxy-hemoglobin concentration (Δ[Hb]) in rat breast 13762NF tumors with respect to oxygen or carbogen inhalation using near-infrared spectroscopy (NIRS). The changes in tumor blood flow can be estimated from the NIRS data provided with certain model assumptions. In the theoretical approach, we modified the Windkessel model so as to associate the mathematical model with such physiological parameters of tumor vasculature as total hemoglobin concentration ([HbT]), tumor blood flow (TBF), and tumor metabolic rate of oxygen (TMRO2). The computational results show that hyperoxic gas administration to the rat tumors always gave rise to improvement of tumor Δ[HbO2], while the same hyperoxic gas intervention could result in different responses in tumor [HbT], TBF, and TMRO2. This preliminary study has demonstrated that NIRS, a noninvasive tool to monitor tumor oxygenation, may also be used to estimate tumor perfusion and oxygen consumption rate in response to therapeutic interventions, if a suitable mathematical model is provided.

  15. Pulmonary tumor thrombotic microangiopathy with cor pulmonale due to desmoplastic small round cell tumor.

    Sadimin, Evita T; Collier, Adrienne G; Gaffney, Joseph W; Fyfe, Billie


    A 12-year-old boy presented acutely after an episode of syncope with perioral cyanosis. He died 19 hours after admission due to cor pulmonale as a complication of metastatic desmoplastic small round cell tumor in the lungs with associated tumor thrombotic microangiopathy.

  16. Aggressive fibromatosis (desmoid tumor) is derived from mesenchymal progenitor cells.

    Wu, Colleen; Amini-Nik, Saeid; Nik-Amini, Saied; Nadesan, Puviindran; Stanford, William L; Alman, Benjamin A


    The cellular origins from which most tumors arise are poorly defined, especially in mesenchymal neoplasms. Aggressive fibromatosis, also known as desmoid tumor, is a locally invasive soft tissue tumor that has mesenchymal characteristics. We found that aggressive fibromatosis tumors express genes and cell surface markers characteristic of mesenchymal stem cells (MSC). In mice that are genetically predisposed to develop aggressive fibromatosis tumors (Apc(wt/1638N)), we found that the number of tumors formed was proportional to the number of MSCs present. Sca-1(-/-) mice, which develop fewer MSCs, were crossed with Apc(wt/1638N) mice. Doubly mutant mice deficient in Sca-1 developed substantially fewer aggressive fibromatosis tumors than wild-type (WT) littermates, but Sca-1 deficiency had no effect on the formation of epithelial-derived intestinal polyps. MSCs isolated from Apc(wt/1638N) mice (or mice expressing a stabilized form of β-catenin) induced aberrant cellular growth reminiscent of aggressive fibromatosis tumors after engraftment to immunocompromised mice, but WT cells and mature fibroblasts from the same animals did not. Taken together, our findings indicate that aggressive fibromatosis is derived from MSCs, and that β-catenin supports tumorigenesis by maintaining mesenchymal progenitor cells in a less differentiated state. Protecting this progenitor cell population might prevent tumor formation in patients harboring a germline APC mutation, where fibromatosis is currently the leading cause of mortality. © 2010 AACR.

  17. Non-Structural protein 1 (NS1) gene of Canine Parvovirus-2 regresses chemically induced skin tumors in Wistar rats.

    Santra, Lakshman; Rajmani, R S; Kumar, G V P P S Ravi; Saxena, Shikha; Dhara, Sujoy K; Kumar, Amit; Sahoo, Aditya Prasad; Singh, Lakshya Veer; Desai, G S; Chaturvedi, Uttara; Kumar, Sudesh; Tiwari, Ashok K


    The Non-Structural protein 1 of Canine Parvovirus-2 (CPV2.NS1) plays a major role in viral cytotoxicity and pathogenicity. CPV2.NS1 has been proven to cause apoptosis in HeLa cells in vitro in our laboratory. Here we report that CPV2.NS1 has no toxic side effects on healthy cells but regresses skin tumors in Wistar rats. Histopathological examination of tumor tissue from CPV2.NS1 treated group revealed infiltration of mononuclear and polymorphonuclear cells with increased extra cellular matrix, indicating signs of regression. Tumor regression was also evidenced by significant decrease in mitotic index, AgNOR count and PCNA index, and increase in TUNEL positive apoptotic cells in CPV2.NS1 treated group. Further, CPV2.NS1 induced anti-tumor immune response through significant increase in CD8(+) and NK cell population in CPV2.NS1 treated group. These findings suggest that CPV2.NS1 can be a possible therapeutic candidate as an alternative to chemotherapy for the treatment of cancer.

  18. Inhibition of hepatic tumor cell proliferation in vitro and tumor growth in vivo by taltobulin,a synthetic analogue of the tripeptide hemiasterlin

    Yogesh K Vashist; Celine Tiffon; Christoforos Stoupis; Claudio A Redaelli


    AIM:To investigate the inhibitory effects of taltobulin (HTI-286),a synthetic analogue of natural hemiasterlin derived from marine sponges, on hepatic tumor growth in vitro andin vivo.METHODS: The potential anti-proliferative effects of HTI-286 on different hepatic tumor cell lines in vitro and in vivo were examined.RESULTS:HTI-286 significantly inhibited proliferation of all three hepatic tumor cell lines (mean IC50 = 2 nmol/L± 1 nmol/L)in vitro. Interestingly, no decrease in viable primary human hepatocytes (PHH) was detected under HTI-286 exposure. Moreover, intravenous administration of HTI-286 significantly inhibited tumor growth in vivo (rat allogratt model).CONCLUSION:HTI-286 might be considered a potent promising drug in treatment of liver malignancies.HTI-286 is currently undergoing clinical evaluation in cancer patients.

  19. From Tumor Immunosuppression to Eradication: Targeting Homing and Activity of Immune Effector Cells to Tumors

    Oana Draghiciu


    Full Text Available Unraveling the mechanisms used by the immune system to fight cancer development is one of the most ambitious undertakings in immunology. Detailed knowledge regarding the mechanisms of induction of tolerance and immunosuppression within the tumor microenvironment will contribute to the development of highly effective tumor eradication strategies. Research within the last few decades has shed more light on the matter. This paper aims to give an overview on the current knowledge of the main tolerance and immunosuppression mechanisms elicited within the tumor microenvironment, with the focus on development of effective immunotherapeutic strategies to improve homing and activity of immune effector cells to tumors.

  20. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival.

    Fischer, Walter; Gustafsson, Lotta; Mossberg, Ann-Kristin; Gronli, Janne; Mork, Sverre; Bjerkvig, Rolf; Svanborg, Catharina


    Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human alpha-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from alpha-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids. After 7 days, HAMLET was administered by intracerebral convection-enhanced delivery for 24 h into the tumor area; and alpha-lactalbumin, the native, folded variant of the same protein, was used as a control. HAMLET reduced the intracranial tumor volume and delayed the onset of pressure symptoms in the tumor-bearing rats. After 8 weeks, all alpha-lactalbumin-treated rats had developed pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic resonance imaging scans revealed large differences in tumor volume (456 versus 63 mm(3)). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact brain tissue or in nontransformed human astrocytes, and no toxic side effects were observed. The results identify HAMLET as a new candidate in cancer therapy and suggest that HAMLET should be additionally explored as a novel approach to controlling GBM progression.

  1. [Frequent allelic losses in tumor-associated stromal cells and tumor epitelium of prostate cancer].

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Zavalishina, L E; Andreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V


    It has become increasingly clear that tumor microenvironment plays a critical role in carcinogenesis. Accumulation of genetic alterations is typical not only for cancer epithelial cells but tumor-associated fibroblasts as well. Tumor epithelia, tumor-associated stroma from prostatectomy specimens of patients with prostate cancer and cells from prostatic intraepithelial neoplasia (PIN) and adjacent stroma from males with PIN were isolated by using laser capture microdissection. Microsatellite allelotyping was evaluated using 4 highly polymorphic markers for chromosomal regions 8p22, 16q23-24 and 13q14. Incidences of alterations (loss of heterozygosity or allelic imbalance) were 48% for region 8p22, 72% for 16q23 and 37% for 13q14. The LOH frequencies in tumor-associated stroma cells were very similar. Alterations at chromosome 13q were significantly associated with advanced tumor stage, whereas AI at 16q was also associated with high Gleason score and lymph node metastasis. We find some incidences of allelic imbalance in premalignant lesions in epithelial (16-27%) and stromal (7-22%) components. Our results show that the frequencies of genetic aberrations are as high in stromal cells as in tumor cells.

  2. Endothelial cell tumor growth is Ape/ref-1 dependent.

    Biswas, Ayan; Khanna, Savita; Roy, Sashwati; Pan, Xueliang; Sen, Chandan K; Gordillo, Gayle M


    Tumor-forming endothelial cells have highly elevated levels of Nox-4 that release H2O2 into the nucleus, which is generally not compatible with cell survival. We sought to identify compensatory mechanisms that enable tumor-forming endothelial cells to survive and proliferate under these conditions. Ape-1/ref-1 (Apex-1) is a multifunctional protein that promotes DNA binding of redox-sensitive transcription factors, such as AP-1, and repairs oxidative DNA damage. A validated mouse endothelial cell (EOMA) tumor model was used to demonstrate that Nox-4-derived H2O2 causes DNA oxidation that induces Apex-1 expression. Apex-1 functions as a chaperone to keep transcription factors in a reduced state. In EOMA cells Apex-1 enables AP-1 binding to the monocyte chemoattractant protein-1 (mcp-1) promoter and expression of that protein is required for endothelial cell tumor formation. Intraperitoneal injection of the small molecule inhibitor E3330, which specifically targets Apex-1 redox-sensitive functions, resulted in a 50% decrease in tumor volume compared with mice injected with vehicle control (n = 6 per group), indicating that endothelial cell tumor proliferation is dependent on Apex-1 expression. These are the first reported results to establish Nox-4 induction of Apex-1 as a mechanism promoting endothelial cell tumor formation.

  3. Tumor Irradiation Increases the Recruitment of Circulating Mesenchymal Stem Cells into the Tumor Microenvironment

    Klopp, Ann H.; Spaeth, Erika L.; Dembinski, Jennifer L.; Woodward, Wendy A.; Munshi, Anupama; Meyn, Raymond E.; Cox, James D.; Andreeff, Michael; Marini, Frank C.


    Mesenchymal stem cells (MSC) migrate to and proliferate within sites of inflammation and tumors as part of the tissue remodeling process. Radiation increases the expression of inflammatory mediators that could enhance the recruitment of MSC into the tumor microenvironment. To investigate this, bilateral murine 4T1 breast carcinomas (expressing renilla luciferase) were irradiated unilaterally (1 or 2 Gy). Twenty-four hours later, 2 × 105 MSC-expressing firefly luciferase were injected i.v. Mice were then monitored with bioluminescent imaging for expression of both renilla (tumor) and firefly (MSC) luciferase. Forty-eight hours postirradiation, levels of MSC engraftment were 34% higher in tumors receiving 2 Gy (P = 0.004) than in the contralateral unirradiated limb. Immunohistochemical staining of tumor sections from mice treated unilaterally with 2 Gy revealed higher levels of MSC in the parenchyma of radiated tumors, whereas a higher proportion of MSC remained vasculature-associated in unirradiated tumors. To discern the potential mediators involved in MSC attraction, in vitro migration assays showed a 50% to 80% increase in MSC migration towards conditioned media from 1 to 5 Gy-irradiated 4T1 cells compared with unirradiated 4T1 cells. Irradiated 4T1 cells had increased expression of the cytokines, transforming growth factor-β1, vascular endothelial growth factor, and platelet-derived growth factor-BB, and this up-regulation was confirmed by immunohistochemistry in tumors irradiated in vivo. Interestingly, the chemokine receptor CCR2 was found to be up-regulated in MSC exposed to irradiated tumor cells and inhibition of CCR2 led to a marked decrease of MSC migration in vitro. In conclusion, clinically relevant low doses of irradiation increase the tropism for and engraftment of MSC in the tumor microenvironment. PMID:18089798

  4. Galectin-3 determines tumor cell adaptive strategies in stressed tumor microenvironments

    Ana Carolina Ferreira Cardoso


    Full Text Available Galectin-3 is a member of the b-galactoside binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein, found in the nucleus and in the cytoplasm; under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (hypoxia and nutrient deprivation, e.g. galectin-3 is upregulated, through the activity of transcription factors such as HIF-1a and NF-kB. Here we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocyte/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, besides its effects in different elements of the immune system, as (i it favors tumor cell adaptation for survival in stressed conditions; (ii upon secretion, galectin-3 induces tumor cell detachment and migration; (iii it attracts endothelial cells and monocytes/macrophages to the tumor mass, inducing both directly and indirectly the process of angiogenesis. These activities are potentially targetable and specific interventions may

  5. Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments

    Cardoso, Ana Carolina Ferreira; Andrade, Luciana Nogueira de Sousa; Bustos, Silvina Odete; Chammas, Roger


    Galectin-3 is a member of the β-galactoside-binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein found in the nucleus and in the cytoplasm, under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (e.g., hypoxia and nutrient deprivation) galectin-3 is upregulated, through the activity of transcription factors, such as HIF-1α and NF-κB. Here, we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins, and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell, and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocytes/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, as (i) it favors tumor cell adaptation for survival in stressed conditions; (ii) upon secretion, galectin-3 induces tumor cell detachment and migration; and (iii) it attracts monocyte/macrophage and endothelial cells to the tumor mass, inducing both directly and indirectly the process of angiogenesis. The two latter activities are potentially targetable, and specific interventions may be designed to counteract the protumoral role of extracellular

  6. Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion

    Vellinga, T T; den Uil, S; Rinkes, IHB; Marvin, D; Ponsioen, B; Alvarez-Varela, A; Fatrai, S; Scheele, C; Zwijnenburg, D A; Snippert, H; Vermeulen, L; Medema, J P; Stockmann, H B; Koster, J; Fijneman, R J A; de Rooij, J; Kranenburg, O


    Gene expression-based classification systems have identified an aggressive colon cancer subtype with mesenchymal features, possibly reflecting epithelial-to-mesenchymal transition (EMT) of tumor cells. However, stromal fibroblasts contribute extensively to the mesenchymal phenotype of aggressive col

  7. Adaptations of Arginine's Intestinal-Renal Axis in Cachectic Tumor-Bearing Rats.

    Buijs, Nikki; Vermeulen, Mechteld A R; Weeda, Viola B; Bading, James R; Houdijk, Alexander P J; van Leeuwen, Paul A M


    Malignancies induce disposal of arginine, an important substrate for the immune system. To sustain immune function, the tumor-bearing host accelerates arginine's intestinal-renal axis by glutamine mobilization from skeletal muscle and this may promote cachexia. Glutamine supplementation stimulates argi-nine production in healthy subjects. Arginine's intestinal-renal axis and the effect of glutamine supplementation in cancer cach-exia have not been investigated. This study evaluated the long-term adaptations of the interorgan pathway for arginine production following the onset of cachexia and the metabolic effect of glutamine supplementation in the cachectic state. Fischer-344 rats were randomly divided into a tumor-bearing group (n = 12), control group (n = 7) and tumor-bearing group receiving a glutamine-enriched diet (n = 9). Amino acid fluxes and net fractional extractions across intestine, kidneys, and liver were studied. Compared to controls, the portal-drained viscera of tumor-bearing rats took up significantly more glutamine and released significantly less citrulline. Renal metabolism was unchanged in the cachectic tumor-bearing rats compared with controls. Glutamine supplementation had no effects on intestinal and renal adaptations. In conclusion, in the cachectic state, an increase in intestinal glutamine uptake is not accompanied by an increase in renal arginine production. The adaptations found in the cachectic, tumor-bearing rat do not depend on glutamine availability.

  8. Tumorer

    Prause, J.U.; Heegaard, S.


    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  9. Brain tumor stem cells: the cancer stem cell hypothesis writ large.

    Dirks, Peter B


    Brain tumors, which are typically very heterogeneous at the cellular level, appear to have a stem cell foundation. Recently, investigations from multiple groups have found that human as well as experimental mouse brain tumors contain subpopulations of cells that functionally behave as tumor stem cells, driving tumor growth and generating tumor cell progeny that form the tumor bulk, but which then lose tumorigenic ability. In human glioblastomas, these tumor stem cells express neural precursor markers and are capable of differentiating into tumor cells that express more mature neural lineage markers. In addition, modeling brain tumors in mice suggests that neural precursor cells more readily give rise to full blown tumors, narrowing potential cells of origin to those rarer brain cells that have a proliferative potential. Applying stem cell concepts and methodologies is giving fresh insight into brain tumor biology, cell of origin and mechanisms of growth, and is offering new opportunities for development of more effective treatments. The field of brain tumor stem cells remains very young and there is much to be learned before these new insights are translated into new patient treatments. Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  10. Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats

    Bennett, L; Montgomery, J; Steinberg, S; Kulp, K


    Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

  11. Adenovirus-mediated gene transfer to tumor cells.

    Cascalló, Manel; Alemany, Ramon


    Cell transduction in vitro is only the first step toward proving that a genetherapy vector can be useful to treat tumors. However, tumor targeting in vivo is now the milestone for gene therapy to succeed against disseminated cancer. Therefore, most valuable information is obtained from studies of vector biodistribution. Owing to the hepatotropism of adenoviral vectors, a particularly important parameter is the tumor/liver ratio. This ratio can be given at the level of gene expression if the amount of transgene expression is measured. To optimize the targeting, however, the levels of viral particles that reach the tumor compared to other organs must be studied. Most of this chapter deals with methods to quantify the virus fate in tumor-bearing animals. We present a radioactive labeling method that can be used to study biodistribution. After a small section dealing with tumor models, we describe methods to quantify different parameters related to adenovirus-mediated tumor targeting.

  12. Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy


    AD_________________ (Leave blank) Award Number: W81XWH-14-1-0350 TITLE: Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After...30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTILE Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy 5a. CONTRACT NUMBER...Innovative reporter gene systems are designed to mark quiescent or proliferating lung cancer cells (Aim 1) and then used to track and trace the dynamics of

  13. S-100 Negative Granular Cell Tumor of the Oral Cavity.

    Solomon, Lynn W; Velez, Ines


    Classic granular cell tumor is a mesenchymal neoplasm that commonly occurs on the skin, but is not infrequently found in the oral cavity, primarily on the dorsal tongue. Diagnosis is usually straightforward with hematoxylin and eosin stained slides. Immunohistochemical studies on classic granular cell tumor shows positive immunostaining for S-100 and vimentin, while CD68 is variably positive. We report a case of otherwise unremarkable oral granular cell tumor that was immunohistochemically negative for S-100, and positive for vimentin and CD68, and discuss the differential diagnosis. The results of the immunohistochemical studies in our case are compared with those of classic S-100 positive oral granular cell tumors, as well as cutaneous and oral S-100 negative granular cell tumors. Classic S-100 positive granular cell tumors and S-100 negative granular cell tumors of the oral cavity can only be distinguished by immunohistochemical studies; however, the necessity of this distinction is unclear, as both are benign lesions in which recurrence is unlikely.

  14. Culture and Isolation of Brain Tumor Initiating Cells.

    Vora, Parvez; Venugopal, Chitra; McFarlane, Nicole; Singh, Sheila K


    Brain tumors are typically composed of heterogeneous cells that exhibit distinct phenotypic characteristics and proliferative potentials. Only a relatively small fraction of cells in the tumor with stem cell properties, termed brain tumor initiating cells (BTICs), possess an ability to differentiate along multiple lineages, self-renew, and initiate tumors in vivo. This unit describes protocols for the culture and isolation BTICs. We applied culture conditions and assays originally used for normal neural stem cells (NSCs) in vitro to a variety of brain tumors. Using fluorescence-activated cell sorting for the neural precursor cell surface marker CD133/CD15, BTICs can be isolated and studied prospectively. Isolation of BTICs from GBM bulk tumor will enable examination of dissimilar morphologies, self-renewal capacities, tumorigenicity, and therapeutic sensitivities. As cancer is also considered a disease of unregulated self-renewal and differentiation, an understanding of BTICs is fundamental to understanding tumor growth. Ultimately, it will lead to novel drug discovery approaches that strategically target the functionally relevant BTIC population. Copyright © 2015 John Wiley & Sons, Inc.

  15.  An Uncommon Presentation of Giant Cell Tumor

    Gopal Malhotra


    Full Text Available  Giant Cell Tumors commonly occur at the ends of long bones. However in rare cases, they can occur in the bones of the hands and feet. Tumors in these locations occur in younger patients; in addition, these tumors are more commonly multifocal and are associated with a higher risk for local recurrence than tumors at the ends of long bones. Since lesions in the small bones may be multifocal, a patient with a giant cell tumor of the small bones should undergo a skeletal survey to exclude similar lesions elsewhere. Primary surgical treatment ranges from curettage or excision with or without bone grafting to amputation. The success of surgical treatment depends on the completeness with which the tumor was removed. We are presenting a case report of a 34 year old female, who presented with a swelling in the right hand, following trauma. X-ray of the hand showed an osteolytic expansile lesion at the base of the 1st metacarpal bone. The lesion was initially curetted and then treated by local resection with bone grafting. Histological examination revealed a typical benign giant cell tumor composed of closely packed stromal cells with a variable admixture of giant cells. Follow up at the end of one year did not reveal any recurrence of the tumor.

  16. Antitumor effect of intra-arterial tumor necrosis factor-{alpha} in rats with transplanted intracerebral glioma and its evaluation by MRI

    Harada, Kunyu; Yoshida, Jun; Wakabayashi, Toshihiko; Sugita, Kenichiro [Nagoya Univ. (Japan). School of Medicine; Kurisu, Kaoru; Uozumi, Tohru; Zieroth, B.F.; Takahashi, Masaya; Yamanaka, Tsuyoshi


    Recombinant human TNF-{alpha} was administrated intra-arterially to rats with transplanted intracerebral glioma. 1 x 10{sup 6} of T9 rat glioma cells were transplanted into Fisher 344 rat brain stereotaxically and 1000 units of TNF-{alpha} was administrated at a rate of 100{mu}l/min via an internal carotid artery 1 or 3 weeks after the transplantation. The effects of TNF-{alpha} were evaluated by MRI and histopathological examinations. Neurological symptoms, i.e. hemiparesis, appeared after 9.0{+-}0.63 days and all rats died of tumor overloading 14.5{+-}0.84 days after the transplantation. Single injection of TNF-{alpha} on 7th day after the transplantation induced regression of the tumor size in one of six rats. The tumors were detected 3 days after transplantation by MRI and they were revealed as low/iso intensity mass in T1WI, iso/high intensity in T2WI, and were enhanced by Gd-DTPA heterogenously. On 7/14 days after the transplantation, the tumor grew approximately 7/10 mm in diameter. The single 1000 units of TNF-{alpha} were administrated via an internal carotid artery. Three days after the administration or TNF-{alpha}, regression of the tumor size was seen in one of six rats and decrease of peritumoral edema was seen in three. These effects of TNF-{alpha} were, however, transient and they were not demonstrated on day 7. Single injection of TNF-{alpha} was not effective for large tumors more than 10 mm in diameter seen 14 days after the transplantation. These data suggest that intra-arterial TNF-{alpha} should be administrated at an early stage of the tumor growth and several injections are needed to cause regression in the size of the gliomas. (author).

  17. Influence of methionine/valine-depleted enteral nutrition on nucleic acid and protein metabolism in tumor-bearing rats

    Yin-Cheng He; Jun Cao; Ji-Wei Chen; Ding-Yu Pan; Ya-Kui Zhou


    AIM: To investigate the effects of methionine/valine-depleted enteral nutrition (EN) on RNA, DNA and protein metabolism in tumor-bearing (TB) rats.METHODS: Sprague-Dawlley (SD) rats underwent jejunostomy for nutritional support. A suspension of Walker256 carcinosarcoma cells was subcutaneously inoculated.48 TB rats were randomly divided in 4 groups: A, B, C and D. The TB rats had respectively received jejunal feedings supplemented with balanced amino acids, methioninedepleted, balanced amino acids and valine-depleted for 6days before injection of 740 KBq 3H- methionine/valine via jejunum. The 3H incorporation rate of the radioactivity into RNA, DNA and proteins in tumor tissues at 0.5, 1, 2, 4 h postinjection of tracers was assessed with liquid scintillation counter.RESULTS: Incorporation of 3H into proteins in groups B and D was (0.500±0.020) % to (3.670±0.110) % and (0.708±0.019) % to (3.813±0.076) % respectively, lower than in groups A [(0.659±0.055) % to (4.492±0.108) %]and C r(0.805±0.098) % to (4.180±0.018) %]. Incorporation of 3H into RNA, DNA in group B was (0.237±0.075) %and (0.231±0.052) % respectively, lower than in group A (P<0.01). There was no significant difference in uptake of 3H by RNA and DNA between group C and D (P>0.05).CONCLUSION: Protein synthesis was inhibited by methionine/valine starvation in TB rats and nucleic acid synthesis was reduced after methionine depletion, thus resulting in suppression of tumor growth.

  18. Correlation between metastatic potential and variants from colorectal tumor cell line HT-29

    Min Wang; Ilka Vogel; Holger Kalthoff


    AIM: To evaluate the relationship between uPA, PAI-1,CEA, PI3K and metastatic potential in three colorectal tumor cell lines.METHODS: Metastatic model in nude rats was established by variants HT-29c and HT-29d cell lines and the metastatic potential of two tumor cell variants was compared.Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) were determined using ELISA in colorectal carcinoma WiDr, HT29 and HT-29d cell lines with different metastatic potentials.Expression of carcinoembryonic antigen (CEA) and phosphoinositide 3-kinase (PI3-Kinase) was analyzed using immunohistochemistry (IHC) in these cell lines in vitro and in vivo. CEA expression was compared using fluorescence activated cell sorter (FACS)in vitro.RESULTS: The number of HT-29d cells arrested in liver dramatically decreased within the initial 24 hours after injection. The taking rate of liver metastases in the variant HT-29d increased as compared with parental HT-29 cells (70 % versus 50 %) and a variant HT-29b cells (70 % versus 60 %), and extensive organs were synchronously involved in metastases. The uPA concentration of variant HT-29d cell line was significantly higher than that of the non-metastatic WiDr and the low metastatic HT-29 cell lines. The variant HT-29d cells produced stronger PI3-kinase expression as compared with the non-metastatic WiDr cells and the low metastatic HT-29 cellsin vivo.CONCLUSION: The selected variant HT-29d cell exhibited an enhanced metastatic potential. The level of uPA and PAI-1 is positively correlated with the metastatic capacity of tumor cells. The expression of PI3-kinase correlates with tumor development and metastasis.

  19. Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression.

    Behnan, Jinan; Isakson, Pauline; Joel, Mrinal; Cilio, Corrado; Langmoen, Iver A; Vik-Mo, Einar O; Badn, Wiaam


    The identity of the cells that contribute to brain tumor structure and progression remains unclear. Mesenchymal stem cells (MSCs) have recently been isolated from normal mouse brain. Here, we report the infiltration of MSC-like cells into the GL261 murine glioma model. These brain tumor-derived mesenchymal stem cells (BT-MSCs) are defined with the phenotype (Lin-Sca-1+CD9+CD44+CD166+/-) and have multipotent differentiation capacity. We show that the infiltration of BT-MSCs correlates to tumor progression; furthermore, BT-MSCs increased the proliferation rate of GL261 cells in vitro. For the first time, we report that the majority of GL261 cells expressed mesenchymal phenotype under both adherent and sphere culture conditions in vitro and that the non-MSC population is nontumorigenic in vivo. Although the GL261 cell line expressed mesenchymal phenotype markers in vitro, most BT-MSCs are recruited cells from host origin in both wild-type GL261 inoculated into green fluorescent protein (GFP)-transgenic mice and GL261-GFP cells inoculated into wild-type mice. We show the expression of chemokine receptors CXCR4 and CXCR6 on different recruited cell populations. In vivo, the GL261 cells change marker profile and acquire a phenotype that is more similar to cells growing in sphere culture conditions. Finally, we identify a BT-MSC population in human glioblastoma that is CD44+CD9+CD166+ both in freshly isolated and culture-expanded cells. Our data indicate that cells with MSC-like phenotype infiltrate into the tumor stroma and play an important role in tumor cell growth in vitro and in vivo. Thus, we suggest that targeting BT-MSCs could be a possible strategy for treating glioblastoma patients.

  20. The expression and regulation of glucose transporters in tumor cells

    Pengfei Zhao


    Full Text Available Glucose transporter proteins are involved in many physiological and biochemical processes. In particular, the high expressions of sodium-glucose cotransporter and glucose transporter proteins in tumor cells show that these two transporters play a key role in tumor cell metabolism. Studying the crystal structure and conformation of human glucose transporter proteins has enabled the development of drugs based on specific binding sites, opening up a new path towards more effective cancer treatments. This mini review serves to summarize our existing understanding of the metabolic pathways of tumor cells, focusing on the roles of glucose transporter proteins.

  1. Natural killer cells: role in local tumor growth and metastasis

    Langers, Inge; Renoux, Virginie M; Thiry, Marc; Delvenne, Philippe; Jacobs, Nathalie


    Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed. PMID:22532775

  2. Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature.

    Bonfim-Silva, R; Souza, L E B; Melo, F U F; Oliveira, V C; Magalhães, D A R; Oliveira, H F; Covas, D T; Fontes, A M


    Tumor expansion is dependent on neovascularization, a process that requires sustained new vessel formation. Although the critical role of angiogenesis by endothelial sprouting in this process, controversy still prevails on whether angiogenesis involving bone marrow-derived endothelial cells, does contribute to this process. This study aims to evaluate the recruitment of bone marrow-derived cells by the melanoma tumor, including endothelial cells, and if they contribute to angiogenesis. A chimeric mouse model of GFP bone marrow was used to induce melanoma tumors derived from murine B16-F10 cell line. These tumors were evaluated for the presence of myeloid cells (CD11b), T lymphocytes (CD3, CD4 and CD8) and endothelial cells (VEGFR2 and CD31) derived from bone marrow. Mice transplanted with GFP+ cells showed significant bone marrow chimerism (90.9 ± 0.87 %) when compared to the GFP transgenic mice (90.66 ± 2.1 %, p = 0.83) demonstrating successful engraftment of donor bone marrow stem/progenitor cells. Analysis of the murine melanoma tumor showed the presence of donor cells in the tumors (3.5 ± 1.7 %) and interestingly, these cells represent endothelial cells (CD31+ cells; 11.5 ± 6.85 %) and myeloid cells (CD11b+ cells; 80 ± 21 %), but also tumor-infiltrating lymphocytes (CD8+ T cells, 13.31 ± 0.2 %; CD4+ T-cells, 2.1 ± 1.2 %). Examination of the tumor endothelium by confocal microscopy suggests the presence of donor CD31+/GFP+ cells in the wall of some blood vessels. This study demonstrates that bone marrow-derived cells are recruited by the murine melanoma tumor, with myeloid cells and CD4 and CD8 T lymphocytes migrating as antitumor immune response, and endothelial cells participating of the tumor blood vessels formation.

  3. Giant cell tumor of the distal ulna: a case report

    Vanni Daniele


    Full Text Available Abstract Introduction Several cases of long bone giant cell tumor have been reported in the literature. We report the case of a patient with a giant cell tumor in the distal ulna. This is very unusual, with a reported incidence of 0.45 to 6%. Case presentation A 17-year-old Colombian man presented with a painful swelling of the left wrist. After performing an instrumental examination, a diagnosis of distal ulna giant cell tumor was made. The tumor was treated with an intralesional curettage, phenol application and bone grafting. Conclusions This tumor may have a good prognosis if it is diagnosed early and radically treated. It is important to be aware of atypical cancer localizations in order to perform a proper diagnosis.

  4. Metachronous bilateral testicular germ cell tumors: Report of two cases

    James Francis


    Full Text Available Metachronous bilateral testicular germ cell tumors is a rare known problem. However, no report of metachronus bilateralism was identified in the PubMed database published from India so far, where testicular cancer is relatively rare. We report the cases of two gentlemen. One had stage 1 nonseminomatous germ cell tumor (NSGCT at the age of 32 in 1990 and developed marker relapse on surveillance and had chemotherapy using cisplatin and etoposide for four cycles. He developed contralateral seminoma in the testis 13 years later. Another patient had left orchidectomy in 2003 for NSGCT, had adjuvant BEP for two cycles, and developed a contralateral testicular tumor 5 years later, which was also seminoma. As more patients with germ cell tumors are cured with chemotherapy, long-term problems become important. Contralateral testicular tumor is one of them. As it can be very late, many years of continued follow-up examination and patients′ awareness are necessary.

  5. Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line.

    Spriggs, D; Imamura, K; Rodriguez, C; Horiguchi, J; Kufe, D W


    Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production...

  6. Stromal Cell-Derived Factor-1 Promotes Cell Migration, Tumor Growth of Colorectal Metastasis

    Otto Kollmar


    Full Text Available In a mouse model of established extrahepatic colorectal metastasis, we analyzed whether stromal cellderived factor (SDF 1 stimulates tumor cell migration in vitro, angiogenesis, tumor growth in vivo. METHODS: Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis, tumor growth in vivo, green fluorescent protein-transfected CT26.WT cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, tumors were locally exposed to SDF-1. Cell proliferation, tumor microvascularization, growth were studied during a further 9-day period using intravital fluorescence microscopy, histology, immunohistochemistry. Tumors exposed to PBS only served as controls. RESULTS:In vitro, > 30% of unstimulated CT26.WT cells showed expression of the SDF-1 receptor CXCR4. On chemotaxis assay, SDF-1 provoked a dose-dependent increase in cell migration. In vivo, SDF-1 accelerated neovascularization, induced a significant increase in tumor growth. Capillaries of SDF-1-treated tumors showed significant dilation. Of interest, SDF-1 treatment was associated with a significantly increased expression of proliferating cell nuclear antigen, a downregulation of cleaved caspase-3. CONCLUSION: Our study indicates that the CXC chemokine SDF-1 promotes tumor cell migration in vitro, tumor growth of established extrahepatic metastasis in vivo due to angiogenesis-dependent induction of tumor cell proliferation, inhibition of apoptotic cell death.

  7. Promotion of thyroid tumors in rats by pregnenolone-16alpha-carbonitrile (PCN) and polychlorinated biphenyl (PCB).

    Vansell, Nichole R; Muppidi, Jagan R; Habeebu, Sultan M; Klaassen, Curtis D


    Pregnenolone-16alpha-carbonitrile (PCN) and Aroclor 1254 (PCB) both reduce serum thyroid hormone levels in rats, but only PCN consistently produces an increase in serum thyrotropin (TSH). PCN-mediated increases in TSH result in increased thyroid follicular cell proliferation and hyperplasia, which may represent early events on a morphological continuum leading to neoplasia. The purpose of this study was to assess whether PCN, a compound that increases serum TSH, and PCB, which does not increase TSH, promote thyroid tumors in a two-stage carcinogenesis model. Male SD rats were administered the thyroid tumor initiator diisopropanolnitrosamine (2.5 g/kg, sc), and after seven days were fed control diet, diet containing 1000 ppm PCN, or diet containing 100 ppm PCB for 19 weeks. Body weights were unaffected by PCN treatment, but were reduced 21% after 19 weeks of PCB treatment compared to control. PCN treatment significantly reduced serum T4 through week 3 before returning to control concentrations, whereas T4 levels following PCB treatment fell below detection limits by week 3 and remained drastically reduced through week 19. TSH concentrations in PCN-treated rats increased three-fold at week 2, then declined to near control values at week 19. After one week of PCB treatment, TSH concentrations reached nearly twice that of controls, and were sustained until week 6. The incidence of thyroid follicular cell proliferative lesions, including cystic and follicular hyperplasia, cystic and follicular adenoma, and follicular carcinoma, was significantly increased following PCN treatment, but not following PCB treatment. PCB treatment caused an increase in thyroid carcinomas (4 of 22 rats) not associated with the proliferative-type lesions produced by PCN, despite an increase in TSH serum concentrations. In conclusion, PCN appears to promote thyroid tumors in a manner consistent with known effects of excessive TSH stimulation. However, thyroid carcinomas stemming from PCB

  8. Expressional patterns of chaperones in ten human tumor cell lines

    Slavc Irene


    Full Text Available Abstract Background Chaperones (CH play an important role in tumor biology but no systematic work on expressional patterns has been reported so far. The aim of the study was therefore to present an analytical method for the concomitant determination of several CH in human tumor cell lines, to generate expressional patterns in the individual cell lines and to search for tumor and non-tumor cell line specific CH expression. Human tumor cell lines of neuroblastoma, colorectal and adenocarcinoma of the ovary, osteosarcoma, rhabdomyosarcoma, malignant melanoma, lung, cervical and breast cancer, promyelocytic leukaemia were homogenised, proteins were separated on two-dimensional gel electrophoresis with in-gel digestion of proteins and MALDI-TOF/TOF analysis was carried out for the identification of CH. Results A series of CH was identified including the main CH groups as HSP90/HATPas_C, HSP70, Cpn60_TCP1, DnaJ, Thioredoxin, TPR, Pro_isomerase, HSP20, ERP29_C, KE2, Prefoldin, DUF704, BAG, GrpE and DcpS. Conclusions The ten individual tumor cell lines showed different expression patterns, which are important for the design of CH studies in tumor cell lines. The results can serve as a reference map and form the basis of a concomitant determination of CH by a protein chemical rather than an immunochemical method, independent of antibody availability or specificity.

  9. Effect of estrogen and antiestrogen therapy in rats bearing mesenchymal tumors.

    Remedi, M M; Demarchi, M; Hliba, E; Depiante-Depaoli, M


    We applied both hormonal and antiestrogen treatment in female Wistar rats to analyze the estrogen dependence of the growth of sarcomas induced with 9,10-dimethyl-1,2-benzanthracene. Animals bearing tumors of 10 mm in diameter were divided at random into five groups and submitted to different treatments during 24 weeks. The treatment with ovariectomy and tamoxifen in tumor-bearing animals resulted in tumor growth suppression and prolonged survival by a protection against the lethal tumor. On the other hand, the estrogen treatment exerted an adverse effect showing a faster growth of the tumors and a great decrease in survival. In summary, the antiestrogen treatment can have an antitumor effect in mesenchymal tumors, possibly by modifying the immunological status of the host.

  10. Gene expression analysis on small numbers of invasive cells collected by chemotaxis from primary mammary tumors of the mouse

    Segall Jeffrey E


    Full Text Available Abstract Background cDNA microarrays have the potential to identify the genes involved in invasion and metastasis. However, when used with whole tumor tissue, the results average the expression patterns of different cell types. We have combined chemotaxis-based cell collection of the invasive subpopulation of cells within the primary tumor with array-based gene expression analysis to identify the genes necessary for the process of carcinoma cell invasion. Results Invasive cells were collected from live primary tumors using microneedles containing chemotactic growth factors to mimic chemotactic signals thought to be present in the primary tumor. When used with mammary tumors of rats and mice, carcinoma cells and macrophages constitute the invasive cell population. Microbeads conjugated with monoclonal anti-CD11b (Mac-1α antibodies were used to separate macrophages from carcinoma cells. We utilized PCR-based cDNA amplification from small number of cells and compared it to the quality and complexity of conventionally generated cDNA to determine if amplified cDNA could be used with fidelity for array analysis of this cell population. These techniques showed a very high level of correlation indicating that the PCR based amplification technique yields a cDNA population that resembles, with high fidelity, the original template population present in the small number of cells used to prepare the cDNA for use with the chip. Conclusions The specific collection of invasive cells from a primary tumor and the analysis of gene expression in these cells are is now possible. By further comparing the gene expression patterns of cells collected by invasion into microneedles with that of carcinoma cells obtained from the whole primary tumor, the blood, and whole metastatic tumors, genes that contribute to the invasive process in carcinoma cells may be identified.

  11. Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats

    Spielmann, J.; Hanke, J; Knauf, D.; Ben-Eliyahu, S.; Jacobs, R.; Stangl, G. I.; B?hr, I.; Kielstein, H.


    Background Obesity was identified as a major risk factor for malignant diseases, but underlying mechanisms remain unclear. Natural killer (NK) cells, a pivotal aspect of innate immunity, are capable of identifying and killing virally infected and tumor cells. Previous studies have shown altered NK cell functions in obesity, and the current study aimed to investigate the relationship between altered NK cell functions and increased cancer risk in obesity. Methods To induce obesity male F344-rat...

  12. Giant cell tumor of bone and tenosynovial tissue : surgical outcome

    Heijden, Lizz van der


    Giant cell tumor of bone (GCTB) is an intermediate, locally aggressive but rarely metastasizing tumor. Radiologically, GCTB shows typical lytic lesions. MR imaging is required to evaluate extent of GCTB for surgical planning. Preferred treatment for GCTB is extended curettage with local adjuvants, w

  13. Tumor Seeding With Renal Cell Carcinoma After Renal Biopsy

    M.F.B. Andersen; Norus, T.P.


    Tumor seeding following biopsy of renal cell carcinoma is extremely rare with an incidence of 1:10.000. In this paper two cases with multiple recurrent RRC metastasis in the biopsy tract following biopsy of renal tumor is presented and the current literature is shortly discussed.

  14. Arrested puberty associated with a Sertoli-Leydig cell tumor.

    Kelly, A C; Feinman, M A; Husami, N


    Androgen-producing ovarian tumors are rarely recognized as a cause of delayed or arrested puberty, despite their frequent association with secondary amenorrhea in the older patient. A case is discussed of a Sertoli-Leydig cell tumor in an 18-year-old girl resulting in arrest of breast development and primary amenorrhea.

  15. Infantile and adult testicular germ cell tumors : a different pathogenesis?

    van Echten, J; Timmer, A; van der Veen, AY; Molenaar, WM; de Jong, B


    Most adult testicular germ cell tumors have a characteristic chromosomal abnormality that is an isochromosome 12p [i(12p)]. Furthermore. these tumors are characterized by a chromosome number in the triploid range and gains and losses of (parts of) specific chromosomes. Cytogenetic investigation of t

  16. Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting

    Munthe, Sune; Sørensen, Mia D; Thomassen, Mads


    -related genes and the HOX-gene list in migrating cells compared to spheroids. Determination of GBM molecular subtypes revealed that subtypes of spheroids and migrating cells were identical. In conclusion, migrating tumor cells preserve expression of stem cell markers and functional CSC characteristics. Since......Glioblastoma (GBM) is the most frequent and malignant brain tumor with an overall survival of only 14.6 months. Although these tumors are treated with surgery, radiation and chemotherapy, recurrence is inevitable. A critical population of tumor cells in terms of therapy, the so-called cancer stem...... cells (CSCs), has been identified in gliomas and many other cancers. These tumor cells have a stem cell-like phenotype and are suggested to be responsible for tumor growth, chemo- and radio-resistance as well as recurrence. However, functional evidence for migrating glioma cells having a stem cell...

  17. Consensus diagnoses and mode of action for the formation of gastric tumors in rats treated with the chloroacetanilide herbicides alachlor and butachlor.

    Furukawa, Satoshi; Harada, Takanori; Thake, Daryl; Iatropoulos, Michael J; Sherman, James H


    A panel of pathologists (Panel) was formed to evaluate the pathogenesis and human relevance of tumors that developed in the fundic region of rat stomachs in carcinogenicity and mechanistic studies with alachlor and butachlor. The Panel evaluated stomach sections stained with hematoxylin and eosin, neuron-specific enolase, and chromogranin A to determine the presence and relative proportion of enterochromaffin-like (ECL) cells in the tumors and concluded all tumors were derived from ECL cells. Biochemical and pathological data demonstrated the tumor formation involved a nongenotoxic threshold mode of action (MOA) initially characterized by profound atrophy of the glandular fundic mucosa that affected gastric glands, but not surface epithelium. This resulted in a substantial loss of parietal cells and a compensatory mucosal cell proliferation. The loss of parietal cells caused a marked increase in gastric pH (hypochlorhydria), leading to sustained and profound hypergastrinemia. The mucosal atrophy, together with the increased gastrin, stimulated cell growth in one or more ECL cell populations, resulting in neoplasia. ECL cell autocrine and paracrine effects led to dedifferentiation of ECL cell tumors. The Panel concluded the tumors develop via a threshold-dependent nongenotoxic MOA, under conditions not relevant to humans.

  18. Increased IMP dehydrogenase gene expression in solid tumor tissues and tumor cell lines

    Collart, F.R.; Chubb, C.B.; Mirkin, B.L.; Huberman, E.


    IMP dehydrogenase, a regulatory enzyme of guanine nucleotide biosynthesis, may play a role in cell proliferation and malignancy. To assess this possibility, we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts. Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts. Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes. These results are consistent with an association between increased IMP dehydrogenase expression and either enhanced cell proliferation or malignant transformation.

  19. Noninvasive Assessment of Tumor Cell Proliferation in Animal Models

    Matthias Edinger


    Full Text Available Revealing the mechanisms of neoplastic disease and enhancing our ability to intervene in these processes requires an increased understanding of cellular and molecular changes as they occur in intact living animal models. We have begun to address these needs by developing a method of labeling tumor cells through constitutive expression of an optical reporter gene, noninvasively monitoring cellular proliferation in vivo using a sensitive photon detection system. A stable line of HeLa cells that expressed a modified firefly luciferase gene was generated, proliferation of these cells in irradiated severe combined immunodeficiency (SCID mice was monitored. Tumor cells were introduced into animals via subcutaneous, intraperitoneal and intravenous inoculation and whole body images, that revealed tumor location and growth kinetics, were obtained. The number of photons that were emitted from the labeled tumor cells and transmitted through murine tissues was sufficient to detect 1×103 cells in the peritoneal cavity, 1×104 cells at subcutaneous sites and 1×106 circulating cells immediately following injection. The kinetics of cell proliferation, as measured by photon emission, was exponential in the peritoneal cavity and at subcutaneous sites. Intravenous inoculation resulted in detectable colonies of tumor cells in animals receiving more than 1×103 cells. Our demonstrated ability to detect small numbers of tumor cells in living animals noninvasively suggests that therapies designed to treat minimal disease states, as occur early in the disease course and after elimination of the tumor mass, may be monitored using this approach. Moreover, it may be possible to monitor micrometastases and evaluate the molecular steps in the metastatic process. Spatiotemporal analyses of neoplasia will improve the predictability of animal models of human disease as study groups can be followed over time, this method will accelerate development of novel therapeutic

  20. [Possibility of overcoming ACNU resistance in ACNU-resistant sublines of rat brain tumors in vitro by a calmodulin inhibitor].

    Yoshida, T; Shimizu, K; Mogami, H; Sakamoto, Y; Egawa, T


    A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxicity of ACNU in vitro in rat C6 glioma, 9L gliosarcoma and their ACNU-resistant sublines (C6/ACNU and 9L/ACNU). Uptake and retention of ACNU in these cells were studied with [14C]ACNU in the absence or presence of trifluoperazine. The results indicated that intracellular uptake and retention of ACNU in C6 and 9L cells were larger than those in C6/ACNU and 9L/ACNU cells, and that trifluoperazine increased the cellular uptake and retention of ACNU in C6 and 9L, especially in C6/ACNU and 9L/ACNU cells. The amounts of ACNU in C6/ACNU and 9L/ACNU cells reached almost the same level as those detected in C6 and 9L cells. When trifluoperazine were added along with ACNU to the culture in vitro at a concentration of 10 and 20 microM, ACNU resistance was completely overcome. Furthermore, treatment of C6 and C6/ACNU cells with 20 microM trifluoperazine did not change the cellular uptake rate of [14C]AIB (alpha-aminoisobutyric acid), which might indicate that the membrane permeability of the cells was kept intact during the drug treatment. The same phenomenon was observed in 9L and 9L/ACNU cells. It might be concluded that the enhanced effect of cytotoxicity of ACNU in ACNU-resistant rat brain tumor cells presented in this study is presumably due to the increase of intracellular concentration of ACNU resulting from the inhibition of the efflux of ACNU by trifluoperazine from the resistant cells. It was also suggested that ACNU resistance in malignant brain tumors could be overcome by combination chemotherapy with ACNU and calmodulin inhibitors.

  1. Soy isoflavone exposure through all life stages accelerates 17β-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats.

    Möller, Frank Josef; Pemp, Daniela; Soukup, Sebastian T; Wende, Kathleen; Zhang, Xiajie; Zierau, Oliver; Muders, Michael H; Bosland, Maarten C; Kulling, Sabine E; Lehmann, Leane; Vollmer, Günter


    There is an ongoing debate whether the intake of soy-derived isoflavones (sISO) mediates beneficial or adverse effects with regard to breast cancer risk. Therefore, we investigated whether nutritional exposure to a sISO-enriched diet from conception until adulthood impacts on 17β-estradiol (E2)-induced carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats were exposed to dietary sISO from conception until postnatal day 285. Silastic tubes containing E2 were used to induce MG tumorigenesis. Body weight, food intake, and tumor growth were recorded weekly. At necropsy, the number, position, size, and weight of each tumor were determined. Plasma samples underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed rats compared to the control rats. Time-to-tumor onset was shortened from 25 to 20 weeks, and larger tumors developed in the sISO-exposed rats. The histological phenotype of the MG tumors was independent of the sISO diet received, and it included both comedo and cribriform phenotypes. Morphological analyses of the whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the time-to-tumor was significantly shortened.

  2. Rapid induction of orthotopic hepatocellular carcinoma in immune-competent rats by non-invasive ultrasound-guided cells implantation

    Pan Huay-Ben


    Full Text Available Abstract Background The fact that prognoses remain poor in patients with advanced hepatocellular carcinoma highlights the demand for suitable animal models to facilitate the development of anti-cancer medications. This study employed a relatively non-invasive approach to establish an orthotopic hepatocellular carcinoma model in immune-competent rats. This was done by ultrasound-guided implantation of cancer cells and the model was used to evaluate the therapeutic efficacy of short-term and low-dose epirubicin chemotherapy. Methods Rat Novikoff hepatoma cells were injected percutaneously into the liver lobes of Sprague-Dawley rats under the guidance of high resolution ultrasound. The implantation rate and the correlation between dissected and ultrasound-measured tumor sizes were evaluated. A similar induction procedure was performed by means of laparotomy in a different group of rats. Pairs of tumor measurement were compared by ultrasound and computerized tomography scan. Rats with a successful establishment of the tumor were divided into the treatment (7-day low-dose epirubicin group and the control group. The tumor sizes were non-invasively monitored by the same ultrasound machine. Blood and tumor tissues from tumor-bearing rats were examined by biochemical and histological analysis respectively. Results Ultrasound-guided implantation of Novikoff hepatoma cells led to the formation of orthotopic hepatocellular carcinoma in 60.4% (55/91 of the Sprague-Dawley rats. Moreover, tumor sizes measured by ultrasound significantly correlated with those measured by calipers after sacrificing the animals (P Conclusions Ultrasound-guided implantation of Novikoff hepatoma cells is an effective means of establishing orthotopic hepatocellular carcinoma in Sprague-Dawley rats. Short-term and low-dose epirubicin chemotherapy had perturbed tumor progression by inducing apoptosis and neovascularization blockade.

  3. Active immunization to luteinizing hormone releasing hormone to inhibit the induction of mammary tumors in the rat

    Ravdin, P.M.; Jordan, V.C.


    Immunization of female rats with a bovine serum albumin-luteinizing hormone releasing hormone conjugate results in suppression of dimethylbenzanthracene mammary tumor incidence. Tumor incidence was 1.3, and 1.29 tumors per rat in bovine serum albumin alone (n = 10) and unimmunized (n = 18) control groups, but no tumors were found in the bovine serum albumin-luteinizing hormone releasing hormone conjugate immunized animals (n = 10). In a second experiment immunization with bovine serum albumin-luteinizing hormone releasing hormone conjugates reduced tumor incidence to 0.3 tumors per rat (n = 10) from the 1.2 tumors per animal seen in the control animals (n = 10) immunized with bovine serum albumin alone. Bovine serum albumin-luteinizing hormone immunization caused the production of anti-LHRH antibodies, an interruption of estrous cycles, lowered serum estradiol and progesterone levels, and atrophy of the ovaries and uteri. Immunization BSA-hormone conjugates is a novel anti-tumor strategy.

  4. Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis

    Ehrhardt, H.; Wachter, F; Grunert, M.; Jeremias, I


    Resting tumor cells represent a huge challenge during anticancer therapy due to their increased treatment resistance. TNF-related apoptosis-inducing ligand (TRAIL) is a putative future anticancer drug, currently in phases I and II clinical studies. We recently showed that TRAIL is able to target leukemia stem cell surrogates. Here, we tested the ability of TRAIL to target cell cycle-arrested tumor cells. Cell cycle arrest was induced in tumor cell lines and xenografted tumor cells in G0, G1 o...

  5. Androgen - secreting steroid cell tumor of the ovary

    Paras Ratilal Udhreja


    Full Text Available Steroid cell tumors (SCTs, not otherwise specified of the ovary are rare subgroup of sex cord tumors, which account for less than 0.1% of all ovarian tumors and also that will present at any age. The majority of these tumors produce steroids with testosterone being the most common. A case of a 28-year-old woman who presented with symptoms of virilization is reported. Although SCTs are generally benign, there is a risk for malignant transformation. Surgery is the most important and hallmark treatment.

  6. Forcing Tumor Cells to Present Their Own Tumor Antigens to the Immune System: a Necessary Design for an Efficient Tumor Immunotherapy

    RobertE.Humphreys; GildaG.Hillman; EricyonHofe; MinzhenXu


    The general principle for tumor cells to escape from immune surveillance is to prevent tumor antigens from being recognized by the immune system. Many methods have been developed to increase the immunogenecity of the tumor cells. The most efficient methods are able to force tumor cells to present their own tumor antigens to the immune system. Stimulating Th cells by converting tumor cells into MHC class II+/Ii- antigen presenting cells is one of the most efficient technologies. Using antisense methods, we suppress the expression of the Ii protein that normally co-expresses with MHC class II molecules and blocks the antigenic peptide binding site of MHC class II molecules during synthesis in the endoplasmic reticulum. In such tumor cells, the"unprotected" MHC class II molecules pick up endogenous tumor antigenic peptides, which have been transported into the ER for binding to MHC class I molecules. Simultaneous presentation of tumor antigens by both MHC class I and II molecules generates a robust and long-lasting anti-tumor immune response. MHC class II+/Ii- tumor cells are potent tumor cell vaccines and also cure a significant number of animals with renal and prostate tumors. We have developed analogous human gene vectors that are suitable for most patients and cancers.

  7. Forcing Tumor Cells to Present Their Own Tumor Antigens to the Immune System: a Necessary Design for an Efficient Tumor Immunotherapy

    Robert E.Humphreys; Gilda G.Hillman; Eric von Hofe; Minzhen Xu


    The general principle for tumor cells to escape from immune surveillance is to prevent tumor antigens from being recognized by the immune system. Many methods have been developed to increase the immunogenecity of the tumor cells. The most efficient methods are able to force tumor cells to present their own tumor antigens to the immune system. Stimulating Th cells by converting tumor cells into MHC class Ⅱ+/Ii- antigen presenting cells is one of the most efficient technologies. Using antisense methods, we suppress the expression of the Ii protein that normally co-expresses with MHC class Ⅱ molecules and blocks the antigenic peptide binding site of MHC class Ⅱ molecules during synthesis in the endoplasmic reticulum. In such tumor cells, the "unprotected" MHC class Ⅱ molecules pick up endogenous tumor antigenic peptides, which have been transported into the ER for binding to MHC class Ⅰ molecules. Simultaneous presentation of tumor antigens by both MHC class Ⅰ and Ⅱ molecules generates a robust and long-lasting anti-tumor immune response. MHC class Ⅱ+/Ii- tumor cells are potent tumor cell vaccines and also cure a significant number of animals with renal and prostate tumors. We have developed analogous human gene vectors that are suitable for most patients and cancers.

  8. Phenotypic characterization of drug resistance and tumor initiating cancer stem cells from human bone tumor osteosarcoma cell line OS-77

    Yue Zhang


    Full Text Available The cancer stem cell theory suggest that presence of small subpopulation of cancer stem cells are the major implication in the cancer treatment and also responsible for tumor recurrence. Based on Hoechst 33342 dye exclusion technique, we have identified about 3.3% of cancer stem like side population (SP cells from human osteosarcoma OS-77 cell line whose prevalence is significantly reduced to 0.3% after treatment with verapamil. The sphere formation assay revealed that osteosarcoma SP cells are highly capable to form tumor spheres (sarcospheres. Further by immunocytochemistry and RT-PCR, we show that OS-77 SP cells have enhanced expression of stem cell surface markers such as CD44, Nanog and ATP-binding cassette (ABC transporter gene (ABCG2 which contributes to self-renewal and drug resistance, respectively. Our findings help to designing a novel therapeutic drug which could effectively target the cancer stem cells and prevent the tumor relapse.

  9. Functional significance of erythropoietin receptor on tumor cells

    Kodetthoor B Udupa


    Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation of these cells through cell signaling. EpoR antagonist can reduce the growth of the tumor in vivo. In view of our current knowledge of Epo, its recombinant forms and receptor,use of Epo in cancer patients to enhance the recovery of hematocrit after chemotherapy treatment has to be carefully evaluated.

  10. Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model.

    Froidevaux, Sylvie; Eberle, Alex N; Christe, Martine; Sumanovski, Lazar; Heppeler, Axel; Schmitt, Jörg S; Eisenwiener, Klaus; Beglinger, Christoph; Mäcke, Helmut R


    Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTR-expressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes (67)Ga and (68)Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suitable for targeting SSTR-expressing tumors. For this purpose, 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometals (111)In, (90)Y and (67)Ga. They were then evaluated for their performance in the AR4-2J pancreatic tumor model by testing SSTR2-binding affinity, internalization/externalization in isolated cells and biodistribution in tumor-bearing nude mice. Surprisingly, we found that, compared to (111)In or (90)Y, labeling with (67)Ga considerably improved the biologic performance of the tested somatostatin analogs with respect to SSTR2 affinity and tissue distribution. (67)Ga-labeled DOTA-somatostatin analogs were rapidly excreted from nontarget tissues, leading to excellent tumor-to-nontarget tissue uptake ratios. Of interest for radiotherapeutic application, [(67)Ga]DOTATOC was strongly internalized by AR4-2J cells. Furthermore, our results suggest a link between the radioligand charge and its kidney retention. The excellent tumor selectivity of Ga-DOTA somatostatin analogs together with the different applications of Ga in nuclear oncology suggests that Ga-DOTA somatostatin analogs will become an important tool in the management of SSTR-positive tumors.

  11. Dentinogenic Ghost Cell Tumor of the Peripheral Variant Mimicking Epulis

    Uddipan Kumar


    Full Text Available Dentinogenic ghost cell tumor (DGCT is an uncommon locally invasive odontogenic tumor regarded by many as a variant of calcifying odontogenic cyst. The peripheral variant of this clinical rarity appears as a well-circumscribed mass mimicking a nonspecific gingival enlargement. Microscopic appearance of odontogenic epithelium admixed with focal areas of dentinoid formation and sheets of ghost cells giving the definitive diagnosis of dentinogenic ghost cell tumor imply that microscopic examination is compulsory for any gingival mass. Van Gieson histochemical stain further confirmed the nature of dentinoid-like material. A complete workup of a case of peripheral dentinogenic ghost cell tumor is presented in this paper and the current concept as well as the appraisal of literature is presented.

  12. Transcriptional Amplification in Tumor Cells with Elevated c-Myc

    Lin, Charles Y.; Lovén, Jakob; Rahl, Peter B.; Paranal, Ronald M.; Burge, Christopher B.; Bradner, James E.; Lee, Tong Ihn; Young, Richard A.


    Summary Elevated expression of the c-Myc transcription factor occurs frequently in human cancers and is associated with tumor aggression and poor clinical outcome. The effect of high levels of c-Myc on global gene regulation is poorly understood, but is widely thought to involve newly activated or repressed “Myc target genes”. We report here that in tumor cells expressing high levels of c-Myc, the transcription factor accumulates in the promoter regions of active genes and causes transcriptional amplification, producing increased levels of transcripts within the cell's gene expression program. Thus, rather than binding and regulating a new set of genes, c-Myc amplifies the output of the existing gene expression program. These results provide an explanation for the diverse effects of oncogenic c-Myc on gene expression in different tumor cells and suggest that transcriptional amplification reduces rate-limiting constraints for tumor cell growth and proliferation. PMID:23021215

  13. General Information about Childhood Extracranial Germ Cell Tumors

    ... tumors include the following: Having certain genetic syndromes : Klinefelter syndrome may increase the risk of germ cell ... and procedures may be used: Physical exam and history : An exam of the body to check general ...

  14. Treatment Options for Childhood Extracranial Germ Cell Tumors

    ... tumors include the following: Having certain genetic syndromes : Klinefelter syndrome may increase the risk of germ cell ... and procedures may be used: Physical exam and history : An exam of the body to check general ...

  15. Perivascular epithelioid cell tumor of the liver coexisting with a gastrointestinal stromal tumor

    Paiva, Carlos Eduardo; Moraes Neto, Francisco Alves; Agaimy, Abbas


    Approximately 10% of patients with gastrointestinal stromal tumors (GIST) develop other neoplasms, either synchronously or metachronously. In this report we describe coexistence of a gastrointestinal stromal tumor and a hepatic perivascular epithelioid cell tumor (PEComa) in a 51-year-old woman...... with no evidence of tuberous sclerosis. A subcapsular hepatic nodule (0.8 cm in diameter) was found during surgery for symptomatic gastric neoplasm (15 cm in diameter) arising from the lesser curvature. Both tumors revealed histomorphological and immunohistochemical features confirming a diagnosis of a small...... incidental hepatic PEComa and a high risky extramural gastric GIST, respectively. The patient remained disease-free 25 mo after surgery with no evidence of tumor recurrence or new neoplasms. To our knowledge, this is the first report of PEComa in a patient with GIST. Hepatic lesions detected synchronously...

  16. Sphere-forming tumor cells possess stem-like properties in human fibrosarcoma primary tumors and cell lines



    Fibrosarcoma is a malignant soft tissue tumor of mesenchymal origin. Despite advances in medical and surgical treatment, patient survival rates have remained poor. According to the cancer stem cell hypothesis, tumors are comprised of heterogeneous cell populations that have different roles in tumor formation and growth. Cancer stem cells are a small cell subpopulation that exhibits stem-like properties to gain aggressiveness and recurrence. These cells have been identified in a variety of cancerous tumors, but not in human fibrosarcoma. In this study, we observed that HT1080 cells and primary fibrosarcoma cells formed spheres and showed higher self-renewal capacity, invasiveness and drug resistance compared with their adherent counterparts. Moreover, we demonstrated that the cells showed higher expression of the embryonic stem cell-related genes Nanog, Oct3/4, Sox2, Sox10 and their encoding proteins, as well as greater tumorigenic capacity in nude mice. In conclusion, our data suggest the presence of a stem-like cell population in human fibrosarcoma tumors, which provides more evidence for the cancer stem cell hypothesis and assistance in designing new therapeutic strategies against human fibrosarcoma. PMID:23205129

  17. Immune control of tumors by antigen presentation improvement.

    Remedi, María Mónica; Bonacci, Gustavo; Vides, Miguel Angel; Donadio, Ana Carolina


    Tumor cells cannot activate T lymphocytes, since they do not usually express major histocompatibility complex (MHC) class II molecules. Thus, tumor antigens can only be presented indirectly to T cells through professional antigen-presenting cells (APC). In our laboratory, we have treated a tumor cell line (Tu1-A) - derived from an induced rat mammary sarcoma - in order to increase the expression of MHC class I and class II molecules. In our tumor model, the transference of these induced cells into normal rats generated a tumor mass that exhibited a lower tumor growth rate and an earlier regression as compared to those observed in rats inoculated with wild-type Tu1-A cells. This earlier tumor regression was associated with the development of an antigen-specific immune response. 85-87% of the rats in both groups rejected the tumor and were alive at day 60 after tumor cell inoculation. However, in rats treated with wild-type cells the rejection was delayed and took place after tumor ulceration. Rats that had rejected tumors were rechallenged with wild-type cells in order to assay the presence of a long-lived antitumor immunity. All the animals were resistant to the second tumor challenge. We conclude that the development of a specific immune response could be achieved by the superexpression of MHC molecules on tumor cells or when tumor ulceration promotes APC to take up necrotic cells and tumor antigens are presented to T lymphocytes.

  18. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

    Bennewith, Kevin L.; Huang, Xin; Ham, Christine M.; Graves, Edward E.; Erler, Janine T.; Kambham, Neeraja; Feazell, Jonathan; Yang, George P.; Koong, Albert


    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted subcutaneously. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by PET imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed co-localization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer. PMID:19179545

  19. Antiapoptotic factor humanin is expressed in normal and tumoral pituitary cells and protects them from TNF-α-induced apoptosis.

    María Florencia Gottardo

    Full Text Available Humanin (HN is a 24-amino acid peptide with cytoprotective action in several cell types such as neurons and testicular germ cells. Rattin (HNr, a homologous peptide of HN expressed in several adult rat tissues, also has antiapoptotic action. In the present work, we demonstrated by immunocytochemical analysis and flow cytometry the expression of HNr in the anterior pituitary of female and male adult rats as well as in pituitary tumor GH3 cells. HNr was localized in lactotropes and somatotropes. The expression of HNr was lower in females than in males, and was inhibited by estrogens in pituitary cells from both ovariectomized female and orquidectomized male rats. However, the expression of HNr in pituitary tumor cells was not regulated by estrogens. We also evaluated HN action on the proapoptotic effect of TNF-α in anterior pituitary cells assessed by the TUNEL method. HN (0.5 µM per se did not modify basal apoptosis of anterior pituitary cells but completely blocked the proapoptotic effect of TNF-α in total anterior pituitary cells, lactotropes and somatotropes from both female and male rats [corrected]. Also, HN inhibited the apoptotic effect of TNF-α on pituitary tumor cells. In summary, our results demonstrate that HNr is present in the anterior pituitary gland, its expression showing sexual dimorphism, which suggests that gonadal steroids may be involved in the regulation of HNr expression in this gland. Antiapoptotic action of HN in anterior pituitary cells suggests that this peptide could be involved in the homeostasis of this gland. HNr is present and functional in GH3 cells, but it lacks regulation by estrogens, suggesting that HN could participate in the pathogenesis of pituitary tumors.

  20. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy.

    Spranger, Stefani; Dai, Daisy; Horton, Brendan; Gajewski, Thomas F


    Effector T cells have the capability of recognizing and killing cancer cells. However, whether tumors can become immune resistant through exclusion of effector T cells from the tumor microenvironment is not known. By using a tumor model resembling non-T cell-inflamed human tumors, we assessed whether adoptive T cell transfer might overcome failed spontaneous priming. Flow cytometric assays combined with intra-vital imaging indicated failed trafficking of effector T cells into tumors. Mechanistically, this was due to the absence of CXCL9/10, which we found to be produced by CD103(+) dendritic cells (DCs) in T cell-inflamed tumors. Our data indicate that lack of CD103(+) DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumorcell response, contributing to immune escape. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Training stem cells for treatment of malignant brain tumors

    Shengwen; Calvin; Li; Mustafa; H; Kabeer; Long; T; Vu; Vic; Keschrumrus; Hong; Zhen; Yin; Brent; A; Dethlefs; Jiang; F; Zhong; John; H; Weiss; William; G; Loudon


    The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for pa-tients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution(i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system.

  2. Localized tenosynovial giant cell tumor in both knee joints

    Kim, Hyun Su [Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Seoul (Korea); Kwon, Jong Won [Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Seoul (Korea); Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea); Ahn, Jin Hwan; Chang, Moon Jong [Sungkyunkwan University School of Medicine, Department of Orthopedic Surgery, Samsung Medical Center, Seoul (Korea); Cho, Eun Yoon [Sungkyunkwan University School of Medicine, Department of Pathology, Samsung Medical Center, Seoul (Korea)


    Tenosynovial giant cell tumor, previously called pigmented villonodular synovitis (PVNS), is a rare benign neoplastic process that may involve the synovium of the joint. The disorder is usually monoarticular and only a few cases have been reported on polyarticular involvement. Herein, we present a case of localized intra-articular tenosynovial giant cell tumor in a 29-year-old man involving both knee joints with a description of the MR imaging and histological findings. (orig.)

  3. Caffeine activates tumor suppressor PTEN in sarcoma cells

    Miwa, Shinji; Sugimoto, Naotoshi; Shirai, Toshiharu; Hayashi, Katsuhiro; Nishida, Hideji; Ohnari, Issei; Takeuchi, Akihiko; Yachie, Akihiro; Tsuchiya, Hiroyuki


    The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Akt activation exerts a strong anti-apoptotic effect and inhibits key pro-apoptotic proteins. We investigated the effect of caffeine in the prevention of tumor cell proliferation and induction of cell death. We found that caffeine induced increased intracellular cAMP levels, PTEN activation and Akt inactivation, which to...

  4. Mediastinal germ cell tumors: a radiologic-pathologic review

    Drevelegas, A. [Dept. of Radiology, Aristoteles Univ., Thessaloniki (Greece); Palladas, P. [Dept. of Radiology, G. Papanicolaou Hospital, Thessaloniki (Greece); Scordalaki, A. [Dept. of Pathology, G. Papanicolaou Hospital, Thessaloniki (Greece)


    Germ cell tumors of the mediastinum are histologically identical to those found in the testes and ovaries. Early diagnosis and treatment improve the survival rate. Imaging studies of teratoma demonstrate a rounded, often lobulated heterogeneous mass containing soft tissue elements with fluid and fat attenuation. Calcification is present in 20-43% of cases. Seminomas are large masses of homogeneous soft tissue attenuation. Malignant nonseminomatous germ cell tumors are heterogeneous tumors with irregular borders due to invasion of adjacent structures. CT shows the location and extent of the tumors as well as intrinsic elements including soft tissue, fat, fluid, and calcification. CT is the modality of choice for the diagnostic evaluation of these tumors. MRI reveals masses of heterogeneous signal intensity, is more sensitive in depicting infiltration of the adjacent structures by fat plane obliteration, and is performed as an ancillary study. (orig.)

  5. Improved Methods to Generate Spheroid Cultures from Tumor Cells, Tumor Cells & Fibroblasts or Tumor-Fragments: Microenvironment, Microvesicles and MiRNA.

    Zheng Lao

    Full Text Available Diagnostic and prognostic indicators are key components to achieve the goal of personalized cancer therapy. Two distinct approaches to this goal include predicting response by genetic analysis and direct testing of possible therapies using cultures derived from biopsy specimens. Optimally, the latter method requires a rapid assessment, but growing xenograft tumors or developing patient-derived cell lines can involve a great deal of time and expense. Furthermore, tumor cells have much different responses when grown in 2D versus 3D tissue environments. Using a modification of existing methods, we show that it is possible to make tumor-fragment (TF spheroids in only 2-3 days. TF spheroids appear to closely model characteristics of the original tumor and may be used to assess critical therapy-modulating features of the microenvironment such as hypoxia. A similar method allows the reproducible development of spheroids from mixed tumor cells and fibroblasts (mixed-cell spheroids. Prior literature reports have shown highly variable development and properties of mixed-cell spheroids and this has hampered the detailed study of how individual tumor-cell components interact. In this study, we illustrate this approach and describe similarities and differences using two tumor models (U87 glioma and SQ20B squamous-cell carcinoma with supporting data from additional cell lines. We show that U87 and SQ20B spheroids predict a key microenvironmental factor in tumors (hypoxia and that SQ20B cells and spheroids generate similar numbers of microvesicles. We also present pilot data for miRNA expression under conditions of cells, tumors, and TF spheroids.

  6. Pc 4 photodynamic therapy of U87 (human glioma) orthotopic tumor in nude rat brain

    Dean, David; George, John E., III; Ahmad, Yusra; Wolfe, Michael S.; Lilge, Lothar; Morris, Rachel L.; Peterson, Allyn; Lust, W. D.; Totonchi, Ali; Varghai, Davood; Li, Xiaolin; Hoppel, Charles L.; Sun, Jiayang; Oleinick, Nancy L.


    Introduction: Photodynamic therapy (PDT) for Barrett"s esophagus, advanced esophageal cancer, and both early and late inoperable lung carcinoma is now FDA-approved using the first generation photosensitizer PhotofrinTM (Axcan Pharma, Birmingham, AL). Photofrin-mediated PDT of glioma is now in Phase III clinical trials. A variety of second generation photosensitizers have been developed to provide improved: (1) specificity for the target tissue, (2) tumoricidal capability, and (3) rapid clearance the vascular compartment, skin, and eyes. The phthalocyanine Pc 4 is a second generation photosensitizer that is in early phase I clinical trials for skin cancer. We have undertaken a preclinical study that seeks to determine if Pc 4-mediated PDT can be of benefit for the intra-operative localization and treatment of glioma. Methods: Using a stereotactic frame, 250,000 U87 cells were injected via Hamilton syringe through a craniotomy, and the dura, 1-2 mm below the cortical surface of nude (athymic) rat brains (N=91). The craniotomy was filled with a piece of surgical PVC and the scalp closed. After two weeks of tumor growth, the animals received 0.5 mg/kg Pc 4 via tail vein injection. One day later the scalp was re-incised, and the PVC removed. The tumor was then illuminated with either 5 or 30 Joule/cm2 of 672-nm light from a diode laser at 50 mW/cm2. The animals were sacrificed one day later and the brain was cold-perfused with formaldehyde. Two thirds of the explanted brains are now being histologically surveyed for necrosis after staining with hematoxylin and eosin and for apoptosis via immunohistochemistry (i.e., TUNEL assay). The other third were analyzed by HPLC-mass spectrometry for the presence of drug in tumor, normal brain, and plasma at sacrifice. Initial histological results show PDT-induced apoptosis and necrosis confined to the growing (live) portion of the tumor. Preliminary analysis shows an average selectivity of Pc 4 uptake in the bulk tumor to be 3

  7. Active targeting of tumor cells using light emitting bacteria

    Moon, Sung Min; Min, Jung Joon; Hong, Yeong Jin; Kim, Hyun Ju; Le, Uuenchi N.; Rhee, Joon Haeng; Song, Ho Chun; Heo, Young Jun; Bom, Hee Seung; Choy, Hyon E [School of Medicine, Chonnam National University, Gwangju (Korea, Republic of)


    The presence of bacteria and viruses in human tumors has been recognized for more than 50 years. Today, with the discovery of bacterial strains that specifically target tumors, and aided by genomic sequencing and genetic engineering, there is new interest in the use of bacteria as tumor vectors. Here, we show that bacteria injected intravenously into live animals entered and replicated in solid tumors and metastases using the novel imaging technology of biophotonics. Bioluminescence operon (LuxCDABE) or fluorescence protein, GFP) has been cloned into pUC19 plasmid to engineer pUC19lux or pUC19gfp. Engineered plasmid was transformed into different kinds of wild type (MG1655) or mutant E. coli (DH5, ppGpp, fnr, purE, crpA, flagella, etc.) strains to construct light emitting bacteria. Xenograft tumor model has been established using CT26 colon cancer cell line. Light emitting bacteria was injected via tail vein into tumor bearing mouse. In vivo bioluminescence imaging has been done after 20 min to 14 days of bacterial injection. We observed localization of tumors by light-emitting E. coli in tumor (CT-26) bearing mice. We confirmed the presence of light-emitting bacteria under the fluorescence microscope with E. coli expressing GFP. Althoug varying mutants strain with deficient invading function has been found in tumor tissues, mutant strains of movement (flagella) couldn't show any light signal from the tumor tissue under the cooled CCD camera, indicating bacteria may actively target the tumor cells. Based on their 'tumor-finding' nature, bacteria may be designed to carry multiple genes or drugs for detection and treatment of cancer, such as prodrug-converting enzymes, toxins, angiogenesis inhibitors and cytokines.

  8. Primitive neuroectodermal tumor in a mixed germ cell tumor - A rare case report

    Khushboo Dewan


    Full Text Available A rare case of testicular tumor in a 20-year-old male with Primitive Neuroectodermal Tumor (PNET was reported. Imaging studies showed a large heterogenous mass in the right scrotal sac and a large retroperitoneal mass with metastasis in the lung and liver. Serum alpha fetoprotein (AFP was markedly elevated with moderate increase in serum β-human chorionic gonadotropin (hCG levels. After orchidectomy, a histological diagnosis of mixed germ cell tumor-teratoma with primitive neuroectodermal, embryonal, and yolk sac components was made. Some scattered embryoid bodies representative of primitive germ cell tumor were also present. Morphological diversity including PNET prompted the authors to report this case as PNET points toward a poor prognosis.

  9. Folic acid supplementation promotes mammary tumor progression in a rat model.

    Deghan Manshadi, Shaidah; Ishiguro, Lisa; Sohn, Kyoung-Jin; Medline, Alan; Renlund, Richard; Croxford, Ruth; Kim, Young-In


    Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression

  10. Chemical sympathectomy increases neutrophil-to-lymphocyte ratio in tumor-bearing rats but does not influence cancer progression.

    Horvathova, Lubica; Tillinger, Andrej; Sivakova, Ivana; Mikova, Lucia; Mravec, Boris; Bucova, Maria


    The sympathetic nervous system regulates many immune functions and modulates the anti-tumor immune defense response, too. Therefore, we studied the effect of 6-hydroxydopamine induced sympathectomy on selected hematological parameters and inflammatory markers in rats with Yoshida AH130 ascites hepatoma. We found that chemically sympathectomized tumor-bearing rats had significantly increased neutrophil-to-lymphocyte ratio, leukocyte-to-lymphocyte ratio, and plasma levels of tumor necrosis factor alpha. Although our findings showed that sympathetic denervation in tumor-bearing rats led to increased neutrophil-to-lymphocyte ratio, that is an indicator of the disease progression, we found no significant changes in tumor growth and survival of sympathectomized tumor-bearing rats.

  11. Klinefelter Syndrome with Poor Risk Extragonadal Germ Cell Tumor

    Jeremy A. Konheim


    Full Text Available Germ cell tumors are the most common malignancy in men aged 15-35 years old, with a small percentage presenting in an extragonadal location. These tumors are seldom identified in the gastrointestinal tract. There is increased risk of extragonadal germ cell tumors (EGCT in men with Klinefelter syndrome (KS. We report a rare case of a 37-year-old male with KS and EGCT discovered in the duodenum and pelvis. After treatment with Bleomycin-Etoposide-Cisplatin (BEP, he developed growing teratoma syndrome (GTS and myelodysplasia. Despite surgical excision of the pelvic growing teratoma, he unfortunately died secondary to complications of severe bone marrow suppression.

  12. Klinefelter Syndrome with Poor Risk Extragonadal Germ Cell Tumor.

    Konheim, Jeremy A; Israel, Jonathan A; Delacroix, Scott E


    Germ cell tumors are the most common malignancy in men aged 15-35 years old, with a small percentage presenting in an extragonadal location. These tumors are seldom identified in the gastrointestinal tract. There is increased risk of extragonadal germ cell tumors (EGCT) in men with Klinefelter syndrome (KS). We report a rare case of a 37-year-old male with KS and EGCT discovered in the duodenum and pelvis. After treatment with Bleomycin-Etoposide-Cisplatin (BEP), he developed growing teratoma syndrome (GTS) and myelodysplasia. Despite surgical excision of the pelvic growing teratoma, he unfortunately died secondary to complications of severe bone marrow suppression.

  13. Myeloperoxidase and crystalline bodies in the granules of DMBA-induced rat chloroma cells.

    Ioachim, H L; Keller, S; Sabbath, M; Andersson, B; Dorsett, B; Essner, E


    Chloroma (chloroleukemia) was induced in a splenectomized rat by repeatedly administering dimethylbenz(a)anthracene (DMBA) and was serially transplanted thereafter. Composed of immature myeloid cells, the tumor imparted a green discoloration to the tissues that it infiltrated extensively. Chloroma cells fluoresced red in ultraviolet light, produced a characteristic curve in spectrophotometry, and contained large amounts of myeloperoxidase. They included numerous intracytoplasmic granules of both types A and B, which contained occasional crystalline bars. Permanent lines of chloroma cells were established in tissue culture. These cells, while maintaining their initial morphology, ceased producing myeloperoxidase and subsequently induced white tumors when they were isotransplanted.

  14. DNA Analysis in Samples From Younger Patients With Germ Cell Tumors and Their Parents or Siblings


    Childhood Malignant Ovarian Germ Cell Tumor; Childhood Malignant Testicular Germ Cell Tumor; Ovarian Choriocarcinoma; Ovarian Embryonal Carcinoma; Ovarian Mixed Germ Cell Tumor; Ovarian Teratoma; Ovarian Yolk Sac Tumor; Testicular Choriocarcinoma; Testicular Embryonal Carcinoma; Testicular Seminoma; Testicular Teratoma; Testicular Yolk Sac Tumor

  15. Review of juxtaglomerular cell tumor with focus on pathobiological aspect

    Pan Chin-Chen


    Full Text Available Abstract Juxtaglomerular cell tumor (JGCT generally affects adolescents and young adults. The patients experience symptoms related to hypertension and hypokalemia due to renin-secretion by the tumor. Grossly, the tumor is well circumscribed with fibrous capsule and the cut surface shows yellow or gray-tan color with frequent hemorrhage. Histologically, the tumor is composed of monotonous polygonal cells with entrapped normal tubules. Immunohistochemically, tumor cells exhibit a positive reactivity for renin, vimentin and CD34. Ultrastructurally, neoplastic cells contain rhomboid-shaped renin protogranules. Genetically, losses of chromosomes 9 and 11 were frequently observed. Clinically, the majority of tumors showed a benign course, but rare tumors with vascular invasion or metastasis were reported. JGCT is a curable cause of hypertensive disease if it is discovered early and surgically removed, but may cause a fatal outcome usually by a cerebrovascular attack or may cause fetal demise in pregnancy. Additionally, pathologists and urologists need to recognize that this neoplasm in most cases pursues a benign course, but aggressive forms may develop in some cases.

  16. Altered expression of glycosaminoglycans in metastatic 13762NF rat mammary adenocarcinoma cells

    Steck, P.A.; Cheong, P.H.; Nakajima, M.; Yung, W.K.A.; Moser, R.P.; Nicolson, G.L.


    A difference in the expression and metabolism of (/sup 35/S)sulfated glycosaminoglycans between rat mammary tumor cells derived from a primary tumor and those from its metastatic lesions has been observed. Cells from the primary tumor possessed about equal quantities of chondroitin sulfate and heparan sulfate on their cell surfaces but released fourfold more chondroitin sulfate than heparan sulfate into their medium. In contrast, cells from distal metastatic lesions expressed approximately 5 times more heparan sulfate than chondroitin sulfate in both medium and cell surface fractions. This was observed to be the result of differential synthesis of the glycosaminoglycans and not of major structural alterations of the individual glycosaminoglycans. The degree of sulfation and size of heparan sulfate were similar for all cells examined. However, chondroitin sulfate, observed to be only chondroitin 4-sulfate, from the metastases-derived cells had a smaller average molecular weight on gel filtration chromatography and showed a decreased quantity of sulfated disaccharides upon degradation with chondroitin ABC lyase compared to the primary tumor derived cells. Major qualitative or quantitative alterations were not observed for hyaluronic acid among the various 13762NF cells. The metabolism of newly synthesized sulfated glycosaminoglycans was also different between cells from primary tumor and metastases. A pulse-chase kinetics study demonstrated that both heparan sulfate and chondroitin sulfate were degraded by the metastases-derived cells, whereas the primary tumor derived cells degraded only heparan sulfate and degraded it at a slower rate. These results suggested that altered glycosaminoglycan expression and metabolism may be associated with the metastatic process in 13762NF rat mammary tumor cells.

  17. Cell jamming: Collective invasion of mesenchymal tumor cells imposed by tissue confinement

    Haeger, A.; Krause, M.; Wolf, K. van der; Friedl, P.


    BACKGROUND: Cancer invasion is a multi-step process which coordinates interactions between tumor cells with mechanotransduction towards the surrounding matrix, resulting in distinct cancer invasion strategies. Defined by context, mesenchymal tumors, including melanoma and fibrosarcoma, develop eithe

  18. Starved and asphyxiated: how can CD8+T cells within a tumor microenvironment prevent tumor progression

    Ying eZhang


    Full Text Available Although cancer immunotherapy has achieved significant breakthroughs in recent years, its overall efficacy remains limited in the majority of patients. One major barrier is exhaustion of tumor antigen (TA-specific CD8+ tumor-infiltrating lymphocytes (TILs, which conventionally has been attributed to persistent stimulation with antigen within the tumor microenvironment (TME. A series of recent studies have highlighted that the TME poses significant metabolic challenges to TILs, which may contribute to their functional exhaustion. Hypoxia increases the expression of co-inhibitors on activated CD8+T cells, which in general reduces the T cells’ effector functions. It also impairs the cells’ ability to gain energy through oxidative phosphorylation (OXPHOS. Glucose limitation increases expression of programmed cell death protein (PD-1 and reduces functions of activated CD8+T cells. A combination of hypoxia and hypoglycemia, as is common in solid tumors, places CD8+TILs at dual metabolic jeopardy by affecting both major pathways of energy production. Recently, a number of studies addressed the effects of metabolic stress on modulating CD8+T cell metabolism, differentiation and functions. Here we discuss recent findings on how different types of metabolic stress within the TME shape the tumor-killing capacity of CD8+T cells. We propose that manipulating the metabolism of TILs to more efficiently utilize nutrients especially during intermittent periods of hypoxia could maximize their performance, prolong their survival and improve the efficacy of active cancer immunotherapy.

  19. Tumor senescence and radioresistant tumor-initiating cells (TICs): let sleeping dogs lie!

    Zafarana, Gaetano; Bristow, Robert G


    Preclinical data from cell lines and experimental tumors support the concept that breast cancer-derived tumor-initiating cells (TICs) are relatively resistant to ionizing radiation and chemotherapy. This could be a major determinant of tumor recurrence following treatment. Increased clonogenic survival is observed in CD24-/low/CD44+ TICs derived from mammosphere cultures and is associated with (a) reduced production of reactive oxygen species, (b) attenuated activation of γH2AX and CHK2-p53 DNA damage signaling pathways, (c) reduced propensity for ionizing radiation-induced apoptosis, and (d) altered DNA double-strand or DNA single-strand break repair. However, recent data have shed further light on TIC radioresistance as irradiated TICs are resistant to tumor cell senescence following DNA damage. Taken together, the cumulative data support a model in which DNA damage signaling and repair pathways are altered in TICs and lead to an altered mode of cell death with unique consequences for long-term clonogen survival. The study of TIC senescence lays the foundation for future experiments in isogenic models designed to directly test the capacity for senescence and local control (that is, not solely local regression) and spontaneous metastases following treatment in vivo. The study also supports the targeting of tumor cell senescence pathways to increase TIC clonogen kill if the targeting also maintains the therapeutic ratio.

  20. Acute effect of lactic acid on tumor-endothelial cell metabolic coupling in the tumor microenvironment

    Zhu, Guanqun; Wang, Degui; Li, Shenqian; Yang, Xuecheng; Cao, Yanwei; Wang, Yonghua; Niu, Haitao


    The present study aimed to systematically analyze alterations in the expression of mitochondrial-associated proteins in human bladder cancer T24 cells co-cultured with tumor-associated human umbilical vein endothelial cells (HUVECs), and to investigate the characteristics of bladder cancer cell energy metabolism. The present study used the following techniques: A co-culture system of T24 cells and HUVECs was constructed using a microfluidic chip as a 3D co-culture system; the concentration of lactic acid in the medium of the cells was determined using an automatic microplate reader; a qualitative analysis of mitochondria-associated protein expression was performed by immunofluorescent staining; and a quantitative analysis of mitochondrial-associated protein expression was conducted using western blotting. The present results revealed that between the control groups (monoculture of T24 cells or HUVECs), the mitochondrial-associated protein fluorescence intensity was increased in the HUVECs compared with the T24 cells. The fluorescence intensity of mitochondrial-associated proteins in the HUVEC control group was increased compared with the HUVECs in the experimental co-culture group. In the T24 cells, the protein fluorescence intensity was increased in the experimental co-culture group compared with the control group. In addition, the expression of mitochondria-associated proteins was increased in HUVECs compared with T24 cells in the control groups, while T24 cells in the experimental co-culture group had an increased expression compared with HUVECs in the experimental group (P<0.05). For T24 cells, the expression of mitochondrial-associated proteins was increased in the experimental group compared with the control group, and contrasting results were observed for the HUVECs (P<0.05). Determination of lactic acid concentration demonstrated that lactic acid concentration was highest in the experimental co-culture group, followed by the T24 control group and the HUVEC

  1. An implantable rat liver tumor model for experimental transarterial chemoembolization therapy and its imaging features

    Xin Li; Chuan-Sheng Zheng; Gan-Sheng Feng; Chen-Kai Zhuo; Jun-Gong Zhao; Xi Liu


    AIM: To establish an ideal implantable rat liver tumor model for interventional therapy study and examine its angiographic signs and MRI, CT features before and after embolization. METHODS: Forty male Wistar rats were implanted with Walker256 tumor in the left lateral lobe of liver. Digital subtraction angiography (DSA) and transarterial chemoembolization were performed on day 14 after implantation. Native computer tomography (CT, n=8) and native magnetic resonance (MR,n=40) were performed between the day 8 and day 21 after implantation. The radiological morphological characteristics were correlated with histological findings.RESULTS: Successful implantation was achieved in all forty rats, which was confirmed by CT and MRI. MR allowed tumor visualization from day 8 while CT from day 11 after implantation. The tumors were hypodensity on CT, hypointense on MR T1-weighted and hyperintense on T2-weighted. The model closely resembled human hepatocardnoma in growth pattem and the lesions were rich in vasculature on angiography and got its filling mainly from the hepatic artery. Before therapy, tumor size was 211.9±48.7 mm3. No ascites, satellite liver nodules or lung metastasis were found. One week after therapy, tumor size was 963.6±214.8 mm3 in the control group and 356.5±78.4mm3 in TACE group. Ascites (4/40), satellite liver nodules (7/40) or lung metastasis (3/40) could be seen on day 21.CONCLUSION: Walker-256 tumor rat model is suitable for the interventional experiment. CT and MRI are helpful in animal optioning and evaluating experimental results.

  2. Distribution and differentiation of mesenchymal stem cells in tumor tissue

    ZHAO Hai-feng; CHEN Jun; XU Zhi-shun; ZHANG Ke-qin


    Background Tumor has an ability to become enriched in mesenchymal stem cells (MSCs) and of guiding MSCs to migrate to tumor tissue. But there are lack of relevant reports on the distribution and differentiation of MSCs in tumor tissue and the effect on tumor growth after MSCs engrafted in tumor tissue. In this study, we observed the distribution of bone marrow MSCs in tumor tissue and the possibility of MSCs differentiating into myofibroblast under the induction of local tumor microenvironment.Methods Twenty-four New Zealand rabbits were randomly classified into the control group and the test group. MSCs were isolated and cultured for each animal, vx-2 tumor tissue was transplanted under the bladder mucosa of each animal. One week after the transplantation, the self F2 passage MSCs marked by 4',6-diamidino-2-phenylindole were transplanted into tumor tissue in the test group while only Dulbecco's modified Eagle's medium-low glucose was infused into the control group. Ultrasonography was performed for each animal 1,2, 3 and 4 week(s) after the vx-2 tumor mass was transplanted. The maximum bladder tumor diameter of each animal was recorded and the mean value of each group was calculated. One animal from each group was sacrificed in the third week and the remaining animals in the fourth week to observe the tumor development. Another animal treated the same as the test group was sacrificed to observe the distribution of MSCs in tumor tissue one week after self MSCs transplantation. Immunofluorescence was used to trace MSCs in tumor tissue. The double labeling immunofluorescence for α-smooth muscle actin (α-SMA) and vimentin was performed to identify whether the MSCs can differentiate into myofibroblast.Results The ultrasonography showed no tumor mass one week after the vx-2 tumor mass transplantation. The mean maximum tumor diameter of the control group and test group was (0.70±0.14) cm and (0.78±0.14) cm, respectively, and there was no significant difference (t=1

  3. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth

    Roland El Ghazal


    Full Text Available In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1 in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4–deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.

  4. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.

    El Ghazal, Roland; Yin, Xin; Johns, Scott C; Swanson, Lee; Macal, Monica; Ghosh, Pradipta; Zuniga, Elina I; Fuster, Mark M


    In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4-deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.

  5. Tumor-derived death receptor 6 modulates dendritic cell development.

    DeRosa, David C; Ryan, Paul J; Okragly, Angela; Witcher, Derrick R; Benschop, Robert J


    Studies in murine models of cancer as well as in cancer patients have demonstrated that the immune response to cancer is often compromised. This paradigm is viewed as one of the major mechanisms of tumor escape. Many therapies focus on employing the professional antigen presenting dendritic cells (DC) as a strategy to overcome immune inhibition in cancer patients. Death receptor 6 (DR6) is an orphan member of the tumor necrosis factor receptor superfamily (TNFRSF21). It is overexpressed on many tumor cells and DR6(-/-) mice display altered immunity. We investigated whether DR6 plays a role in tumorigenesis by negatively affecting the generation of anti-tumor activity. We show that DR6 is uniquely cleaved from the cell surface of tumor cell lines by the membrane-associated matrix metalloproteinase (MMP)-14, which is often overexpressed on tumor cells and is associated with malignancy. We also demonstrate that >50% of monocytes differentiating into DC die when the extracellular domain of DR6 is present. In addition, DR6 affects the cell surface phenotype of the resulting immature DC and changes their cytokine production upon stimulation with LPS/IFN-gamma. The effects of DR6 are mostly amended when these immature DC are matured with IL-1beta/TNF-alpha, as measured by cell surface phenotype and their ability to present antigen. These results implicate MMP-14 and DR6 as a mechanism tumor cells can employ to actively escape detection by the immune system by affecting the generation of antigen presenting cells.

  6. Functional EpoR pathway utilization is not detected in primary tumor cells isolated from human breast, non-small cell lung, colorectal, and ovarian tumor tissues.

    Scott D Patterson

    Full Text Available Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1 were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot. Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues.

  7. Selenium prevents tumor development in a rat model for chemical carcinogenesis

    Bjorkhem-Bergman, L.; Torndal, U. B.; Eken, S.


    Previous studies in animals and humans have shown that selenium compounds can prevent cancer development. In this work we studied the tumor preventive effect of selenium supplementation, administrated as selenite, in the initiation, promotion and progression phases in a synchronized rat model for...

  8. Laminin from rat yolk sac tumor: isolation, partial characterization, and comparison with mouse laminin

    Engvall, E; Krusius, T; Wewer, U


    Laminin was isolated from a rat yolk sac tumor by salt extraction, gel filtration, and affinity chromatography on heparin-Sepharose. The purified laminin gave two polypeptide chains with approximate Mr of 200,000 and 400,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its amino...

  9. D-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB.

    Rengarajan, Thamaraiselvan; Nandakumar, Natarajan; Rajendran, Peramaiyan; Ganesh, Mohanraj Karthik; Balasubramanian, Maruthaiveeran Periyasamy; Nishigaki, Ikuo


    Breast cancer is the most prevalent malignant neoplasm in the world, and chemoprevention through dietary intervention strategy is an emerging option to reduce the incidence. D-pinitol (DP), a major component of soya bean, possesses attractive biological actions. We have investigated whether D-pinitol have an effect on tumor growth in vivo against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis and investigated its mechanism of action. Tumors were induced in Sprague-Dawley (SD) rats by a gastric dose of 20 mg/kg DMBA, and after 13 weeks of induction period, the rats were orally administered with D-pinitol for 45 days. At the end of the assay, animals in carcinogen control group prompted a tumor incidence of 100 % and developed a tumor volume of 8.35 ± 0.56, which was significantly reduced to 5.74 ± 0.32 for the animals treated with D-pinitol. The D-pinitol treatment not only decreased the tumor volume but also further examination revealed that tumors from animals that received D-pinitol reduced nuclear factor kappa B (NF-κB) activation which in turn results in modulation of its downstreaming p53 and proteins of caspase-3 family. Bcl-2 expression and caspase-3 activation were also decreased after D-pinitol supplementation leading to induction of apoptosis and finally cell death. Furthermore, the status of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and tumor markers, lipid profile, and hormones was also significantly declined up on D-pinitol administration. Thus, it reveals the collective involvement of the above-mentioned parameters along with NF-κB signaling through which D-pinitol induces apoptosis and subsequently suppresses breast cancer during DMBA-induced rat breast carcinogenesis.

  10. Microfluidic cell isolation technology for drug testing of single tumor cells and their clusters

    Bithi, Swastika S.; Vanapalli, Siva A.


    Drug assays with patient-derived cells such as circulating tumor cells requires manipulating small sample volumes without loss of rare disease-causing cells. Here, we report an effective technology for isolating and analyzing individual tumor cells and their clusters from minute sample volumes using an optimized microfluidic device integrated with pipettes. The method involves using hand pipetting to create an array of cell-laden nanoliter-sized droplets immobilized in a microfluidic device without loss of tumor cells during the pipetting process. Using this technology, we demonstrate single-cell analysis of tumor cell response to the chemotherapy drug doxorubicin. We find that even though individual tumor cells display diverse uptake profiles of the drug, the onset of apoptosis is determined by accumulation of a critical intracellular concentration of doxorubicin. Experiments with clusters of tumor cells compartmentalized in microfluidic drops reveal that cells within a cluster have higher viability than their single-cell counterparts when exposed to doxorubicin. This result suggests that circulating tumor cell clusters might be able to better survive chemotherapy drug treatment. Our technology is a promising tool for understanding tumor cell-drug interactions in patient-derived samples including rare cells. PMID:28150812

  11. Translational research in ovarian carcinoma : cell biological aspects of drug resistance and tumor aggressiveness

    Zee, Ate Gerard Jan van der


    In this thesis diverse cell biological features that in cultured (ovarian) tumor cells have been linked to drug resistance and/or tumor aggressiveness are studied in tumor specimens of epithelial ovarian carcinomas.

  12. T and NK cells: two sides of tumor immunoevasion.

    Fruci, Doriana; Lo Monaco, Elisa; Cifaldi, Loredana; Locatelli, Franco; Tremante, Elisa; Benevolo, Maria; Giacomini, Patrizio


    Natural Killer (NK) cells are known to reject several experimental murine tumors, but their antineoplastic activity in humans is not generally agreed upon, as exemplified by an interesting correspondence recently appeared in Cancer Research. In the present commentary, we join the discussion and bring to the attention of the readers of the Journal of Translational Medicine a set of recent, related reports. These studies demonstrate that effectors of the adaptive and innate immunity need to actively cooperate in order to reject tumors and, conversely, tumors protect themselves by dampening both T and NK cell responses. The recently reported ability of indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) expressed by melanoma cells to down-regulate activating NK receptors is yet another piece of evidence supporting combined and highly effective T/NK cell disabling. Major Histocompatibility Complex class I (MHC-I) molecules, including Human Leukocyte Antigen E (HLA-E), represent another class of shared activating/inhibitory ligands. Ongoing clinical trials with small molecules interfering with IDO and PGE2 may be exploiting an immune bonus to control cancer. Conversely, failure to simultaneously engage effectors of both the innate and the adaptive immunity may contribute to explain the limited clinical efficacy of T cell-only vaccination trials. Shared (T/NK cells) natural immunosuppressants and activating/inhibitory ligands expressed by tumor cells may provide mechanistic insight into impaired gathering and function of immune effectors at the tumor site.

  13. HAMLET interacts with histones and chromatin in tumor cell nuclei.

    Düringer, Caroline; Hamiche, Ali; Gustafsson, Lotta; Kimura, Hiroshi; Svanborg, Catharina


    HAMLET is a folding variant of human alpha-lactalbumin in an active complex with oleic acid. HAMLET selectively enters tumor cells, accumulates in their nuclei and induces apoptosis-like cell death. This study examined the interactions of HAMLET with nuclear constituents and identified histones as targets. HAMLET was found to bind histone H3 strongly and to lesser extent histones H4 and H2B. The specificity of these interactions was confirmed using BIAcore technology and chromatin assembly assays. In vivo in tumor cells, HAMLET co-localized with histones and perturbed the chromatin structure; HAMLET was found associated with chromatin in an insoluble nuclear fraction resistant to salt extraction. In vitro, HAMLET bound strongly to histones and impaired their deposition on DNA. We conclude that HAMLET interacts with histones and chromatin in tumor cell nuclei and propose that this interaction locks the cells into the death pathway by irreversibly disrupting chromatin organization.

  14. Chemotherapeutic (cyclophosphamide) effects on rat breast tumor hemodynamics monitored by multi-channel NIRS

    Kim, Jae G.; Zhao, Dawen; Mason, Ralph P.; Liu, Hanli


    We previously suggested that the two time constants quantified from the increase of tumor oxyhemoglobin concentration, ▵ [HbO2], during hyperoxic gas intervention are associated with two blood flow/perfusion rates in well perfused and poorly perfused regions of tumors. In this study, our hypothesis is that when cancer therapy is applied to a tumor, changes in blood perfusion will occur and be detected by the NIRS. For experiments, systemic chemotherapy, cyclophosphamide (CTX), was applied to two groups of rats bearing syngeneic 13762NF mammary adenocarcinomas: one group received a single high dose i. p. (200 mg/kg CTX) and the other group continuous low doses (20 mg/kg CTX i. p. for 10 days). Time courses of changes in tumor ▵ [HbO2] were measured at four different locations on the breast tumors non-invasively with an inhaled gas sequence of air-oxygen-air before and after CTX administration. Both rat body weight and tumor volume decreased after administration of high dose CTX, but continuous low doses showed decrease of tumor volume only. Baselines (without any therapy) intra- and inter-tumor heterogeneity of vascular oxygenation during oxygen inhalation were similar to our previous observations. After CTX treatment, significant changes in vascular hemodynamic response to oxygen inhalation were observed from both groups. By fitting the increase of ▵ [HbO2] during oxygen inhalation, we have obtained changes of vascular structure ratio and also of perfusion rate ratio before and after chemotherapy. The preliminary results suggest that cyclophosphamide has greatest effect on the well perfused tumor vasculature. Overall, our study supports our earlier hypothesis, proving that the effects of chemotherapy in tumor may be monitored non-invasively by using NIRS to detect changes of hemodynamics induced with respiratory challenges.

  15. High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney

    Kerstin Stemmer


    Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens or partially resistant (DIOres to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1, interleukin (IL-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3 and mammalian target of rapamycin (mTOR phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.

  16. Local hyperthermia treatment of tumors induces CD8+ T cell-mediated resistance against distal and secondary tumors

    Zhang, Peisheng; Chen, Lei; Baird, Jason R.; Demidenko, Eugene; Turk, Mary Jo; Hoopes, P. Jack; Conejo-Garcia, Jose R.; Fiering, Steven


    Combinatorial use of iron oxide nanoparticles (IONPs) and an alternating magnetic filed (AMF) can induce local hyperthermia in tumors in a controlled and uniform manner. Heating B16 primary tumors at 43°C for 30 minutes activated dendritic cells (DCs) and subsequently CD8+ T cells in the draining lymph node (dLN) and conferred resistance against rechallenge with B16 (but not unrelated Lewis Lung carcinoma) given 7 days post hyperthermia on both the primary tumor side and the contralateral side in a CD8+ T cell-dependent manner. Mice with heated primary tumors also resisted rechallenge given 30 days post hyperthermia. Mice with larger heated primary tumors had greater resistance to secondary tumors. No rechallenge resistance occurred when tumors were heated at 45°C. Our results demonstrate the promising potential of local hyperthermia treatment applied to identified tumors in inducing anti-tumor immune responses that reduce the risk of recurrence and metastasis. PMID:24566274

  17. Extensive FDG uptake and its modification with corticosteroid in a granuloma rat model: an experimental study for differentiating granuloma from tumors

    Zhao, Songji; Takei, Toshiki; Zhao, Yan; Tamaki, Nagara [Graduate School of Medicine, Hokkaido University, Department of Nuclear Medicine, Sapporo (Japan); Kuge, Yuji [Graduate School of Medicine, Hokkaido University, Department of Molecular Imaging, Sapporo (Japan); Graduate School of Pharmaceutical Sciences, Kyoto University, Department of Patho-functional Bioanalysis, Kyoto (Japan); Kohanawa, Masashi [Graduate School of Medicine, Hokkaido University, Department of Microbiology, Sapporo (Japan); Takahashi, Toshiyuki [Hokkaido Gastroenterology Hospital, Department of Pathology, Sapporo (Japan); Kawashima, Hidekazu; Temma, Takashi [Graduate School of Pharmaceutical Sciences, Kyoto University, Department of Patho-functional Bioanalysis, Kyoto (Japan); Seki, Koh-ichi [Hokkaido University, Central Institute of Isotope Science, Sapporo (Japan)


    Increased {sup 18}F-fluorodeoxyglucose (FDG) uptake in inflammatory lesions, particularly in granulomatous inflammation (e.g., sarcoidosis), makes it difficult to differentiate malignant tumors from benign lesions and is the main source of false-positive FDG-PET findings in oncology. Here, we developed a rat granuloma model and examined FDG uptake in the granuloma. The effects of corticosteroid on FDG uptake in the granuloma were compared with those in a malignant tumor. Rats were inoculated with Mycobacterium bovis bacillus Calmette-Guerin (BCG) or allogenic hepatoma cells, and subdivided into control and pretreated (methylprednisolone acetate, 8 mg/kg i.m.) groups. Radioactivity in tissues was determined 1 h after the FDG injection. FDG-PET was performed in rats bearing BCG granulomas or tumors before and after prednisolone treatment. Mature epithelioid cell granuloma-formation and massive lymphocyte-infiltration were observed in the control group of granuloma, histologically similar to sarcoidosis. The mean FDG uptake in the granuloma was comparable to that in the hepatoma. Prednisolone reduced epithelioid cell granuloma-formation and lymphocyte-infiltration. Prednisolone significantly decreased the level of FDG uptake in the granuloma (52% of control), but not in the hepatoma. The FDG uptake levels in the granulomas and tumors were clearly imaged with PET. We developed an intramuscular granuloma rat model that showed a high FDG uptake comparable to that of the tumor. The effect of prednisolone pretreatment on FDG uptake was greater in the granuloma than in the tumor. These results suggest that BCG-induced granuloma may be a valuable model and may provide a biological basis for FDG studies. (orig.)

  18. Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells.

    Henrich, Frederik C; Singer, Katrin; Poller, Kerstin; Bernhardt, Luise; Strobl, Carolin D; Limm, Katharina; Ritter, Axel P; Gottfried, Eva; Völkl, Simon; Jacobs, Benedikt; Peter, Katrin; Mougiakakos, Dimitrios; Dettmer, Katja; Oefner, Peter J; Bosserhoff, Anja-Katrin; Kreutz, Marina P; Aigner, Michael; Mackensen, Andreas


    The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5'-deoxy-5'-methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTA-catabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death. Conversely, if MTA is added to highly activated T cells, MTA exerts cytotoxic effects on T cells. We identified the Akt pathway, a critical signal pathway for T cell activation, as a target of MTA, while, for example, p38 remained unaffected. Next, we provide evidence that MTA exerts its immunosuppressive effects by interfering with protein methylation in T cells. To confirm the relevance of the suppressive effects of exogenously added MTA on human T cells, we used an MTAP-deficient tumor cell-line that was stably transfected with the MTAP-coding sequence. We observed that T cells stimulated with MTAP-transfected tumor cells revealed a higher proliferative capacity compared to T cells stimulated with Mock-transfected cells. In conclusion, our findings reveal a novel immune evasion strategy of human tumor cells that could be of interest for therapeutic targeting.

  19. The evaluation of non-enzymatic antioxidants effects in limiting tumor- associated oxidative stress, in a tumor rat model.

    Grigorescu, R; Gruia, M I; Nacea, V; Nitu, C; Negoita, V; Glavan, D


    Active oxygen species are produced as a consequence of normal aerobic metabolism. Of these, free radicals are usually metabolized or inactivated in vivo by a team of antioxidants. Individual members are a trained team fighting antioxidants to prevent the generation of ROS, destroy or oxidizing potential of capture. In terms of physiological oxidative stress, induced tissue attack is minimal. A relative or absolute deficiency in the antioxidant defense may lead to increased oxidative stress and this event is associated with both the causes and consequences of diseases and cancer, included here. The aim of the study is to identify the role of antioxidant defense systems and the reduction of oxidative stress in dynamic growth and development of malignant tumors. Our in vivo study was developed and referred to carcinosarcoma carriers Wistar rats treated with non-enzymatic antioxidants: vitamin C, vitamin A, zinc salt (II), and arginine in various combinations. Treatment was initiated three weeks before tumor induction.

  20. Alvocidib and Oxaliplatin With or Without Fluorouracil and Leucovorin Calcium in Treating Patients With Relapsed or Refractory Germ Cell Tumors


    Recurrent Extragonadal Seminoma; Recurrent Malignant Extragonadal Germ Cell Tumor; Recurrent Malignant Extragonadal Non-Seminomatous Germ Cell Tumor; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage III Testicular Cancer; Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Seminoma; Stage IV Ovarian Germ Cell Tumor

  1. Tumor radio-sensitivity assessment by means of volume data and magnetic resonance indices measured on prostate tumor bearing rats.

    Belfatto, Antonella; White, Derek A; Mason, Ralph P; Zhang, Zhang; Stojadinovic, Strahinja; Baroni, Guido; Cerveri, Pietro


    Radiation therapy is one of the most common treatments in the fight against prostate cancer, since it is used to control the tumor (early stages), to slow its progression, and even to control pain (metastasis). Although many factors (e.g., tumor oxygenation) are known to influence treatment efficacy, radiotherapy doses and fractionation schedules are often prescribed according to the principle "one-fits-all," with little personalization. Therefore, the authors aim at predicting the outcome of radiation therapy a priori starting from morphologic and functional information to move a step forward in the treatment customization. The authors propose a two-step protocol to predict the effects of radiation therapy on individual basis. First, one macroscopic mathematical model of tumor evolution was trained on tumor volume progression, measured by caliper, of eighteen Dunning R3327-AT1 bearing rats. Nine rats inhaled 100% O2 during irradiation (oxy), while the others were allowed to breathe air. Second, a supervised learning of the weight and biases of two feedforward neural networks was performed to predict the radio-sensitivity (target) from the initial volume and oxygenation-related information (inputs) for each rat group (air and oxygen breathing). To this purpose, four MRI-based indices related to blood and tissue oxygenation were computed, namely, the variation of signal intensity ΔSI in interleaved blood oxygen level dependent and tissue oxygen level dependent (IBT) sequences as well as changes in longitudinal ΔR1 and transverse ΔR2(*) relaxation rates. An inverse correlation of the radio-sensitivity parameter, assessed by the model, was found with respect the ΔR2(*) (-0.65) for the oxy group. A further subdivision according to positive and negative values of ΔR2(*) showed a larger average radio-sensitivity for the oxy rats with ΔR2(*)<0 and a significant difference in the two distributions (p < 0.05). Finally, a leave-one-out procedure yielded a radio

  2. Myoepithelial cells: Current perspectives in salivary gland tumors

    C Pramod Redder


    Full Text Available Myoepithelial cells are normal constituent of the salivary acini and smaller ducts, and are found between the epithelial cells and the basement membrane. Microscopic examination shows that myoepithelial cells are thin and spindle-shaped and situated between the basement membrane and epithelial cells. Ultrastructurally they possess a number of cytoplasmic processes that extend between and over the acinar and ductal-lining cells. They display features of both smooth muscle and epithelium, such as numerous microfilaments with focal densities in the cytoplasmic processes, and desmosomes which attach the myoepithelial to the epithelial cells. Neoplastic myoepithelial cells in both benign and malignant tumors can take several forms, including epithelioid, spindle, plasmacytoid, and clear, and this variability largely accounts for difficulties in histopathological diagnosis. This review article highlights the role of myoepithelial cells in salivary gland tumors.

  3. Hsp60 is actively secreted by human tumor cells.

    Anna M Merendino

    Full Text Available BACKGROUND: Hsp60, a Group I mitochondrial chaperonin, is classically considered an intracellular chaperone with residence in the mitochondria; nonetheless, in the last few years it has been found extracellularly as well as in the cell membrane. Important questions remain pertaining to extracellular Hsp60 such as how generalized is its occurrence outside cells, what are its extracellular functions and the translocation mechanisms that transport the chaperone outside of the cell. These questions are particularly relevant for cancer biology since it is believed that extracellular chaperones, like Hsp70, may play an active role in tumor growth and dissemination. METHODOLOGY/PRINCIPAL FINDINGS: Since cancer cells may undergo necrosis and apoptosis, it could be possible that extracellular Hsps are chiefly the result of cell destruction but not the product of an active, physiological process. In this work, we studied three tumor cells lines and found that they all release Hsp60 into the culture media by an active mechanism independently of cell death. Biochemical analyses of one of the cell lines revealed that Hsp60 secretion was significantly reduced, by inhibitors of exosomes and lipid rafts. CONCLUSIONS/SIGNIFICANCE: Our data suggest that Hsp60 release is the result of an active secretion mechanism and, since extracellular release of the chaperone was demonstrated in all tumor cell lines investigated, our observations most likely reflect a general physiological phenomenon, occurring in many tumors.

  4. Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI.

    Feng Chen

    Full Text Available A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA. As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1 Zd6126 (Zd; 2 Thalidomide (Tha; 3 Zd in combination with Tha (ZdTha; and 4 controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs and plasma stromal cell-derived factor-1α (SDF-1α were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.

  5. Primary cerebellar extramedullary myeloid cell tumor mimicking oligodendroglioma.

    Ho, D M; Wong, T T; Guo, W Y; Chang, K P; Yen, S H


    Extramedullary myeloid cell tumors (EMCTs) are tumors consisting of immature cells of the myeloid series that occur outside the bone marrow. Most of them are associated with acute myelogenous leukemia or other myeloproliferative disorders, and a small number occur as primary lesions, i.e., are not associated with hematological disorders. Occurrence inside the cranium is rare, and there has been only one case of primary EMCT involving the cerebellum reported in the literature. The case we report here is a blastic EMCT occurring in the cerebellum of a 3-year-old boy who had no signs of leukemia or any hematological disorder throughout the entire course. The cerebellar tumor was at first misdiagnosed as an "oligodendroglioma" because of the uniformity and "fried egg" artifact of the tumor cells. The tumor disappeared during chemotherapy consisting of 12 treatments. However, it recurred and metastasized to the cerebrospinal fluid (CSF) shortly after the therapy was completed. A diagnosis of EMCT was suspected because of the presence of immature myeloid cells in the CSF, and was confirmed by anti-myeloperoxidase and anti-lysozyme immunoreactivity of the cerebellar tumor. The patient succumbed 1 year and 3 months after the first presentation of the disease.

  6. Advances in Research on Circulating Tumor Cells in Lung Cancer

    Yingjian SONG


    Full Text Available Metastatic and recurrent tumors have been identified as the leading attribute to the lung cancer deaths. Cancer research has demonstrated the critical role circulating tumor cells (CTCs play in the metastatic spread of carcinomas and the recurrence of lung cancer. The rapid advancement of technology in targeted therapy resolves the embarrassing situation for those late-stage patients whose tumor tissues cannot be obtained. CTCs, as a substitute for the tumor tissues, represent a decisive tool to the cancer treatment strategy. Thus, CTCs exert a fundamental role in the early detection of micro-metastasis, assisting in diagnosis, prognosis and monitoring of the recurrent tumors, and subsequently choosing an individualized approach for the therapeutic treatment. This article will review the advances, which have been made in the research area of CTCs with the aid of its applications in cancer therapy.

  7. Ability of cell-sized beads bearing tumor cell membrane proteins to stimulate LAK cells to secrete interferon-gamma and tumor necrosis factor-alpha.

    Chong, A S; Pinkard, J K; Lam, K S; Scuderi, P; Hersh, E M; Grimes, W J


    We recently reported that lymphokine activated killer (LAK) cells were stimulated to release both interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) when stimulated by a variety of tumor cells. We proposed then that the released cytokines may play a role in mediating tumor cell regression in vivo. In this paper, we provide further information on the nature of the signals, provided by the tumor cells (K562 erythroleukemia), that stimulate LAK cells to secrete IFN-gamma and TNF-alpha. Using a previously published protocol for coating tumor-membrane molecules onto cell-sized hydrophobic beads (also called pseudocytes), we demonstrate that the signal provided by the tumor cell is membrane associated. Beads coated with K562 membranes stimulated LAK cells to release IFN-gamma and TNF-alpha. The pretreatment of these beads with trypsin and sodium periodate eliminated the ability of these pseudocytes to stimulate cytokine release in LAK cells. The glycoproteins that stimulate LAK cells to secrete IFN-gamma and TNF-alpha were further enriched by their ability to bind concanavalin A (Con A, Jack Bean). To determine if the tumor-associated molecules that stimulate LAK cells to release IFN-gamma and TNF-alpha are also the molecules involved in mediating tumor cell lysis, we tested the ability of the Con A binding and nonbinding proteins to inhibit the LAK cell-mediated lysis of K562 cells. Our results demonstrate that molecules that inhibited LAK cell-mediated cytotoxicity were not enriched by Con A. These results are therefore consistent with the conclusion that different sets of tumor-associated molecules are involved in the stimulation of LAK cells to secrete cytokine and in the induction of LAK cells to mediate tumor cell cytolysis.

  8. Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation - implications for cancer therapies.

    Frey, B; Rubner, Y; Wunderlich, R; Weiss, E-M; Pockley, A G; Fietkau, R; Gaipl, U S


    Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.

  9. Effects of charged particles on human tumor cells

    Kathryn D Held


    Full Text Available The use of charged particle therapy in cancer treatment is growing rapidly, in large part because the exquisite dose localization of charged particles allows for higher radiation doses to be given to tumor tissue while normal tissues are exposed to lower doses and decreased volumes of normal tissues are irradiated. In addition, charged particles heavier than protons have substantial potential clinical advantages because of their additional biological effects including greater cell killing effectiveness, decreased radiation resistance of hypoxic cells in tumors and reduced cell cycle dependence of radiation response. These biological advantages depend on many factors such as endpoint, cell or tissue type, dose, dose rate or fractionation, charged particle type and energy, and oxygen concentration. This review summarizes the unique biological advantages of charged particle therapy and highlights recent research and areas of particular research needs, such as quantification of Relative Biological Effectiveness (RBE for various tumor types and radiation qualities, role of genetic background of tumor cells in determining response to charged particles, sensitivity of cancer stem-like cells to charged particles, role of charged particles in tumors with hypoxic fractions and importance of fractionation, including use of hypofractionation, with charged particles.

  10. HAMLET binding to α-actinin facilitates tumor cell detachment.

    Trulsson, Maria; Yu, Hao; Gisselsson, Lennart; Chao, Yinxia; Urbano, Alexander; Aits, Sonja; Mossberg, Ann-Kristin; Svanborg, Catharina


    Cell adhesion is tightly regulated by specific molecular interactions and detachment from the extracellular matrix modifies proliferation and survival. HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is a protein-lipid complex with tumoricidal activity that also triggers tumor cell detachment in vitro and in vivo, suggesting that molecular interactions defining detachment are perturbed in cancer cells. To identify such interactions, cell membrane extracts were used in Far-western blots and HAMLET was shown to bind α-actinins; major F-actin cross-linking proteins and focal adhesion constituents. Synthetic peptide mapping revealed that HAMLET binds to the N-terminal actin-binding domain as well as the integrin-binding domain of α-actinin-4. By co-immunoprecipitation of extracts from HAMLET-treated cancer cells, an interaction with α-actinin-1 and -4 was observed. Inhibition of α-actinin-1 and α-actinin-4 expression by siRNA transfection increased detachment, while α-actinin-4-GFP over-expression significantly delayed rounding up and detachment of tumor cells in response to HAMLET. In response to HAMLET, adherent tumor cells rounded up and detached, suggesting a loss of the actin cytoskeletal organization. These changes were accompanied by a reduction in β1 integrin staining and a decrease in FAK and ERK1/2 phosphorylation, consistent with a disruption of integrin-dependent cell adhesion signaling. Detachment per se did not increase cell death during the 22 hour experimental period, regardless of α-actinin-4 and α-actinin-1 expression levels but adherent cells with low α-actinin levels showed increased death in response to HAMLET. The results suggest that the interaction between HAMLET and α-actinins promotes tumor cell detachment. As α-actinins also associate with signaling molecules, cytoplasmic domains of transmembrane receptors and ion channels, additional α-actinin-dependent mechanisms are discussed.

  11. Antitumor Cell-Complex Vaccines Employing Genetically Modified Tumor Cells and Fibroblasts

    Antonio Miguel


    Full Text Available The present study evaluates the immune response mediated by vaccination with cell complexes composed of irradiated B16 tumor cells and mouse fibroblasts genetically modified to produce GM-CSF. The animals were vaccinated with free B16 cells or cell complexes. We employed two gene plasmid constructions: one high producer (pMok and a low producer (p2F. Tumor transplant was performed by injection of B16 tumor cells. Plasma levels of total IgG and its subtypes were measured by ELISA. Tumor volumes were measured and survival curves were obtained. The study resulted in a cell complex vaccine able to stimulate the immune system to produce specific anti-tumor membrane proteins (TMP IgG. In the groups vaccinated with cells transfected with the low producer plasmid, IgG production was higher when we used free B16 cell rather than cell complexes. Nonspecific autoimmune response caused by cell complex was not greater than that induced by the tumor cells alone. Groups vaccinated with B16 transfected with low producer plasmid reached a tumor growth delay of 92% (p ≤ 0.01. When vaccinated with cell complex, the best group was that transfected with high producer plasmid, reaching a tumor growth inhibition of 56% (p ≤ 0.05. Significant survival (40% was only observed in the groups vaccinated with free transfected B16 cells.

  12. Genomic Analysis of Immune Cell Infiltrates Across 11 Tumor Types.

    Iglesia, Michael D; Parker, Joel S; Hoadley, Katherine A; Serody, Jonathan S; Perou, Charles M; Vincent, Benjamin G


    Immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors. The precise makeup and prognostic relevance of immune infiltrates across a broad spectrum of tumors remain unclear. Using mRNA sequencing data from The Cancer Genome Atlas (TCGA) from 11 tumor types representing 3485 tumors, we evaluated lymphocyte and macrophage gene expression by tissue type and by genomic subtypes defined within and across tumor tissue of origin (Cox proportional hazards, Pearson correlation). We investigated clonal diversity of B-cell infiltrates through calculating B-cell receptor (BCR) repertoire sequence diversity. All statistical tests were two-sided. High expression of T-cell and B-cell signatures predicted improved overall survival across many tumor types including breast, lung, and melanoma (breast CD8_T_Cells hazard ratio [HR] = 0.36, 95% confidence interval [CI] = 0.16 to 0.81, P = .01; lung adenocarcinoma B_Cell_60gene HR = 0.71, 95% CI = 0.58 to 0.87, P = 7.80E-04; melanoma LCK HR = 0.86, 95% CI = 0.79 to 0.94, P = 6.75E-04). Macrophage signatures predicted worse survival in GBM, as did B-cell signatures in renal tumors (Glioblastoma Multiforme [GBM]: macrophages HR = 1.62, 95% CI = 1.17 to 2.26, P = .004; renal: B_Cell_60gene HR = 1.17, 95% CI = 1.04 to 1.32, P = .009). BCR diversity was associated with survival beyond gene segment expression in melanoma (HR = 2.67, 95% CI = 1.32 to 5.40, P = .02) and renal cell carcinoma (HR = 0.36, 95% CI = 0.15 to 0.87, P = .006). These data support existing studies suggesting that in diverse tissue types, heterogeneous immune infiltrates are present and typically portend an improved prognosis. In some tumor types, BCR diversity was also associated with survival. Quantitative genomic signatures of immune cells warrant further testing as prognostic markers and potential biomarkers of response to cancer immunotherapy.

  13. Wilms’ Tumor Blastemal Stem Cells Dedifferentiate to Propagate the Tumor Bulk

    Rachel Shukrun


    Full Text Available An open question remains in cancer stem cell (CSC biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms’ tumor (WT, composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1+ aldehyde dehydrogenase 1-positive (ALDH1+ CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1+ WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.

  14. Molecular aspects of tumor cell migration and invasion

    Giuseppina Bozzuto


    Full Text Available Cell migration and invasion are crucial steps in many physiological events. However, they are also implicated in the physiopathology of many diseases, such as cancer. To spread through the tissues, tumor cells use mechanisms that involve several molecular actors: adhesion receptor families, receptor tyrosine kinases, cytoskeleton proteins, adapter and signalling proteins interplay in a complex scenario. The balance of cellular signals for proliferation and survival responses also regulates migratory behaviours of tumor cells. To complicate the scene of crime drug resistance players can interfere thus worsening this delicate situation. The complete understanding of this molecular jungle is an impossible mission: some molecular aspects are reviewed in this paper.

  15. Tumor metabolism: cancer cells give and take lactate.

    Semenza, Gregg L


    Tumors contain well-oxygenated (aerobic) and poorly oxygenated (hypoxic) regions, which were thought to utilize glucose for oxidative and glycolytic metabolism, respectively. In this issue of the JCI, Sonveaux et al. show that human cancer cells cultured under hypoxic conditions convert glucose to lactate and extrude it, whereas aerobic cancer cells take up lactate via monocarboxylate transporter 1 (MCT1) and utilize it for oxidative phosphorylation (see the related article beginning on page 3930). When MCT1 is inhibited, aerobic cancer cells take up glucose rather than lactate, and hypoxic cancer cells die due to glucose deprivation. Treatment of tumor-bearing mice with an inhibitor of MCT1 retarded tumor growth. MCT1 expression was detected exclusively in nonhypoxic regions of human cancer biopsy samples, and in combination, these data suggest that MCT1 inhibition holds potential as a novel cancer therapy.

  16. Cytomorphology of Circulating Colorectal Tumor Cells: A Small Case Series

    Dena Marrinucci


    Full Text Available Several methodologies exist to enumerate circulating tumor cells (CTCs from the blood of cancer patients; however, most methodologies lack high-resolution imaging, and thus, little is known about the cytomorphologic features of these cells. In this study of metastatic colorectal cancer patients, we used immunofluorescent staining with fiber-optic array scanning technology to identify CTCs, with subsequent Wright-Giemsa and Papanicolau staining. The CTCs were compared to the corresponding primary and metastatic tumors. The colorectal CTCs showed marked intrapatient pleomorphism. In comparison to the corresponding tissue biopsies, cells from all sites showed similar pleomorphism, demonstrating that colorectal CTCs retain the pleomorphism present in regions of solid growth. They also often retain particular cytomorphologic features present in the patient's primary and/or metastatic tumor tissue. This study provides an initial analysis of the cytomorphologic features of circulating colon cancer cells, providing a foundation for further investigation into the significance and metastatic potential of CTCs.

  17. Apoptosis induced by norcantharidin in human tumor cells

    Zhen Xiao Sun; Qing Wen Ma; Tian De Zhao; Yu Lin Wei; Guang Sheng Wang; Jia Shi Li


    @@INTRODUCTION The antitumor activity of norcantharidin (NCTD),the demethylated analogue of cantharidin, was studied in the early 1980s in China. NCTD has no side effects on urinary organs which cantharidin has shown and is easier to synthesize, and it can inhibit the proliferation of several tumor cell lines as well as transplanted tumors. Clinical trials with NCTD as a monotherapeutic agent indicated that NCTD had beneficial effects in patients with different kinds of digestive tract cancers, such as primary hepatoma,carcinomas of esophagus and gastric cancer, but no depressive effect on bone marrow cells. NCTD can increase the white blood cell count by stimulating the bone marrow and has some antagonistic effect against leukopenia caused by other agents. The exact cellular and molecular mechanisms of NCTD on tumor cells have not yet been elucidated to date[1-3].

  18. Testicular germ cell tumors: Molecular genetic and clinicomorphological aspects

    M. V. Nemtsova


    Full Text Available Testicular tumors are the most common form of solid cancer in young men. According to the 2004 WHO classification, testicular germ cell tumors (TGCT may present with different histological types. Embryonic cells of varying grade may be a source of TGCT and the occurrence of this type of tumors is directly related to the formation of a pool of male sex cells and gametogenesis. The paper gives information on mo- lecular stages for the process of formation of male sex cells in health, as well as ways of their impairments leading to TGCT. An investigation of the profiles of gene expression and the spectrum of molecular damages revealed genes responsible for a predisposition to the sporadic and hereditary forms of TGCT. The paper presents the current molecular genetic and clinicomorphological characteristics of TGCT. 

  19. Testicular germ cell tumors: Molecular genetic and clinicomorphological aspects

    M. V. Nemtsova


    Full Text Available Testicular tumors are the most common form of solid cancer in young men. According to the 2004 WHO classification, testicular germ cell tumors (TGCT may present with different histological types. Embryonic cells of varying grade may be a source of TGCT and the occurrence of this type of tumors is directly related to the formation of a pool of male sex cells and gametogenesis. The paper gives information on mo- lecular stages for the process of formation of male sex cells in health, as well as ways of their impairments leading to TGCT. An investigation of the profiles of gene expression and the spectrum of molecular damages revealed genes responsible for a predisposition to the sporadic and hereditary forms of TGCT. The paper presents the current molecular genetic and clinicomorphological characteristics of TGCT. 

  20. Central granular cell odontogenic tumor: Report of an unusual case

    Mani Madan


    Full Text Available Central granular cell odontogenic tumor (CGCOT is an unusual benign odontogenic neoplasm characterized by the presence of granular cells associated with apparently inactive odontogenic epithelium. These tumors tend to occur in the posterior mandible and usually present as well-defined unilocular or multilocular radiolucent lesions. So far, only <40 cases of CGCOT have been described in the literature under various terminologies. Though these tumors were not considered as distinct entity in the recent WHO classification of odontogenic tumors, long-term follow-up is recommended as malignant counterpart of CGCOT has already been reported. The main aim of this article is to report an additional case of CGCOT to the literature, occurring in a 73-year-old male.

  1. Dendritic cells and their role in tumor immunosurveillance

    Strioga, M.M.; Schijns, V.E.J.C.; Powell, D.J.; Pasukoniene, V.; Dobrovolskiene, N.T.; Michalek, J.


    Dendritic cells (DCs) comprise a heterogeneous population of cells that play a key role in initiating, directing and regulating adaptive immune responses, including those critically involved in tumor immunosurveillance. As a riposte to the central role of DCs in the generation of antitumor immune re

  2. Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes.

    Naomi Ohta

    Full Text Available Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP and follistatin (FST, that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species' breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-over-expressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression.

  3. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    Mazen A. Juratli


    Full Text Available Circulating tumor cells (CTCs are a promising diagnostic and prognostic biomarker for metastatic tumors. We demonstrate that CTCs’ diagnostic value might be increased through real-time monitoring of CTC dynamics. Using preclinical animal models of breast cancer and melanoma and in vivo flow cytometry with photoacoustic and fluorescence detection schematics, we show that CTC count does not always correlate with the primary tumor size. Individual analysis elucidated many cases where the highest level of CTCs was detected before the primary tumor starts progressing. This phenomenon could be attributed to aggressive tumors developing from cancer stem cells. Furthermore, real-time continuous monitoring of CTCs reveals that they occur at highly variable rates in a detection point over a period of time (e.g., a range of 0–54 CTCs per 5 min. These same fluctuations in CTC numbers were observed in vivo in epithelial and non-epithelial metastatic tumors, in different stages of tumor progression, and in different vessels. These temporal CTC fluctuations can explain false negative results of a one-time snapshot test in humans. Indeed, we observed wide variations in the number of CTCs in subsequent blood samples taken from the same metastatic melanoma patient, with some samples being CTC-free. If these phenomena are confirmed in our ongoing in vivo clinical trials, this could support a personalized strategy of CTC monitoring for cancer patients.

  4. Dynamic Fluctuation of Circulating Tumor Cells during Cancer Progression

    Juratli, Mazen A.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A. [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Melerzanov, Alexander V. [Moscow Institute of Physics and Technology (MIPT), Moscow Region, 141700 (Russian Federation); Zharov, Vladimir P. [Phillips Classic Laser and Nanomedicine Laboratories, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States);