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Sample records for tumor suppressive roles

  1. Tumor-Derived Exosomes and Their Role in Tumor-Induced Immune Suppression

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    Theresa L. Whiteside

    2016-10-01

    Full Text Available Tumor-derived exosomes (TEX are emerging as critical components of an intercellular information network between the tumor and the host. The tumor escapes from the host immune system by using a variety of mechanisms designed to impair or eliminate anti-tumor immunity. TEX carrying a cargo of immunoinhibitory molecules and factors represent one such mechanism. TEX, which are present in all body fluids of cancer patients, deliver negative molecular or genetic signals to immune cells re-programming their functions. Although TEX can also stimulate immune activity, in the microenvironments dominated by the tumor, TEX tend to mediate immune suppression thus promoting tumor progression. The TEX content, in part resembling that of the parent cell, may serve as a source of cancer biomarkers. TEX also interfere with immune therapies. A better understanding of TEX and their contribution to cancer progression and cancer patients’ response to immune therapies represents a challenging new field of investigation.

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

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

    2016-01-01

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

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

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

    2016-05-01

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

  4. Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression.

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    Alejo Efeyan

    Full Text Available Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.

  5. Roles for miR-375 in Neuroendocrine Differentiation and Tumor Suppression via Notch Pathway Suppression in Merkel Cell Carcinoma.

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    Abraham, Karan J; Zhang, Xiao; Vidal, Ricardo; Paré, Geneviève C; Feilotter, Harriet E; Tron, Victor A

    2016-04-01

    Dysfunction of key miRNA pathways regulating basic cellular processes is a common driver of many cancers. However, the biological roles and/or clinical applications of such pathways in Merkel cell carcinoma (MCC), a rare but lethal cutaneous neuroendocrine (NE) malignancy, have yet to be determined. Previous work has established that miR-375 is highly expressed in MCC tumors, but its biological role in MCC remains unknown. Herein, we show that elevated miR-375 expression is a specific feature of well-differentiated MCC cell lines that express NE markers. In contrast, miR-375 is strikingly down-regulated in highly aggressive, undifferentiated MCC cell lines. Enforced miR-375 expression in these cells induced NE differentiation, and opposed cancer cell viability, migration, invasion, and survival, pointing to tumor-suppressive roles for miR-375. Mechanistically, miR-375-driven phenotypes were caused by the direct post-transcriptional repression of multiple Notch pathway proteins (Notch2 and RBPJ) linked to cancer and regulation of cell fate. Thus, we detail a novel molecular axis linking tumor-suppressive miR-375 and Notch with NE differentiation and cancer cell behavior in MCC. Our findings identify miR-375 as a putative regulator of NE differentiation, provide insight into the cell of origin of MCC, and suggest that miR-375 silencing may promote aggressive cancer cell behavior through Notch disinhibition. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. The role of TGFBI in mesothelioma and breast cancer: association with tumor suppression

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    Li, Bingyan; Wen, Gengyun; Zhao, Yongliang; Tong, Jian; Hei, Tom K

    2012-01-01

    Transforming growth factor β induced (TGFBI) product, an extracellular matrix (ECM) protein, has been implicated as a putative tumor suppressor in recent studies. Our previous findings revealed that expression of TGFBI gene is down-regulated in a variety of cancer cell lines and clinical tissue samples. In this study, ectopic expression of TGFBI was used to ascertain its role as a tumor suppressor and to determine the underlying mechanism of mesothelioma and breast cancer. Cells were stably transfected with pRc/CMV2-TGFBI and pRc/CMV2-empty vector with Lipofectamine Plus. Ectopic expression of TGFBI was quantified by using quantitative PCR and Western-blotting. Characterization of cell viability was assessed using growth curve, clonogenic survival and soft agar growth. The potential of tumor formation was evaluated by an in vivo mouse model. Cell cycle was analyzed via flow cytometry. Expressions of p21, p53, p16 and p14 were examined using Western-blotting. Senescent cells were sorted by using a Senescence β-Galactosidase Staining Kit. Telomerase activity was measured using quantitative telomerase detection kit. In this study, an ectopic expression of TGFBI in two types of cancer cell lines, a mesothelioma cell line NCI-H28 and a breast cancer cell line MDA-MB-231 was found to have reduced the cellular growth, plating efficiency, and anchorage-independent growth. The tumorigenicity of these cancer cell lines as determined by subcutaneous inoculation in nude mice was similarly suppressed by TGFBI expression. Likewise, TGFBI expression reduced the proportion of S-phase while increased the proportion of G1 phase in these cells. The redistribution of cell cycle phase after re-expression of TGFBI was correspondent with transiently elevated expression of p21 and p53. The activities of senescence-associated β-galactosidase and telomerase were enhanced in TGFBI-transfected cells. Collectively, these results imply that TGFBI plays a suppressive role in the development

  7. Role of Gd-DTPA enhanced fat-suppression MR imaging on ovarian tumors

    International Nuclear Information System (INIS)

    Kang, Heoung Keun; Moon, Woong Jae; Seo, Jeong Jin; Kim, Jae Kyu; Park, Jin Gyoon; Choi, Ho Sun

    1995-01-01

    To determine the value of Gd-DTPA enhanced fat-suppression (GEFS) MR imaging in the characterization and differentiation of benign from malignant ovarian tumors. MRI findings of thirty-seven patients with surgically proved 44 ovarian tumors (30 benign, 14 malignant) were studied retrospectively. MR imaging with conventional spin echo (CSE; T1-weighted image TR/TE 450/20, T2-weighted image TR/TE 3500/30, 90) and GEFS were performed with a 1.5T GE signa. MRI findings of tumors including cystic or solid, wall and septal thickness, necrosis, invasion to adjacent organ, ascites and lymphadenopathy were assessed separately by using CSE and GEFS images, and then tumors were characterized as benign or malignant. Compared with CSE image, GEFS MR image showed better visualization of solid component in 5 malignant lesions, wall thickness in 5 malignant and 1 benign lesions, septal thickness in 3 malignant and 1 benign lesions, necrosis in 1 malignant lesion, and adjacent soft tissue invasion in 5 malignant lesions. Correct characterization of malignant tumors was increased from 71% on CSE image to 93% on GEFS image. However, correct characterization of benign tumors was 93% on both images. GEFS MR imaging could be useful for characterization of ovarian tumors, especially in malignant cases, and employed for differentiation of benign from malignant tumors

  8. A Novel Ras Effector Pathway Found to Play Significant Role in Tumor Suppression | Poster

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    By Nancy Parrish, Staff Writer; photo by Richard Frederickson, Staff Photographer Normal cells have mechanisms to prevent the development of cancer. Among these is a type of tumor suppressor mechanism known as oncogene-induced senescence, or OIS, which halts the uncontrolled growth of cells caused by mutations in oncogenes. The oncogene Ras plays a crucial role in inducing OIS

  9. Replicative Stress and the FHIT Gene: Roles in Tumor Suppression, Genome Stability and Prevention of Carcinogenesis

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    Karras, Jenna R.; Paisie, Carolyn A.; Huebner, Kay, E-mail: kay.huebner@osumc.edu [Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210 (United States)

    2014-06-04

    The fragile FHIT gene, encompassing the chromosomal fragile site FRA3B, is an early target of DNA damage in precancerous cells. While vulnerable to DNA damage itself, FHIT protein expression is essential to protect from DNA damage-induced cancer initiation and progression by modulating genome stability, oxidative stress and levels of accumulating DNA damage. Thus, FHIT, whose expression is lost or reduced in many human cancers, is a tumor suppressor and genome caretaker whose loss initiates genome instability in preneoplastic lesions. Ongoing studies are seeking more detailed understanding of the role of FHIT in the cellular response to oxidative damage. This review discusses the relationship between FHIT, reactive oxygen species production, and DNA damage in the context of cancer initiation and progression.

  10. Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-α/VEGF/Rho-GTPases: pivotal role of STAT-3.

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    Srinivas Reddy Boreddy

    Full Text Available Our previous studies have shown that benzyl isothiocyanate (BITC suppresses pancreatic tumor growth by inhibiting STAT-3; however, the exact mechanism of tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis. Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane. Furthermore, BITC blocks the migration and invasion of BxPC-3 and PanC-1 pancreatic cancer cells in a dose dependant manner. Moreover, secretion of VEGF and MMP-2 in normoxic and hypoxic BxPC-3 and PanC-1 cells was significantly suppressed by BITC. Both VEGF and MMP-2 play a critical role in angiogenesis and metastasis. Our results reveal that BITC significantly suppresses the phosphorylation of VEGFR-2 (Tyr-1175, and expression of HIF-α. Rho-GTPases, which are regulated by VEGF play a crucial role in pancreatic cancer progression. BITC treatment reduced the expression of RhoC whereas up-regulated the expression of tumor suppressor RhoB. STAT-3 over-expression or IL-6 treatment significantly induced HIF-1α and VEGF expression; however, BITC substantially suppressed STAT-3 as well as STAT-3-induced HIF-1α and VEGF expression. Finally, in vivo tumor growth and matrigel-plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC, indicating reduced tumor angiogenesis. Immunoblotting of BITC treated tumors show reduced expression of STAT-3 phosphorylation (Tyr-705, HIF-α, VEGFR-2, VEGF, MMP-2, CD31 and RhoC. Taken together, our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through STAT-3-dependant pathway.

  11. Novel "Elements" of Immune Suppression within the Tumor Microenvironment.

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    Gurusamy, Devikala; Clever, David; Eil, Robert; Restifo, Nicholas P

    2017-06-01

    Adaptive evolution has prompted immune cells to use a wide variety of inhibitory signals, many of which are usurped by tumor cells to evade immune surveillance. Although tumor immunologists often focus on genes and proteins as mediators of immune function, here we highlight two elements from the periodic table-oxygen and potassium-that suppress the immune system in previously unappreciated ways. While both are key to the maintenance of T-cell function and tissue homeostasis, they are exploited by tumors to suppress immuno-surveillance and promote metastatic spread. We discuss the temporal and spatial roles of these elements within the tumor microenvironment and explore possible therapeutic interventions for effective and promising anticancer therapies. Cancer Immunol Res; 5(6); 426-33. ©2017 AACR . ©2017 American Association for Cancer Research.

  12. ARF tumor suppression in the nucleolus.

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    Maggi, Leonard B; Winkeler, Crystal L; Miceli, Alexander P; Apicelli, Anthony J; Brady, Suzanne N; Kuchenreuther, Michael J; Weber, Jason D

    2014-06-01

    Since its discovery close to twenty years ago, the ARF tumor suppressor has played a pivotal role in the field of cancer biology. Elucidating ARF's basal physiological function in the cell has been the focal interest of numerous laboratories throughout the world for many years. Our current understanding of ARF is constantly evolving to include novel frameworks for conceptualizing the regulation of this critical tumor suppressor. As a result of this complexity, there is great need to broaden our understanding of the intricacies governing the biology of the ARF tumor suppressor. The ARF tumor suppressor is a key sensor of signals that instruct a cell to grow and proliferate and is appropriately localized in nucleoli to limit these processes. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Addressing the selective role of distinct prefrontal areas in response suppression: A study with brain tumor patients.

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    Arbula, Sandra; Pacella, Valentina; De Pellegrin, Serena; Rossetto, Marta; Denaro, Luca; D'Avella, Domenico; Della Puppa, Alessandro; Vallesi, Antonino

    2017-06-01

    The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies. Copyright © 2017 The Authors

  14. Tumor Suppression and Promotion by Autophagy

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    Yenniffer Ávalos

    2014-01-01

    Full Text Available Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.

  15. Tumor suppression and promotion by autophagy.

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    Ávalos, Yenniffer; Canales, Jimena; Bravo-Sagua, Roberto; Criollo, Alfredo; Lavandero, Sergio; Quest, Andrew F G

    2014-01-01

    Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.

  16. [Punish or cherish: p53, metabolism and tumor suppression].

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    Albagli, Olivier

    2015-10-01

    The p53 gene is essential for tumor suppression, but how it does so remains unclear. Upon genotoxic or oncogenic stresses, increased p53 activity induces transient cell cycle arrest, senescence or apoptosis, the three cornerstones of the so-called triumvirate. Accordingly, it has long been thought that p53 suppresses tumorigenesis by somehow counteracting cell proliferation or survival. However, several recently described genetically modified mice indicate that p53 can suppress tumorigenesis without triggering these three responses. Rather, as an important mechanism for tumor suppression, these mutant mice point to the ability of p53 to prevent the Warburg effect, that is to dampen glycolysis and foster mitochondrial respiration. Interestingly, these metabolic functions of p53 rely, in part, on its "unstressed" (basal) expression, a feature shared by its mechanistically linked anti-oxydant function. Together, these "conservative" activities of p53 may prevent tumor initiation by promoting and maintaining a normal oxidative metabolism and hence underly the "daily" tumor suppression by p53 in most cells. Conversely, destructive activities elicited by high p53 levels and leading to senescence or apoptosis provide a shield against partially or overtly transformed cells. This last situation, although relatively infrequent throughout life, is usual in experimental settings, which could explain the disproportionally high number of data implicating the triumvirate in tumor suppression by p53. © 2015 médecine/sciences – Inserm.

  17. Methanol Extract of Polyopes lancifolius Suppresses Tumor ...

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    Tumor Necrosis Factor-α-Induced Matrix ... 614-054,4Department of Biomaterial Control (BK21 program) and Blue-Bio Industry Regional Innovation Center,. Dongeui ..... Molecules 2008; 13: ... pancreatic ductal carcinoma is associated with.

  18. Non-cell autonomous or secretory tumor suppression.

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    Chua, Christelle En Lin; Chan, Shu Ning; Tang, Bor Luen

    2014-10-01

    Many malignancies result from deletions or loss-of-function mutations in one or more tumor suppressor genes, the products of which curb unrestrained growth or induce cell death in those with dysregulated proliferative capacities. Most tumor suppressors act in a cell autonomous manner, and only very few proteins are shown to exert a non-cell autonomous tumor suppressor function on other cells. Examples of these include members of the secreted frizzled-related protein (SFRP) family and the secreted protein acidic and rich in cysteine (SPARC)-related proteins. Very recent findings have, however, considerably expanded our appreciation of non-cell autonomous tumor suppressor functions. Broadly, this may occur in two ways. Intracellular tumor suppressor proteins within cells could in principle inhibit aberrant growth of neighboring cells by conditioning an antitumor microenvironment through secreted factors. This is demonstrated by an apparent non-cell autonomous tumor suppressing property of p53. On the other hand, a tumor suppressor produced by a cell may be secreted extracellularly, and taken up by another cell with its activity intact. Intriguingly, this has been recently shown to occur for the phosphatase and tensin homolog (PTEN) by both conventional and unconventional modes of secretion. These recent findings would aid the development of therapeutic strategies that seek to reinstate tumor suppression activity in therapeutically recalcitrant tumor cells, which have lost it in the first place. © 2014 Wiley Periodicals, Inc.

  19. Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR

    International Nuclear Information System (INIS)

    Tippin, Brigette L; Kwong, Alan M; Inadomi, Michael J; Lee, Oliver J; Park, Jae Man; Materi, Alicia M; Buslon, Virgilio S; Lin, Amy M; Kudo, Lili C; Karsten, Stanislav L; French, Samuel W; Narumiya, Shuh; Urade, Yoshihiro; Salido, Eduardo; Lin, Henry J

    2014-01-01

    Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D 2 ) caused more adenomas in Apc Min/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D 2 (PGD 2 ) binds to the prostaglandin D 2 receptor known as PTGDR (or DP1). PGD 2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD 2 . To assess, we produced Apc Min/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc Min/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc Min/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc Min/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD 2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD 2 signals acting through PTGDR in suppression of intestinal tumors

  20. The role of suppression in amblyopia.

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    Li, Jingrong; Thompson, Benjamin; Lam, Carly S Y; Deng, Daming; Chan, Lily Y L; Maehara, Goro; Woo, George C; Yu, Minbin; Hess, Robert F

    2011-06-13

    This study had three main goals: to assess the degree of suppression in patients with strabismic, anisometropic, and mixed amblyopia; to establish the relationship between suppression and the degree of amblyopia; and to compare the degree of suppression across the clinical subgroups within the sample. Using both standard measures of suppression (Bagolini lenses and neutral density [ND] filters, Worth 4-Dot test) and a new approach involving the measurement of dichoptic motion thresholds under conditions of variable interocular contrast, the degree of suppression in 43 amblyopic patients with strabismus, anisometropia, or a combination of both was quantified. There was good agreement between the quantitative measures of suppression made with the new dichoptic motion threshold technique and measurements made with standard clinical techniques (Bagolini lenses and ND filters, Worth 4-Dot test). The degree of suppression was found to correlate directly with the degree of amblyopia within our clinical sample, whereby stronger suppression was associated with a greater difference in interocular acuity and poorer stereoacuity. Suppression was not related to the type or angle of strabismus when this was present or the previous treatment history. These results suggest that suppression may have a primary role in the amblyopia syndrome and therefore have implications for the treatment of amblyopia.

  1. Identification and Reconstruction of Prostate Tumor-Suppressing Exosomes for Therapeutic Applications

    Science.gov (United States)

    2016-03-01

    to the altered contents of exosomes , those from prostate cancer cells (tumor exosomes ) no longer have tumor suppressive functions. If this... cancer . To develop this concept, exosomes will be isolated from normal prostate epithelial cells by differential centrifugations or affinity...purifications and evaluated for tumor suppressing activities against various prostate cancer cells (Aim 1). Then the components of the tumor suppressing exosomes

  2. Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity

    International Nuclear Information System (INIS)

    Svirshchevskaya, Elena V; Mariotti, Jacopo; Wright, Mollie H; Viskova, Natalia Y; Telford, William; Fowler, Daniel H; Varticovski, Lyuba

    2008-01-01

    Rapamycin, an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. However, the role of Rapamycin-induced immune suppression on tumor progression has not been examined. We developed a transplantation model for generation of mammary tumors in syngeneic recipients that can be used to address the role of the immune system on tumor progression. We examined the effect of Rapamycin on the immune system and growth of MMTV-driven Wnt-1 mammary tumors which were transplanted into irradiated and bone marrow-reconstituted, or naïve mice. Rapamycin induced severe immunosuppression and significantly delayed the growth of Wnt-1 tumors. T cell depletion in spleen and thymus and reduction in T cell cytokine secretion were evident within 7 days of therapy. By day 20, splenic but not thymic T cell counts, and cytokine secretion recovered. We determined whether adoptive T cell therapy enhances the anti-cancer effect using ex vivo generated Rapamycin-resistant T cells. However, T cell transfer during Rapamycin therapy did not improve the outcome relative to drug therapy alone. Thus, we could not confirm that suppression of T cell immunity contributes to tumor growth in this model. Consistent with suppression of the mTOR pathway, decreased 4E-BP1, p70 S6-kinase, and S6 protein phosphorylation correlated with a decrease in Wnt-1 tumor cell proliferation. Rapamycin has a direct anti-tumor effect on Wnt-1 breast cancer in vivo that involves inhibition of the mTOR pathway at doses that also suppress host immune responses

  3. Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function

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    Cheng-Fei Liu

    2017-11-01

    Full Text Available Complement receptor 3 (CR3 is expressed abundantly on natural killer (NK cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance. Mice deficient in CR3 (CD11b−/− mice exhibited a more activated NK phenotype and had enhanced NK-dependent tumor killing. In a B16-luc melanoma-induced lung tumor growth and metastasis model, mice deficient in CR3 had reduced tumor growth and metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice mediated more efficient suppression of tumor growth and metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with iC3b (classical CR3 ligand on NK cells negatively regulated NK cell activity and effector functions (i.e. direct tumor cell killing, antibody-dependent NK-mediated tumor killing. Cell signaling analyses showed that iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1 and JNK, and suppression of ERK in NK cells, supporting that iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent tumor surveillance and suggest that the iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in cancer patients and improving NK cell-based therapy.

  4. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation

    NARCIS (Netherlands)

    Hamid, A.R.; Verhaegh, G.W.C.T.; Smit, F.P.; RIjt-van de Westerlo, C.; Armandari, I.; Brandt, A.; Sweep, F.C.; Sedelaar, J.P.M.; Schalken, J.A.

    2015-01-01

    PURPOSE: Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are

  5. The Yin and Yang of Invariant Natural Killer T Cells in Tumor Immunity—Suppression of Tumor Immunity in the Intestine

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    Ying Wang

    2018-01-01

    Full Text Available CD1d-restricted invariant natural killer T (iNKT cells are known as early responding, potent regulatory cells of immune responses. Besides their established role in the regulation of inflammation and autoimmune disease, numerous studies have shown that iNKT cells have important functions in tumor immunosurveillance and control of tumor metastasis. Tumor-infiltrating T helper 1 (TH1/cytotoxic T lymphocytes have been associated with a positive prognosis. However, inflammation has a dual role in cancer and chronic inflammation is believed to be a driving force in many cancers as exemplified in patients with inflammatory bowel disease that have an increased risk of colorectal cancer. Indeed, NKT cells promote intestinal inflammation in human ulcerative colitis, and the associated animal model, indicating that NKT cells may favor tumor development in intestinal tissue. In contrast to other cancers, recent data from animal models suggest that iNKT cells promote tumor formation in the intestine by supporting an immunoregulatory tumor microenvironment and suppressing TH1 antitumor immunity. Here, we review the role of iNKT cells in suppression of tumor immunity in light of iNKT-cell regulation of intestinal inflammation. We also discuss suppression of immunity in other situations as well as factors that may influence whether iNKT cells have a protective or an immunosuppressive and tumor-promoting role in tumor immunity.

  6. Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

    Science.gov (United States)

    Soh, Hendrick; Venkatesan, Natarajan; Veena, Mysore S.; Ravichandran, Sandhiya; Zinabadi, Alborz; Basak, Saroj K.; Parvatiyar, Kislay; Srivastava, Meera; Liang, Li-Jung; Gjertson, David W.; Torres, Jorge Z.; Moatamed, Neda A.

    2016-01-01

    We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB. We further demonstrated decreased phosphorylation of IκB kinase (IKKβ) and IκBα in the presence of tumor necrosis factor alpha (TNF-α), confirming the role of cystatin E/M in the regulation of the NF-κB signaling pathway. Growth suppression of nude mouse xenograft tumors carrying a tetracycline-inducible vector system was observed with the addition of doxycycline in drinking water, confirming that the cystatin E/M gene is a tumor suppressor gene. Finally, immunohistochemical analyses of cervical carcinoma in situ and primary tumors have shown a statistically significant inverse relationship between the expression of cystatin E/M and cathepsin L and a direct relationship between the loss of cystatin E/M expression and nuclear expression of NF-κB. We therefore propose that the cystatin E/M suppressor gene plays an important role in the regulation of NF-κB. PMID:27090639

  7. Increased suppression of oncolytic adenovirus carrying mutant k5 on colorectal tumor

    International Nuclear Information System (INIS)

    Fan Junkai; Xiao Tian; Gu Jinfa; Wei Na; He Lingfeng; Ding Miao; Liu Xinyuan

    2008-01-01

    Angiogenesis plays a key role in the development of a wide variety of malignant tumors. The approach of targeting antiangiogenesis has become an important field of cancer gene therapy. In this study, the antiangiogenesis protein K5 (the kringle 5 of human plasminogen) has been mutated by changing leucine71 to arginine to form mK5. Then the ZD55-mK5, which is an oncolytic adenovirus expressing mK5, was constructed. It showed stronger inhibition on proliferation of human umbilical vein endothelial cell. Moreover, in tube formation and embryonic chorioallantoic membrane assay, ZD55-mK5 exhibited more effective antiangiogenesis than ZD55-K5. In addition, ZD55-mK5 generated obvious suppression on the growth of colorectal tumor xenografts and prolonged the life span of nude mice. These results indicate that ZD55-mK5 is a potent agent for inhibiting the tumor angiogenesis and tumor growth

  8. Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models.

    Science.gov (United States)

    Leu, Jyh-Der; Wang, Bo-Shen; Chiu, Shu-Jun; Chang, Chun-Yuan; Chen, Chien-Chih; Chen, Fu-Du; Avirmed, Shiirevnyamba; Lee, Yi-Jang

    2016-12-01

    Fisetin (3,7,3',4'-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

  9. Active Roles of Tumor Stroma in Breast Cancer Metastasis

    International Nuclear Information System (INIS)

    Khamis, Z.I.; Sang, Q.A.; Sahab, Z.J.

    2012-01-01

    Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome

  10. Active Roles of Tumor Stroma in Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Zahraa I. Khamis

    2012-01-01

    Full Text Available Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome.

  11. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

    Science.gov (United States)

    Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo

    2014-07-01

    Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

  12. Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression

    Directory of Open Access Journals (Sweden)

    Shang-Jui Wang

    2016-10-01

    Full Text Available Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53. Whereas the loss of K98 acetylation (p53K98R alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p534KR: K98R+ 3KR[K117R+K161R+K162R] completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Notably, in contrast to p533KR, p534KR is severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KR is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated. Together, these data indicate the critical role of p53 acetylation in ferroptotic responses and its remaining tumor suppression activity.

  13. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-06-01

    The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

  14. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  15. miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Xiao; Zhang, Haiping [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Lian, Shi [Department of Dermatology and Venereal Disease, Capital Medical University, Beijing 100069 (China); Zhu, Wei, E-mail: zhuwei_2020@163.com [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

    2016-07-01

    As an oncogene, aurora kinase A (AURKA) is overexpressed in various types of human cancers. However, the expression and roles of AURKA in malignant melanoma are largely unknown. In this study, a miR-137-AURKA axis was revealed to regulate melanoma growth. We found a significant increase in levels of AURKA in melanoma. Both genetic knockdown and pharmacologic inhibition of AURKA decreased tumor cell growth in vitro and in vivo. Further found that miR-137 reduced AURKA expression through interaction with its 3′ untranslated region (3′UTR) and that miR-137 was negatively correlated with AURKA expression in melanoma specimens. Overexpression of miR-137 decreased cell proliferation and colony formation in vitro. Notably, re-expression of AURKA significantly rescued miR-137-mediated suppression of cell growth and clonality. In summary, these results reveal that miR-137 functions as a tumor suppressor by targeting AURKA, providing new insights into investigation of therapeutic strategies against malignant melanoma. -- Highlights: •First reported overexpression of AURKA in melanoma. •Targeting AURKA inhibits melanoma growth in vitro and in vivo. •Further found miR-137 suppressed cell growth by binding to AURKA 3′UTR. •Re-expression of AURKA rescued miR-137-mediated suppression. •miR-137-AURKA axis may be potential therapeutic targets of melanoma.

  16. Tumor-specific RNA interference targeting Pokemon suppresses tumor growth and induces apoptosis in prostate cancer.

    Science.gov (United States)

    Li, Yining; Xu, Shuxiong; Wang, Xiangwei; Shi, Hua; Sun, Zhaolin; Yang, Zhao

    2013-02-01

    To explore the exact mechanism of Pokemon in prostate cancer. Pokemon is a member of the POK family of transcriptional repressors. Its main function is suppression of the p14ARF (alternate reading frame) tumor suppressor gene. Although Pokemon expression has been found to be increased in various types of lymphoma, the exact mechanism of the gene in prostate cancer is not clear. In the present study, prostate cancer cells were transfected with the specific short hairpin ribonucleic acid (RNA) expression vector targeting Pokemon. The expression of Pokemon messenger RNA and its protein was detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cell growth and cell apoptosis were also examined using the methyl thiazolyl tetrazolium assay and flow cytometry. The results demonstrated that specific RNA interference (RNAi) could decrease the expression levels of Pokemon gene messenger RNA and protein in prostate cancer cells. In addition, that specific RNAi significantly inhibited the cell proliferation and increased the apoptotic rate. In vivo experiments showed that specific RNAi inhibited the tumorigenicity of prostate cancer cells and significantly suppressed tumor growth. Therefore, an RNAi-targeted Pokemon gene strategy could be a potential approach to prostate cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Type I collagen gene suppresses tumor growth and invasion of malignant human glioma cells

    Directory of Open Access Journals (Sweden)

    Miyata Teruo

    2007-06-01

    Full Text Available Abstract Background Invasion is a hallmark of a malignant tumor, such as a glioma, and the progression is followed by the interaction of tumor cells with an extracellular matrix (ECM. This study examined the role of type I collagen in the invasion of the malignant human glioma cell line T98G by the introduction of the human collagen type I α1 (HCOL1A1 gene. Results The cells overexpressing HCOL1A1 were in a cluster, whereas the control cells were scattered. Overexpression of HCOL1A1 significantly suppressed the motility and invasion of the tumor cells. The glioma cell growth was markedly inhibited in vitro and in vivo by the overexpression of HCOL1A1; in particular, tumorigenicity completely regressed in nude mice. Furthermore, the HCOL1A1 gene induced apoptosis in glioma cells. Conclusion These results indicate that HCOL1A1 have a suppressive biological function in glioma progression and that the introduction of HCOL1A1 provides the basis of a novel therapeutic approach for the treatment of malignant human glioma.

  18. Implication of p53-dependent cellular senescence related gene, TARSH in tumor suppression

    International Nuclear Information System (INIS)

    Wakoh, Takeshi; Uekawa, Natsuko; Terauchi, Kunihiko; Sugimoto, Masataka; Ishigami, Akihito; Shimada, Jun-ichi; Maruyama, Mitsuo

    2009-01-01

    A novel target of NESH-SH3 (TARSH) was identified as a cellular senescence related gene in mouse embryonic fibroblasts (MEFs) replicative senescence, the expression of which has been suppressed in primary clinical lung cancer specimens. However, the molecular mechanism underlying the regulation of TARSH involved in pulmonary tumorigenesis remains unclear. Here we demonstrate that the reduction of TARSH gene expression by short hairpin RNA (shRNA) system robustly inhibited the MEFs proliferation with increase in senescence-associated β-galactosidase (SA-β-gal) activity. Using p53 -/- MEFs, we further suggest that this growth arrest by loss of TARSH is evoked by p53-dependent p21 Cip1 accumulation. Moreover, we also reveal that TARSH reduction induces multicentrosome in MEFs, which is linked in chromosome instability and tumor development. These results suggest that TARSH plays an important role in proliferation of replicative senescence and may serve as a trigger of tumor development.

  19. p53 regulates cytoskeleton remodeling to suppress tumor progression.

    Science.gov (United States)

    Araki, Keigo; Ebata, Takahiro; Guo, Alvin Kunyao; Tobiume, Kei; Wolf, Steven John; Kawauchi, Keiko

    2015-11-01

    Cancer cells possess unique characteristics such as invasiveness, the ability to undergo epithelial-mesenchymal transition, and an inherent stemness. Cell morphology is altered during these processes and this is highly dependent on actin cytoskeleton remodeling. Regulation of the actin cytoskeleton is, therefore, important for determination of cell fate. Mutations within the TP53 (tumor suppressor p53) gene leading to loss or gain of function (GOF) of the protein are often observed in aggressive cancer cells. Here, we highlight the roles of p53 and its GOF mutants in cancer cell invasion from the perspective of the actin cytoskeleton; in particular its reorganization and regulation by cell adhesion molecules such as integrins and cadherins. We emphasize the multiple functions of p53 in the regulation of actin cytoskeleton remodeling in response to the extracellular microenvironment, and oncogene activation. Such an approach provides a new perspective in the consideration of novel targets for anti-cancer therapy.

  20. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of withaferin A on tumor growth and metastasis in liver in a nude mouse model. Methods: Withaferin A was injected through a portal vein to the orthotopic liver tumor in a nude mice model. Xenogen in vivo imaging system was used to monitor tumor growth and metastasis. The effect of ...

  1. Adoptively transferred immune T cells eradicate established tumors in spite of cancer-induced immune suppression

    Science.gov (United States)

    Arina, Ainhoa; Schreiber, Karin; Binder, David C.; Karrison, Theodore; Liu, Rebecca B.; Schreiber, Hans

    2014-01-01

    Myeloid-derived CD11b+Gr1+ suppressor cells (MDSC) and tumor-associated macrophages (TAM) are considered a major obstacle for effective adoptive T cell therapy. Myeloid cells suppress naive T cell proliferation ex vivo and can prevent the generation of T cell responses in vivo. We find, however, that immune T cells adoptively transferred eradicate well-established tumors in the presence of MDSC and TAM which are strongly immunosuppressive ex vivo. These MDSC and TAM were comparable in levels and immunosuppression among different tumor models. Longitudinal microscopy of tumors in vivo revealed that after T cell transfer tumor vasculature and cancer cells disappeared simultaneously. During T-cell mediated tumor destruction, the tumor stroma contained abundant myeloid cells (mainly TAM) that retained their suppressive properties. Preimmunized but not naive mice resisted immune suppression caused by an unrelated tumor-burden supporting the idea that in vivo, myeloid immunosuppressive cells can suppress naive but not memory T cell responses. PMID:24367029

  2. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization

    International Nuclear Information System (INIS)

    Jang, Ji-Young; Lee, Jong-Kuen; Jeon, Yoon-Kyung; Kim, Chul-Woo

    2013-01-01

    Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-κB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-β) and low (TNF-α) expression in M2 macrophages, and molecules in NF-κB pathway (IKKα and Iκ-B) were evaluated by RT-qPCR or western blot. EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-β and increased TNF-α. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKα suppression and concomitant I-κB accumulation; increase of IL-6 and TGF-β; and, decrease of TNF-α. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-κB pathway elicited by EGCG-treated exosomes. Our data demonstrate that EGCG up-regulates miR-16 in

  3. Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression.

    Science.gov (United States)

    Isakov, Noah

    2018-02-01

    The AGC family of serine/threonine kinases (PKA, PKG, PKC) includes more than 60 members that are critical regulators of numerous cellular functions, including cell cycle and differentiation, morphogenesis, and cell survival and death. Mutation and/or dysregulation of AGC kinases can lead to malignant cell transformation and contribute to the pathogenesis of many human diseases. Members of one subgroup of AGC kinases, the protein kinase C (PKC), have been singled out as critical players in carcinogenesis, following their identification as the intracellular receptors of phorbol esters, which exhibit tumor-promoting activities. This observation attracted the attention of researchers worldwide and led to intense investigations on the role of PKC in cell transformation and the potential use of PKC as therapeutic drug targets in cancer diseases. Studies demonstrated that many cancers had altered expression and/or mutation of specific PKC genes. However, the causal relationships between the changes in PKC gene expression and/or mutation and the direct cause of cancer remain elusive. Independent studies in normal cells demonstrated that activation of PKC is essential for the induction of cell activation and proliferation, differentiation, motility, and survival. Based on these observations and the general assumption that PKC isoforms play a positive role in cell transformation and/or cancer progression, many PKC inhibitors have entered clinical trials but the numerous attempts to target PKC in cancer has so far yielded only very limited success. More recent studies demonstrated that PKC function as tumor suppressors, and suggested that future clinical efforts should focus on restoring, rather than inhibiting, PKC activity. The present manuscript provides some historical perspectives on the tumor promoting function of PKC, reviewing some of the observations linking PKC to cancer progression, and discusses the role of PKC in the pathogenesis of cancer diseases and its

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  5. Inhibition of IL-17A suppresses enhanced-tumor growth in low dose pre-irradiated tumor beds.

    Directory of Open Access Journals (Sweden)

    Eun-Jung Lee

    Full Text Available Ionizing radiation induces modification of the tumor microenvironment such as tumor surrounding region, which is relevant to treatment outcome after radiotherapy. In this study, the effects of pre-irradiated tumor beds on the growth of subsequently implanted tumors were investigated as well as underlying mechanism. The experimental model was set up by irradiating the right thighs of C3H/HeN mice with 5 Gy, followed by the implantation of HCa-I and MIH-2. Both implanted tumors in the pre-irradiated bed showed accelerated-growth compared to the control. Tumor-infiltrated lymphocyte (TIL levels were increased, as well as pro-tumor factors such as IL-6 and transforming growth factor-beta1 (TGF-β1 in the pre-irradiated group. In particular, the role of pro-tumor cytokine interleukin-17A (IL-17A was investigated as a possible target mechanism because IL-6 and TGF-β are key factors in Th17 cells differentiation from naïve T cells. IL-17A expression was increased not only in tumors, but also in CD4+ T cells isolated from the tumor draining lymph nodes. The effect of IL-17A on tumor growth was confirmed by treating tumors with IL-17A antibody, which abolished the acceleration of tumor growth. These results indicate that the upregulation of IL-17A seems to be a key factor for enhancing tumor growth in pre-irradiated tumor beds.

  6. Differences in the effects of host suppression on the adoptive immunotherapy of subcutaneous and visceral tumors

    International Nuclear Information System (INIS)

    Chang, A.E.; Shu, S.Y.; Chou, T.; Lafreniere, R.; Rosenberg, S.A.

    1986-01-01

    A syngeneic transplantable sarcoma induced in C57BL/6 mice, MCA 105, was used in studies to examine host suppression on the adoptive immunotherapy of established intradermal and experimentally induced pulmonary and hepatic metastases. Fresh immune splenocytes were generated from mice immunized to the MCA 105 tumor by a mixture of viable tumor cells and Corynebacterium parvum. The adoptive immunotherapy of intradermal MCA 105 tumor with immune cells required prior immunosuppression of the recipient by sublethal irradiation with 500 R or T-cell depletion. The effect of whole-body sublethal irradiation appeared to eliminate a systemic host suppression mechanism, since partialbody irradiation involving the tumor-bearing area did not permit successful immunotherapy. Host irradiation was not required to achieve successful immunotherapy of experimentally induced pulmonary or hepatic metastases. In nonirradiated recipients bearing both intradermal and pulmonary tumors, host suppression did not affect the function of transferred immune cells to induce regression of pulmonary metastases. Thus, suppression of adoptive immunotherapy appears to be relevant to tumors confined to the skin and subcutaneous tissue but not to tumor in visceral sites, such as the lung and liver

  7. L-Asparaginase delivered by Salmonella typhimurium suppresses solid tumors

    Directory of Open Access Journals (Sweden)

    Kwangsoo Kim

    Full Text Available Bacteria can be engineered to deliver anticancer proteins to tumors via a controlled expression system that maximizes the concentration of the therapeutic agent in the tumor. L-asparaginase (L-ASNase, which primarily converts asparagine to aspartate, is an anticancer protein used to treat acute lymphoblastic leukemia. In this study, Salmonellae were engineered to express L-ASNase selectively within tumor tissues using the inducible araBAD promoter system of Escherichia coli. Antitumor efficacy of the engineered bacteria was demonstrated in vivo in solid malignancies. This result demonstrates the merit of bacteria as cancer drug delivery vehicles to administer cancer-starving proteins such as L-ASNase to be effective selectively within the microenvironment of cancer tissue.

  8. A stressful microenvironment: opposing effects of the endoplasmic reticulum stress response in the suppression and enhancement of adaptive tumor immunity.

    Science.gov (United States)

    Rausch, Matthew P; Sertil, Aparna Ranganathan

    2015-03-01

    The recent clinical success of immunotherapy in the treatment of certain types of cancer has demonstrated the powerful ability of the immune system to control tumor growth, leading to significantly improved patient survival. However, despite these promising results current immunotherapeutic strategies are still limited and have not yet achieved broad acceptance outside the context of metastatic melanoma. The limitations of current immunotherapeutic approaches can be attributed in part to suppressive mechanisms present in the tumor microenvironment that hamper the generation of robust antitumor immune responses thus allowing tumor cells to escape immune-mediated destruction. The endoplasmic reticulum (ER) stress response has recently emerged as a potent regulator of tumor immunity. The ER stress response is an adaptive mechanism that allows tumor cells to survive in the harsh growth conditions inherent to the tumor milieu such as low oxygen (hypoxia), low pH and low levels of glucose. Activation of ER stress can also alter the cancer cell response to therapies. In addition, the ER stress response promotes tumor immune evasion by inducing the production of protumorigenic inflammatory cytokines and impairing tumor antigen presentation. However, the ER stress response can boost antitumor immunity in some situations by enhancing the processing and presentation of tumor antigens and by inducing the release of immunogenic factors from stressed tumor cells. Here, we discuss the dualistic role of the ER stress response in the modulation of tumor immunity and highlight how strategies to either induce or block ER stress can be employed to improve the clinical efficacy of tumor immunotherapy.

  9. Inflammasomes and Cancer: The Dynamic Role of the Inflammasome in Tumor Development

    Directory of Open Access Journals (Sweden)

    Melvin Kantono

    2017-09-01

    Full Text Available Chronic Inflammation in tumor microenvironments is not only associated with various stages of tumor development, but also has significant impacts on tumor immunity and immunotherapy. Inflammasome are an important innate immune pathway critical for the production of active IL-1β and interleukin 18, as well as the induction of pyroptosis. Although extensive studies have demonstrated that inflammasomes play a vital role in infectious and autoimmune diseases, their role in tumor progression remains elusive. Multiple studies using a colitis-associated colon cancer model show that inflammasome components provide protection against the development of colon cancer. However, very recent studies demonstrate that inflammasomes promote tumor progression in skin and breast cancer. These results indicate that inflammasomes can promote and suppress tumor development depending on types of tumors, specific inflammasomes involved, and downstream effector molecules. The complicated role of inflammasomes raises new opportunities and challenges to manipulate inflammasome pathways in the treatment of cancer.

  10. Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

    International Nuclear Information System (INIS)

    Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng

    2015-01-01

    Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice.

  11. Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng, E-mail: zhouqs@suda.edu.cn

    2015-10-15

    Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice.

  12. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    tumor cell invasiveness in colon cancer [7] and is related to angiogenesis in ... Hsp90, phosphorylated STAT3 and annexin II. [18,20-24]. ..... Herbstritt CJ, Ruiz A, Zhang L, Hanson AD, Conner. BP, Rougas J, Pribluda VS. Withaferin A is a ...

  13. The Analysis of the Adverse Reaction of Traditional Chinese Medicine Tumor Bone Marrow Suppression

    Science.gov (United States)

    Wei, Zhenzhen; Fang, Xiaoyan; Miao, Mingsan

    2018-01-01

    With the rapid increase of cancer patients, chemotherapy is the main method for the clinical treatment of cancer, but also in the treatment of the adverse reactions--bone marrow suppression is often a serious infection caused by patients after chemotherapy and the important cause of mortality. Chinese medicine has obvious advantages in the prevention and treatment of bone marrow depression after chemotherapy. According to tumor bone marrow suppression after chemotherapy of etiology and pathogenesis of traditional Chinese medicine and China national knowledge internet nearly 10 years of traditional Chinese medicine in the prevention and control of the status of clinical and laboratory research of tumor bone marrow suppression, the author analyzed and summarized its characteristics, so as to provide the basis for treating bone marrow suppression of drug research and development, and promote small adverse reactions of the development and utilization of natural medicine and its preparations.

  14. Cinnamic aldehyde suppresses hypoxia-induced angiogenesis via inhibition of hypoxia-inducible factor-1α expression during tumor progression.

    Science.gov (United States)

    Bae, Woom-Yee; Choi, Jae-Sun; Kim, Ja-Eun; Jeong, Joo-Won

    2015-11-01

    During tumor progression, hypoxia-inducible factor 1 (HIF-1) plays a critical role in tumor angiogenesis and tumor growth by regulating the transcription of several genes in response to a hypoxic environment and changes in growth factors. This study was designed to investigate the effects of cinnamic aldehyde (CA) on tumor growth and angiogenesis and the mechanisms underlying CA's anti-angiogenic activities. We found that CA administration inhibits tumor growth and blocks tumor angiogenesis in BALB/c mice. In addition, CA treatment decreased HIF-1α protein expression and vascular endothelial growth factor (VEGF) expression in mouse tumors and Renca cells exposed to hypoxia in vitro. Interestingly, CA treatment did not affect the stability of von Hippel-Lindau protein (pVHL)-associated HIF-1α and CA attenuated the activation of mammalian target of rapamycin (mTOR) pathway. Collectively, these findings strongly indicate that the anti-angiogenic activity of CA is, at least in part, regulated by the mTOR pathway-mediated suppression of HIF-1α protein expression and these findings suggest that CA may be a potential drug for human cancer therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yu-Ling Lin

    2013-01-01

    Full Text Available Glioblastoma multiforme (GBM is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.

  16. Precise let-7 expression levels balance organ regeneration against tumor suppression

    Science.gov (United States)

    Wu, Linwei; Nguyen, Liem H; Zhou, Kejin; de Soysa, T Yvanka; Li, Lin; Miller, Jason B; Tian, Jianmin; Locker, Joseph; Zhang, Shuyuan; Shinoda, Gen; Seligson, Marc T; Zeitels, Lauren R; Acharya, Asha; Wang, Sam C; Mendell, Joshua T; He, Xiaoshun; Nishino, Jinsuke; Morrison, Sean J; Siegwart, Daniel J; Daley, George Q; Shyh-Chang, Ng; Zhu, Hao

    2015-01-01

    The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09431.001 PMID:26445246

  17. NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion.

    Science.gov (United States)

    Li, Liwen; Han, Lei; Sun, Fan; Zhou, Jingjiao; Ohaegbulam, Kim C; Tang, Xudong; Zang, Xingxing; Steinbrecher, Kris A; Qu, Zhaoxia; Xiao, Gutian

    2018-01-01

    Activation of the inflammatory transcription factor NF-κB in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-κB drives the antitumor macrophages to become pro-tumorigenic have not been determined in any cancer type yet. Similarly, how TAMs repress CD8 + cytotoxic T lymphocytes (CTLs) remains largely unknown, although their importance in regulatory T (Treg) cell regulation and tumor promotion has been well appreciated. Here, using an endogenous lung cancer model we uncover a direct crosstalk between TAMs and CTLs. TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner. Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs. Notably, one major role of cell-intrinsic NF-κB RelA is to drive TAMs to suppress CTLs for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes. These studies help understand how immunity is shaped in lung tumorigenesis, and suggest a RelA-targeted immunotherapy for this deadliest cancer.

  18. USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

    Directory of Open Access Journals (Sweden)

    Zhenghong Lin

    2013-12-01

    Full Text Available The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell-cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell-cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.

  19. The Enigmatic Roles of Caspases in Tumor Development

    Energy Technology Data Exchange (ETDEWEB)

    Jäger, Richard; Zwacka, Ralf M., E-mail: ralf.zwacka@nuigalway.ie [National University of Ireland, Galway, National Centre for Biomedical Engineering Science and Apoptosis Research Centre, Molecular Therapeutics Group, Galway (Ireland)

    2010-11-24

    One function ascribed to apoptosis is the suicidal destruction of potentially harmful cells, such as cancerous cells. Hence, their growth depends on evasion of apoptosis, which is considered as one of the hallmarks of cancer. Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a family of intracellular proteases involved in dismantling the cell in an ordered fashion. In cancer, therefore, one would anticipate caspases to be frequently rendered inactive, either by gene silencing or by somatic mutations. From clinical data, however, there is little evidence that caspase genes are impaired in cancer. Executioner caspases have only rarely been found mutated or silenced, and also initiator caspases are only affected in particular types of cancer. There is experimental evidence from transgenic mice that certain initiator caspases, such as caspase-8 and -2, might act as tumor suppressors. Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. These data seem to question a general tumor-suppressive role of caspases. We discuss several possible ways how tumor cells might evade the need for alterations of caspase genes. First, alternative splicing in tumor cells might generate caspase variants that counteract apoptosis. Second, in tumor cells caspases might be kept in check by cellular caspase inhibitors such as c-FLIP or XIAP. Third, pathways upstream of caspase activation might be disrupted in tumor cells. Finally, caspase-independent cell death mechanisms might abrogate the selection pressure for caspase inactivation during tumor development. These scenarios, however, are hardly compatible with the considerable frequency of spontaneous apoptosis occurring in several cancer types. Therefore, alternative concepts might come into play, such as compensatory proliferation. Herein, apoptosis and/or non-apoptotic functions of caspases may

  20. The Enigmatic Roles of Caspases in Tumor Development

    International Nuclear Information System (INIS)

    Jäger, Richard; Zwacka, Ralf M.

    2010-01-01

    One function ascribed to apoptosis is the suicidal destruction of potentially harmful cells, such as cancerous cells. Hence, their growth depends on evasion of apoptosis, which is considered as one of the hallmarks of cancer. Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a family of intracellular proteases involved in dismantling the cell in an ordered fashion. In cancer, therefore, one would anticipate caspases to be frequently rendered inactive, either by gene silencing or by somatic mutations. From clinical data, however, there is little evidence that caspase genes are impaired in cancer. Executioner caspases have only rarely been found mutated or silenced, and also initiator caspases are only affected in particular types of cancer. There is experimental evidence from transgenic mice that certain initiator caspases, such as caspase-8 and -2, might act as tumor suppressors. Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. These data seem to question a general tumor-suppressive role of caspases. We discuss several possible ways how tumor cells might evade the need for alterations of caspase genes. First, alternative splicing in tumor cells might generate caspase variants that counteract apoptosis. Second, in tumor cells caspases might be kept in check by cellular caspase inhibitors such as c-FLIP or XIAP. Third, pathways upstream of caspase activation might be disrupted in tumor cells. Finally, caspase-independent cell death mechanisms might abrogate the selection pressure for caspase inactivation during tumor development. These scenarios, however, are hardly compatible with the considerable frequency of spontaneous apoptosis occurring in several cancer types. Therefore, alternative concepts might come into play, such as compensatory proliferation. Herein, apoptosis and/or non-apoptotic functions of caspases may

  1. Triparanol suppresses human tumor growth in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Bi, Xinyu [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China); Han, Xingpeng [Department of Pathology, Tianjin Chest Hospital, Tianjin 300051 (China); Zhang, Fang [Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, Zhejiang (China); He, Miao [Life Sciences School, Sun Yat-sen University, Guangzhou 510275 (China); Zhang, Yi [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhi, Xiu-Yi, E-mail: xiuyizhi@yahoo.com.cn [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhao, Hong, E-mail: zhaohong9@sina.com [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China)

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Demonstrate Triparanol can block proliferation in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrate Triparanol can induce apoptosis in multiple cancer cells. Black-Right-Pointing-Pointer Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  2. Triparanol suppresses human tumor growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Bi, Xinyu; Han, Xingpeng; Zhang, Fang; He, Miao; Zhang, Yi; Zhi, Xiu-Yi; Zhao, Hong

    2012-01-01

    Highlights: ► Demonstrate Triparanol can block proliferation in multiple cancer cells. ► Demonstrate Triparanol can induce apoptosis in multiple cancer cells. ► Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. ► Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  3. ω-3 Polyunsaturated fatty acids and their cytochrome P450-derived metabolites suppress colorectal tumor development in mice.

    Science.gov (United States)

    Wang, Weicang; Yang, Jun; Nimiya, Yoshiki; Lee, Kin Sing Stephen; Sanidad, Katherine; Qi, Weipeng; Sukamtoh, Elvira; Park, Yeonhwa; Liu, Zhenhua; Zhang, Guodong

    2017-10-01

    Many studies have shown that dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) reduces the risks of colorectal cancer; however, the underlying mechanisms are not well understood. Here we used a LC-MS/MS-based lipidomics to explore the role of eicosanoid signaling in the anti-colorectal cancer effects of ω-3 PUFAs. Our results showed that dietary feeding of ω-3 PUFAs-rich diets suppressed growth of MC38 colorectal tumor, and modulated profiles of fatty acids and eicosanoid metabolites in C57BL/6 mice. Notably, we found that dietary feeding of ω-3 PUFAs significantly increased levels of epoxydocosapentaenoic acids (EDPs, metabolites of ω-3 PUFA produced by cytochrome P450 enzymes) in plasma and tumor tissue of the treated mice. We further showed that systematic treatment with EDPs (dose=0.5 mg/kg per day) suppressed MC38 tumor growth in mice, with reduced expressions of pro-oncogenic genes such as C-myc, Axin2, and C-jun in tumor tissues. Together, these results support that formation of EDPs might contribute to the anti-colorectal cancer effects of ω-3 PUFAs. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Locoregional injection of F-18 radiopharmaceuticals suppresses tumor xenograft growth in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wong, C -L [The Univ. of Texas M.D. Anderson Cancer Center, Texas (United States)

    2004-07-01

    The energetic positrons (0.633 Mev) from F-18 dissipate kinetic energies before annihilation to produce two 0.511 Mev photons which also contribute to the radiation absorbed dose to the surroundings. In living organism, the contribution from the positron itself to the surrounding tissues (up to 2 mm) is larger than from the 2 photons. Apoptosis has been reported in rat tumors after systemic injection of F-18 FDG although no growth retardation was noted. This study is designed to exploit the pharmacokinetic advantages of locoregional injection of positron emitters in the suppression of tumor growth in rats. Methods: Groups of Fisher 344 adult female rats were inoculated with rat mammary tumors (100,000 cells) intramuscularly (IM) in the thigh. Locoregional injection with F-18 NaF or F-18 FDG was accomplished in days 3 or 7 with single doses of increasing strengths (0.2 to 3 mCi). Tumor growth rates were noted and compared to control (sham injection with saline). The locoregional distribution and clearance of F-18 were estimated from serial tomograms using a Concord MicroPET (R4) after intramuscular injection of 0.1-0.2 mCi of F-18 NaF or F-18 FDG in groups of triplicate rats. Results: A dose-related pattern of tumor suppression is noted with F-18 FDG, whether treatment occurs in day 3 or 7 after inoculation. Additional experiment of injection of 5 mci of F-18 FDG at day 14 also suppressed the growth of a well-formed tumor. Tumor suppression by F-18 NaF is less obvious and only occurs with high dose (2 mCi). MicroPET images demonstrate that F-18 FDG is retained in the injection site while F-18 NaF dissipates rapidly. Conclusion: Locoregional injection of positron-emitters may be sufficient to suppress tumor growth. The mechanism is likely related to the pharmacokinetic profile of the compound within the tissue. Discussion: Locoregional application of radionuclides may provide feasible alternatives to slow tumor growth or prevent tumor recurrence. The use of

  5. 'Obligate' anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice.

    Science.gov (United States)

    Li, Chang-Xian; Yu, Bin; Shi, Lei; Geng, Wei; Lin, Qiu-Bin; Ling, Chang-Chun; Yang, Mei; Ng, Kevin T P; Huang, Jian-Dong; Man, Kwan

    2017-01-01

    The antitumor properties of bacteria have been demonstrated over the past decades. However, the efficacy is limited and unclear. Furthermore, systemic infection remains a serious concern in bacteria treatment. In this study, the effect of YB1, a rationally designed 'obligate' anaerobic Salmonella typhimurium strain, on liver tumor growth and metastasis in a nude mouse orthotopic liver tumor model was investigated. The orthotopic liver tumor model was established in nude mice using the hepatocellular carcinoma cell line MHCC-97L. Two weeks after orthotopic liver tumor implantation, YB1, SL7207 and saline were respectively administered through the tail vein of the mice. Longitudinal monitoring of tumor growth and metastasis was performed using Xenogen IVIS, and direct measurements of tumor volume were taken 3 weeks after treatment. In vitro , MHCC-97L and PLC cells were incubated with YB1 or SL7207 under anaerobic conditions. YB1 was observed to invade tumor cells and induce tumor cell apoptosis and death. The results revealed that all mice in the YB1 group were alive 3 weeks after YB1 injection while all mice in the SL7207 group died within 11 days of the SL7207 injection. The body weight decreased by ~9% on day 1 after YB1 injection and but subsequently recovered. Liver tumor growth and metastases were significantly inhibited following YB1 treatment. By contrast to the control group, a large number of Gr1-positive cells were detected on days 1 to 21 following YB1 treatment. Furthermore, YB1 also effectively invaded tumor cells and induced tumor cell apoptosis and death. In conclusion, YB1 suppressed liver tumor growth and metastasis in a nude mice liver tumor model. The potential mechanism may be through enhancing innate immune response and inducing tumor cell apoptosis and cell death.

  6. Down-regulation of HSP40 gene family following OCT4B1 suppression in human tumor cell lines

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Mirzaei

    2016-02-01

    Full Text Available Objective(s: The OCT4B1, as one of OCT4 variants, is expressed in cancer cell lines and tissues more than other variants and plays an important role in apoptosis and stress (heat shock protein pathways. The present study was designed to determine the effects of OCT4B1 silencing on expressional profile of HSP40 gene family expression in three different human tumor cell lines. Materials and Methods: The OCT4B1 expression was suppressed by specific siRNA transfection in AGS (gastric adenocarcinoma, 5637 (bladder tumor and U-87MG (brain tumor cell lines employing Lipofectamine reagent. Real-time PCR array technique was employed for RNA qualification. The fold changes were calculated using RT2 Profiler PCR array data analysis software version 3.5. Results: Our results indicated that fifteen genes (from 36 studied genes were down-regulated and two genes (DNAJC11 and DNAJC5B were up-regulated in all three studied tumor cell lines by approximately more than two folds. The result of other studied genes (19 genes showed different expressional pattern (up or down-expression based on tumor cell lines. Conclusion: According to the findings of the present study, we may suggest that there is a direct correlation between OCT4B1 expression in tumor cell lines (and tissues and HSP40 family gene expressions to escape from apoptosis and cancer expansion.

  7. Aging, tumor suppression and cancer: High-wire act!

    Energy Technology Data Exchange (ETDEWEB)

    Campisi, Judith

    2004-08-15

    Evolutionary theory holds that aging is a consequence of the declining force of natural selection with age. We discuss here the evidence that among the causes of aging in complex multicellular organisms, such as mammals, is the antagonistically pleiotropic effects of the cellular responses that protect the organism from cancer. Cancer is relatively rare in young mammals, owing in large measure to the activity of tumor suppressor mechanisms. These mechanisms either protect the genome from damage and/or mutations, or they elicit cellular responses--apoptosis or senescence--that eliminate or prevent the proliferation of somatic cells at risk for neoplastic transformation.We focus here on the senescence response, reviewing its causes, regulation and effects. In addition, we describe recent data that support the idea that both senescence and apoptosis may indeed be the double-edged swords predicted by the evolutionary hypothesis of antagonistic pleiotropy--protecting organisms from cancer early in life, but promoting aging phenotypes, including late life cancer, in older organisms.

  8. Claudin-1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells.

    Science.gov (United States)

    Chang, Ti Ling; Ito, Kosei; Ko, Tun Kiat; Liu, Qiang; Salto-Tellez, Manuel; Yeoh, Khay Guan; Fukamachi, Hiroshi; Ito, Yoshiaki

    2010-01-01

    The transcription factor RUNX3 is a gastric tumor suppressor. Tumorigenic Runx3(-/-) gastric epithelial cells attach weakly to each other, compared with nontumorigenic Runx3(+/+) cells. We aimed to identify RUNX3 target genes that promote cell-cell contact to improve our understanding of RUNX3's role in suppressing gastric carcinogenesis. We compared gene expression profiles of Runx3(+/+) and Runx3(-/-) cells and observed down-regulation of genes associated with cell-cell adhesion in Runx3(-/-) cells. Reporter, mobility shift, and chromatin immunoprecipitation assays were used to examine the regulation of these genes by RUNX3. Tumorigenesis assays and immunohistological analyses of human gastric tumors were performed to confirm the role of the candidate genes in gastric tumor development. Mobility shift and chromatin immunoprecipitation assays revealed that the promoter activity of the gene that encodes the tight junction protein claudin-1 was up-regulated via the binding of RUNX3 to the RUNX consensus sites. The tumorigenicity of gastric epithelial cells from Runx3(-/-) mice was significantly reduced by restoration of claudin-1 expression, whereas knockdown of claudin-1 increased the tumorigenicity of human gastric cancer cells. Concomitant expression of RUNX3 and claudin-1 was observed in human normal gastric epithelium and cancers. The tight junction protein claudin-1 has gastric tumor suppressive activity and is a direct transcriptional target of RUNX3. Claudin-1 is down-regulated during the epithelial-mesenchymal transition; RUNX3 might therefore act as a tumor suppressor to antagonize the epithelial-mesenchymal transition. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  9. miR-129 suppresses tumor cell growth and invasion by targeting PAK5 in hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhai, Jian [Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Qu, Shuping [Department II of Special Medical Care, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Li, Xiaowei; Zhong, Jiaming; Chen, Xiaoxia [Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Qu, Zengqiang, E-mail: drquzengqiang@163.com [Department II of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China); Wu, Dong, E-mail: wudongstc@126.com [Department II of Special Medical Care, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438 (China)

    2015-08-14

    Emerging evidence suggests that microRNAs (miRNAs) play important roles in regulating HCC development and progression; however, the mechanisms by which their specific functions and mechanisms remained to be further explored. miR-129 has been reported in gastric cancers, lung cancer and colon cancer. In this study, we disclosed a new tumor suppresser function of miR-129 in HCC. We also found the downregulation of miR-129 occurred in nearly 3/4 of the tumors examined (56/76) compared with adjacent nontumorous tissues, which was more importantly, correlated to the advanced stage and vascular invasion. We then demonstrated that miR-129 overexpression attenuated HCC cells proliferation and invasion, inducing apoptosis in vitro. Moreover, we used miR-129 antagonist and found that anti-miR-129 promoted HCC cells malignant phenotypes. Mechanistically, our further investigations revealed that miR-129 suppressed cell proliferation and invasion by targeting the 3’-untranslated region of PAK5, as well as miR-129 silencing up-regulated PAK5 expression. Moreover, miR-129 expression was inversely correlated with PAK5 expression in 76 cases of HCC samples. RNA interference of PAK5 attenuated anti-miR-129 mediated cell proliferation and invasion in HCC cells. Taken together, these results demonstrated that miR-129 suppressed tumorigenesis and progression by directly targeting PAK5, defining miR-129 as a potential treatment target for HCC. - Highlights: • Decreased of miR-129 is found in HCC and associated with advanced stage and metastasis. • miR-129 suppresses proliferation and invasion of HCC cells. • miR-129 directly targets the 3′ UTR of PAK5 and diminishes PAK5 expression. • PAK5 is involved in miR-129 mediated suppression functions.

  10. Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells.

    Directory of Open Access Journals (Sweden)

    Gang Cheng

    Full Text Available Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved.We co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway.Our results provide detailed, quantitative insight into the role of micro-environmental mechanical stress in tumor spheroid growth dynamics, and suggest how tumors grow in confined locations where the level of solid stress becomes high. An important implication is that apoptosis via the mitochondrial pathway, induced by compressive stress, may be involved in tumor dormancy, in which tumor growth is held in check by a balance of apoptosis and proliferation.

  11. Receptor for activated protein kinase C 1 suppresses gastric tumor progression through nuclear factor-kB pathway.

    Science.gov (United States)

    Yong-Zheng, X; Wan-Li, M; Ji-Ming, M; Xue-Qun, R

    2015-12-01

    Nuclear factor-kB (NF-kB) activity is crucial for survival and proliferation of many kinds of malignancies, including gastric cancer (GC). The receptor for activated protein kinase C 1 (RACK1) is known to regulate tumor development, whereas the underlined mechanism has not been described clearly. We analyzed expression of RACK1 in paired human GC samples by both real-time polymerase chain reaction (PCR) and western blot. Effects of RACK inhibition with small interfering RNA or its overexpression in cultured GC cell lines were evaluated in cell viabilities. NF-kB signaling was investigated using luciferase reporter assay and real-time PCR. RACK1 was significantly decreased in GC samples. Knockdown of RACK elevated GC cell viabilities, whereas overexpression of RACK1 suppressed tumorigenesis of GC cells. Importantly, NF-kB signaling was enhanced after RACK1 expression was inhibited, suggesting the negative regulation of the pro-oncogenic NF-kB activity by RACK1 might contribute to its tumor suppressor role in GC cells. Our results support that RACK1 suppresses gastric tumor progression through the NF-kB signaling pathway.

  12. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

    Science.gov (United States)

    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-07

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging.

    Science.gov (United States)

    Nelson, David M; McBryan, Tony; Jeyapalan, Jessie C; Sedivy, John M; Adams, Peter D

    2014-06-01

    Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.

  14. Sunlight suppressing rejection of 280- to 320-nm UV-radiation-induced skin tumors in mice

    International Nuclear Information System (INIS)

    Morison, W.L.; Kelley, S.P.

    1985-01-01

    Repeated exposure of female C3H/HeNCR- mice to sunlight prevented the normal immunologic rejection of a UV-induced tumor. This systemic immunologic alteration was transferred to syngeneic lethally X-irradiated animals with lymphoid cells from mice exposed to sunlight. The lymphoid cells also were able to suppress the capacity of lymphoid cells from normal animals to reject a UV-induced tumor. The 295- to 320-nm wave band appeared to be responsible for this immunosuppressive effect of sunlight because suppression was prevented by filtration of the radiation through Mylar and by application of a sunscreen containing para-aminobenzoic acid. These observations may have importance in understanding the pathogenesis of sunlight-induced skin cancer in humans

  15. Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth.

    Science.gov (United States)

    McIntyre, Alan; Hulikova, Alzbeta; Ledaki, Ioanna; Snell, Cameron; Singleton, Dean; Steers, Graham; Seden, Peter; Jones, Dylan; Bridges, Esther; Wigfield, Simon; Li, Ji-Liang; Russell, Angela; Swietach, Pawel; Harris, Adrian L

    2016-07-01

    Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. 3D view to tumor suppression: Lkb1, polarity and the arrest of oncogenic c-Myc.

    Science.gov (United States)

    Partanen, Johanna I; Nieminen, Anni I; Klefstrom, Juha

    2009-03-01

    Machiavelli wrote, in his famous political treatise Il Principe, about disrupting organization by planting seeds of dissension or by eliminating necessary support elements. Tumor cells do exactly that by disrupting the organized architecture of epithelial cell layers during progression from contained benign tumor to full-blown invasive cancer. However, it is still unclear whether tumor cells primarily break free by activating oncogenes powerful enough to cause chaos or by eliminating tumor suppressor genes guarding the order of the epithelial organization. Studies in Drosophila have exposed genes that encode key regulators of the epithelial apicobasal polarity and which, upon inactivation, cause disorganization of the epithelial layers and promote unscheduled cell proliferation. These polarity regulator/tumor suppressor proteins, which include products of neoplastic tumor suppressor genes (nTSGs), are carefully positioned in polarized epithelial cells to maintain the order of epithelial structures and to impose a restraint on cell proliferation. In this review, we have explored the presence and prevalence of somatic mutations in the human counterparts of Drosophila polarity regulator/tumor suppressor genes across the human cancers. The screen points out LKB1, which is a causal genetic lesion in Peutz-Jeghers cancer syndrome, a gene mutated in certain sporadic cancers and a human homologue of the fly polarity gene par-4. We review the evidence linking Lkb1 protein to polarity regulation in the scope of our recent results suggesting a coupled role for Lkb1 as an architect of organized acinar structures and a suppressor of oncogenic c-Myc. We finally present models to explain how Lkb1-dependent formation of epithelial architecture is coupled to suppression of normal and oncogene-induced proliferation.

  17. Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Xuemei [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China); Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Wu, Xinchao [Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Zhang, Xiao; Hua, Wenjuan; Zhang, Yajing [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China); Maimaiti, Yusufu [Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Gao, Zairong, E-mail: gaobonn@163.com [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China); Zhang, Yongxue [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province (China); Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, Hubei Province (China)

    2016-01-15

    Thyroid cancer is a common malignancy of the endocrine system. Although radioiodine {sup 131}I treatment on differentiated thyroid cancer is widely used, many patients still fail to benefit from {sup 131}I therapy. Therefore, exploration of novel targeted therapies to suppress tumor growth and improve radioiodine uptake remains necessary. Bromodomain-containing protein 4 (BRD4) is an important member of the bromodomain and extra terminal domain family that influences transcription of downstream genes by binding to acetylated histones. In the present study, we found that BRD4 was up-regulated in thyroid cancer tissues and cell lines. Inhibition of BRD4 in thyroid cancer cells by JQ1 resulted in cell cycle arrest at G0/G1 phase and enhanced {sup 131}I uptake in vitro and suppressed tumor growth in vivo. Moreover, JQ1 treatment suppressed C-MYC but enhanced NIS expression. We further demonstrated that BRD4 was enriched in the promoter region of C-MYC, which could be markedly blocked by JQ1 treatment. In conclusion, our findings revealed that the aberrant expression of BRD4 in thyroid cancer is possibly involved in tumor progression, and JQ1 is potentially an effective chemotherapeutic agent against human thyroid cancer. - Highlights: • BRD4 is upregulated in thyroid cancer tissues and cell lines. • Inhibition of BRD4 induced cell cycle arrest and enhanced radioiodine uptake in vitro and impaired tumor growth in vivo. • JQ1 suppressed the expression of C-MYC and promoted the expression of NIS and P21. • JQ1 attenuated the recruitment of BRD4 to MYC promoter in thyroid cancer.

  18. Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer

    International Nuclear Information System (INIS)

    Gao, Xuemei; Wu, Xinchao; Zhang, Xiao; Hua, Wenjuan; Zhang, Yajing; Maimaiti, Yusufu; Gao, Zairong; Zhang, Yongxue

    2016-01-01

    Thyroid cancer is a common malignancy of the endocrine system. Although radioiodine "1"3"1I treatment on differentiated thyroid cancer is widely used, many patients still fail to benefit from "1"3"1I therapy. Therefore, exploration of novel targeted therapies to suppress tumor growth and improve radioiodine uptake remains necessary. Bromodomain-containing protein 4 (BRD4) is an important member of the bromodomain and extra terminal domain family that influences transcription of downstream genes by binding to acetylated histones. In the present study, we found that BRD4 was up-regulated in thyroid cancer tissues and cell lines. Inhibition of BRD4 in thyroid cancer cells by JQ1 resulted in cell cycle arrest at G0/G1 phase and enhanced "1"3"1I uptake in vitro and suppressed tumor growth in vivo. Moreover, JQ1 treatment suppressed C-MYC but enhanced NIS expression. We further demonstrated that BRD4 was enriched in the promoter region of C-MYC, which could be markedly blocked by JQ1 treatment. In conclusion, our findings revealed that the aberrant expression of BRD4 in thyroid cancer is possibly involved in tumor progression, and JQ1 is potentially an effective chemotherapeutic agent against human thyroid cancer. - Highlights: • BRD4 is upregulated in thyroid cancer tissues and cell lines. • Inhibition of BRD4 induced cell cycle arrest and enhanced radioiodine uptake in vitro and impaired tumor growth in vivo. • JQ1 suppressed the expression of C-MYC and promoted the expression of NIS and P21. • JQ1 attenuated the recruitment of BRD4 to MYC promoter in thyroid cancer.

  19. The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action.

    Science.gov (United States)

    Griveau, A; Devailly, G; Eberst, L; Navaratnam, N; Le Calvé, B; Ferrand, M; Faull, P; Augert, A; Dante, R; Vanacker, J M; Vindrieux, D; Bernard, D

    2016-09-22

    Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression.

  20. Protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production on macrophages and microglia by a standard aqueous extract of Mangifera indica L. (VIMANG). Role of mangiferin isolated from the extract.

    Science.gov (United States)

    Garrido, Gabino; Delgado, René; Lemus, Yeny; Rodríguez, Janet; García, Dagmar; Núñez-Sellés, Alberto J

    2004-08-01

    The present study illustrates the effects of a standard aqueous extract, used in Cuba under the brand name of VIMANG, from the stem bark of Mangifera indica L. on the production of tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) in in vivo and in vitro experiments. In vivo was determined by the action of the extract and its purified glucosylxanthone (mangiferin) on TNFalpha in a murine model of endotoxic shock using Balb/c mice pre-treated with lipopolysaccharide (LPS) 0.125 mg kg(-1), i.p. In vitro, M. indica extract and mangiferin were tested on TNFalpha and NO production in activated macrophages (RAW264.7 cell line) and microglia (N9 cell line) stimulated with LPS (10ng ml(-1)) and interferon gamma (IFNgamma, 2U ml(-1)). M. indica extract reduced dose-dependently TNFalpha production in the serum (ED50 = 64.5 mg kg(-1)) and the TNFalpha mRNA expression in the lungs and livers of mice. Mangiferin also inhibited systemic TNFalpha at 20 mg kg(-1). In RAW264.7, the extract inhibited TNFalpha (IC50 = 94.1 microg ml(-1)) and NO (IC50 = 64.4 microg ml(-1)). In microglia the inhibitions of the extract were IC50 = 76.0 microg ml(-1) (TNFalpha) and 84.0 microg ml(-1) (NO). These findings suggest that the anti-inflammatory response observed during treatment with M. indica extract must be related with inhibition of TNFalpha and NO production. Mangiferin, a main component in the extract, is involved in these effects. The TNFalpha and NO inhibitions by M. indica extract and mangiferin on endotoxic shock and microglia are reported here for the first time. Copyright 2004 Elsevier Ltd.

  1. Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activatio.

    Science.gov (United States)

    Wang, Yurong; Wang, Bin; Guerram, Mounia; Sun, Li; Shi, Wei; Tian, Chongchong; Zhu, Xiong; Jiang, Zhenzhou; Zhang, Luyong

    2015-10-06

    Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.

  2. FAM49B, a novel regulator of mitochondrial function and integrity that suppresses tumor metastasis.

    Science.gov (United States)

    Chattaragada, M S; Riganti, C; Sassoe, M; Principe, M; Santamorena, M M; Roux, C; Curcio, C; Evangelista, A; Allavena, P; Salvia, R; Rusev, B; Scarpa, A; Cappello, P; Novelli, F

    2018-02-08

    Mitochondrial dysregulation plays a central role in cancers and drives reactive oxygen species (ROS)-dependent tumor progression. We investigated the pro-tumoral roles of mitochondrial dynamics and altered intracellular ROS levels in pancreatic ductal adenocarcinoma (PDAC). We identified 'family with sequence similarity 49 member B' (FAM49B) as a mitochondria-localized protein that regulates mitochondrial fission and cancer progression. Silencing FAM49B in PDAC cells resulted in increased fission and mitochondrial ROS generation, which enhanced PDAC cell proliferation and invasion. Notably, FAM49B expression levels in PDAC cells were downregulated by the tumor microenvironment. Overall, the results of this study show that FAM49B acts as a suppressor of cancer cell proliferation and invasion in PDAC by regulating tumor mitochondrial redox reactions and metabolism.

  3. Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor Bearing Mice

    Directory of Open Access Journals (Sweden)

    Jian-Li Gao

    2013-01-01

    Full Text Available Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Thus, there is a great need to develop new treatment regimens to suppress tumor cells that have escaped surgical removal or that may have already disseminated. We have found that tetrandrine (TET exhibits anticolon cancer activity. Here, we investigate the inhibition effect of TET to breast cancer metastasis, angiogenesis and its molecular basis underlying TET’s anticancer activity. We compare TET with chemotherapy drug doxorubicin in 4T1 tumor bearing BALB/c mice model and find that TET exhibits an anticancer metastatic and antiangiogenic activities better than those of doxorubicin. The lung metastatic sites were decreased by TET, which is confirmed by bioluminescence imaging in vivo. On the other hand, laser doppler perfusion imaging (LDI was used for measuring the blood flow of tumor in 4T1-tumor bearing mice. As a result, the local blood perfusion of tumor was markedly decreased by TET after 3 weeks. Mechanistically, TET treatment leads to a decrease in p-ERK level and an increase in NF-κB levels in HUVECs. TET also regulated metastatic and angiogenic related proteins, including vascular endothelial growth factor, hypoxia-inducible factor-1α, integrin β5, endothelial cell specific molecule-1, and intercellular adhesion molecule-1 in vivo.

  4. TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor

    Directory of Open Access Journals (Sweden)

    Danilo Swann Matassa

    2018-04-01

    Full Text Available Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1 is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90 family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.

  5. Suppressive versus augmenting effect of the same pretreatment regimen in two murine tumor systems with distinct effector mechanisms

    International Nuclear Information System (INIS)

    Fujiwara, Hiromi; Hamaoka, Toshiyuki; Kitagawa, Masayasu

    1978-01-01

    The effect of presensitization with x-irradiated tumor cells on the development of host's immune resistance against the tumor-associated transplantation antigens (TATA) was investigated in two syngeneic tumor systems with distinct effector mechanisms. When X5563 plasmacytoma, to which immune resistance was mediated exclusively by killer T lymphocytes, was intravenously inoculated into syngeneic C3H/He mice with lower number after 7000 R x-irradiation, the mice failed to exhibit any protective immunity against the subsequent challenge with viable tumor cells. Moreover, these mice lost their capability to develop any immune resistance even after an appropriate immunization procedure. The immunodepression induced by such a pretreatment regimen was specific for X5563 tumor. While no suppressor cell activity was detected in the above pretreated mice, serum factor(s) from these mice was virtually responsible for this suppression. When the serum factor mediating this tumor-specific suppression was fractionated on the Sephadex G-200 column, the suppressive activity was found in albumin-corresponding fraction, free of any immunoglobulin component. In contrast, in MM102 mammary tumor system, in which immune resistance is solely mediated by tumor-specific antibody, the pretreatment with x-irradiated MM102 cells augmented the induction of anti-tumor immunity. These results indicate that while tumor antigens given in the form of x-irradiated tumor cells suppress the induction of killer T cell-mediated immunity in one system, the same presensitization regimen of tumor antigens augments the antibody-mediated immunity in another system, thus giving a divergent effect on the distinct effector mechanisms of syngeneic tumor immunity. (author)

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

    LENUS (Irish Health Repository)

    Abdel Aziz, Mohamed T

    2011-05-05

    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

  7. Improved MR imaging of head and neck tumors with use of fat suppression with and without Gd-DTPA

    International Nuclear Information System (INIS)

    Tien, R.D.; Hesselink, J.R.; Szumowski, J.; Robbins, K.T.

    1990-01-01

    This paper determines the feasibility of using MR fat-suppression techniques for tumors and lymphadenopathies of the head and neck. To date, 28 patients with various tumors and lymphadenopathies have been evaluated. All patients were studied with standard spin-echo T1-weighted images (T1WI) and T2-weighted images (T2WI), with and without fat-suppression technique. T1WI with Gd-DTPA and fat suppression was performed in 17 patients. Conventional and paired fat-suppression MR images were compared by means of a grading system. The post-Gd-DTPA fat-suppression T1WI and fat-suppression T2WI were found to be most useful. Fat-suppression T2WI were generally even better than post-Gd-DTPA fat-suppression T1WI in cases of squamous cell carcinoma, due to its medium contrast enhancement. Post-Gd-DTPA fat-suppression T1WI were more useful than fat-suppression T2WI in a case of plexiform neurofibroma, due to its fibrous component and lack of protons

  8. Mast cells: potential positive and negative roles in tumor biology.

    Science.gov (United States)

    Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

    2013-11-01

    Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. ©2013 AACR.

  9. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression

    NARCIS (Netherlands)

    Nantasanti, Sathidpak; Toussaint, Mathilda J. M.; Youssef, Sameh A.; Tooten, Peter C. J.; de Bruin, Alain

    2016-01-01

    The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver

  10. Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells.

    Science.gov (United States)

    Završnik, Janja; Butinar, Miha; Prebanda, Mojca Trstenjak; Krajnc, Aleksander; Vidmar, Robert; Fonović, Marko; Grubb, Anders; Turk, Vito; Turk, Boris; Vasiljeva, Olga

    2017-09-26

    Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro , indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations.

  11. Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells

    Science.gov (United States)

    2011-01-01

    Background Gum resins obtained from trees of the Burseraceae family (Boswellia sp.) are important ingredients in incense and perfumes. Extracts prepared from Boswellia sp. gum resins have been shown to possess anti-inflammatory and anti-neoplastic effects. Essential oil prepared by distillation of the gum resin traditionally used for aromatic therapy has also been shown to have tumor cell-specific anti-proliferative and pro-apoptotic activities. The objective of this study was to optimize conditions for preparing Boswellea sacra essential oil with the highest biological activity in inducing tumor cell-specific cytotoxicity and suppressing aggressive tumor phenotypes in human breast cancer cells. Methods Boswellia sacra essential oil was prepared from Omani Hougari grade resins through hydrodistillation at 78 or 100 oC for 12 hours. Chemical compositions were identified by gas chromatography-mass spectrometry; and total boswellic acids contents were quantified by high-performance liquid chromatography. Boswellia sacra essential oil-mediated cell viability and death were studied in established human breast cancer cell lines (T47D, MCF7, MDA-MB-231) and an immortalized normal human breast cell line (MCF10-2A). Apoptosis was assayed by genomic DNA fragmentation. Anti-invasive and anti-multicellular tumor properties were evaluated by cellular network and spheroid formation models, respectively. Western blot analysis was performed to study Boswellia sacra essential oil-regulated proteins involved in apoptosis, signaling pathways, and cell cycle regulation. Results More abundant high molecular weight compounds, including boswellic acids, were present in Boswellia sacra essential oil prepared at 100 oC hydrodistillation. All three human breast cancer cell lines were sensitive to essential oil treatment with reduced cell viability and elevated cell death, whereas the immortalized normal human breast cell line was more resistant to essential oil treatment. Boswellia sacra

  12. NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression

    Science.gov (United States)

    Simon, Priscilla S.; Bardhan, Kankana; Chen, May R.; Paschall, Amy V.; Lu, Chunwan; Bollag, Roni J.; Kong, Feng-Chong; Jin, JianYue; Kong, Feng-Ming; Waller, Jennifer L.; Pollock, Raphael E.; Liu, Kebin

    2016-01-01

    Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression. PMID:27014915

  13. Role of CD44 in Tumor Progression

    National Research Council Canada - National Science Library

    Underhill, Charles

    1999-01-01

    ...) that we isolated from cartilage by affinity chromatography. We found that the HAbc was able to block the growth of tumors cells in mice as well as in the chorioallantoic membrane (CAM) of chicken embryos...

  14. Suppression of tumor growth by a new glycosaminoglycan isolated from the African giant snail Achatina fulica.

    Science.gov (United States)

    Lee, Yeon Sil; Yang, Hyun Ok; Shin, Kuk Hyun; Choi, Hyung Seok; Jung, Sang Hoon; Kim, Yong Man; Oh, Deok Kun; Linhardt, Robert J; Kim, Yeong Shik

    2003-03-28

    Acharan sulfate is a new type of glycosaminoglycan from the giant African snail, Achatina fulica. Acharan sulfate, which has a primary repeating disaccharide structure of alpha-D-N-acetylglucosaminyl-2-O-sulfo-alpha-L-iduronic acid, was studied as a potential antitumor agent in both in vivo and in vitro assays. The antiangiogenic activity of acharan sulfate was evaluated in the chorioallantoic membrane assay and by measuring its effect on the proliferation of calf pulmonary artery endothelial cells. In vivo, a matrigel plug assay showed that acharan sulfate suppressed basic fibroblast growth factor (bFGF)-stimulated angiogenesis and lowered the hemoglobin (Hb) content inside the plug. Acharan sulfate was administered s.c. at two doses for 15 days to C57BL/6 mice implanted with murine Lewis lung carcinoma in the back. It was also administered i.p. to ICR mice bearing sarcoma 180 at a dose of 30 mg/kg. Subcutaneous injection of acharan sulfate at doses of 10 and 30 mg/kg decreased tumor weight and tumor volume by 40% without toxicity or resistance. Intraperitoneal injection of acharan sulfate also decreased tumor weight and volume by 40% in sarcoma 180-bearing mice. These results suggest that the antitumor activity of acharan sulfate may be related to the inhibition of angiogenesis.

  15. Role of the immune system in the peritoneal tumor spread of high grade serous ovarian cancer.

    Science.gov (United States)

    Auer, Katharina; Bachmayr-Heyda, Anna; Sukhbaatar, Nyamdelger; Aust, Stefanie; Schmetterer, Klaus G; Meier, Samuel M; Gerner, Christopher; Grimm, Christoph; Horvat, Reinhard; Pils, Dietmar

    2016-09-20

    The immune system plays a critical role in cancer progression and overall survival. Still, it is unclear if differences in the immune response are associated with different patterns of tumor spread apparent in high grade serous ovarian cancer patients and previously described by us. In this study we aimed to assess the role of the immune system in miliary (widespread, millet-sized lesions) and non-miliary (bigger, exophytically growing implants) tumor spread. To achieve this we comprehensively analyzed tumor tissues, blood, and ascites from 41 patients using immunofluorescence, flow cytometry, RNA sequencing, multiplexed immunoassays, and immunohistochemistry. Results showed that inflammation markers were systemically higher in miliary. In contrast, in non-miliary lymphocyte and monocyte/macrophage infiltration into the ascites was higher as well as the levels of PD-1 expression in tumor associated cytotoxic T-lymphocytes and PD-L1 expression in tumor cells. Furthermore, in ascites of miliary patients more epithelial tumor cells were present compared to non-miliary, possibly due to the active down-regulation of anti-tumor responses by B-cells and regulatory T-cells. Summarizing, adaptive immune responses prevailed in patients with non-miliary spread, whereas in patients with miliary spread a higher involvement of the innate immune system was apparent while adaptive responses were counteracted by immune suppressive cells and factors.

  16. The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

    Science.gov (United States)

    2011-09-01

    recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re-growth is triggered by shifting of...microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize that the balance of...dormancy and recurrence is determined by the ability of the tumor stem cells to recruit TAM which in turn promotes self-renewal of the stem cell . We

  17. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    Directory of Open Access Journals (Sweden)

    Shellese A. Cannonier

    2015-08-01

    Full Text Available Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung, directly invade into bone (head and neck or originate from the bone (melanoma, chondrosarcoma where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.

  18. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    Energy Technology Data Exchange (ETDEWEB)

    Cannonier, Shellese A.; Sterling, Julie A., E-mail: Julie.sterling@vanderbilt.edu [Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37235 (United States); Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology Vanderbilt University, Nashville, TN 372335 (United States); Department of Cancer Biology, Vanderbilt University, Nashville, TN 37235 (United States)

    2015-08-26

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.

  19. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    International Nuclear Information System (INIS)

    Cannonier, Shellese A.; Sterling, Julie A.

    2015-01-01

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors

  20. Molecular Targets of Nutraceuticals Derived from Dietary Spices: Potential Role in Suppression of Inflammation and Tumorigenesis

    Science.gov (United States)

    Aggarwal, Bharat B.; Van Kuiken, Michelle E.; Iyer, Laxmi H.; Harikumar, Kuzhuvelil B.; Sung, Bokyung

    2011-01-01

    Despite the fact cancer is primarily a preventable disease, recent statistics indicate cancer will become the number one killer worldwide in 2010. Since certain cancers are more prevalent in the people of some countries than others, suggests the role of lifestyle. For instance cancer incidence among people from the Indian subcontinent, where most spices are consumed, is much lower than that in the Western World. Spices have been consumed for centuries for a variety of purposes—as flavoring agents, colorants, and preservatives. However, there is increasing evidence for the importance of plant-based foods in regular diet to lowering the risk of most chronic diseases, so spices are now emerging as more than just flavor aids, but as agents that can not only prevent but may even treat disease. In this article, we discuss the role of 41 common dietary spices with over 182 spice-derived nutraceuticals for their effects against different stages of tumorigenesis. Besides suppressing inflammatory pathways, spice-derived nutraceuticals can suppress survival, proliferation, invasion, and angiogenesis of tumor cells. We discuss how spice-derived nutraceuticals mediate such diverse effects and what their molecular targets are. Overall our review suggests “adding spice to your life” may serve as a healthy and delicious way to ward off cancer and other chronic diseases. PMID:19491364

  1. Inhibition of Calcium-Activated Chloride Channel ANO1/TMEM16A Suppresses Tumor Growth and Invasion in Human Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Linghan Jia

    Full Text Available Lung cancer or pulmonary carcinoma is primarily derived from epithelial cells that are thin and line on the alveolar surfaces of the lung for gas exchange. ANO1/TMEM16A, initially identified from airway epithelial cells, is a member of Ca2+-activated Cl- channels (CaCCs that function to regulate epithelial secretion and cell volume for maintenance of ion and tissue homeostasis. ANO1/TMEM16A has recently been shown to be highly expressed in several epithelium originated carcinomas. However, the role of ANO1 in lung cancer remains unknown. In this study, we show that inhibition of calcium-activated chloride channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer. ANO1 is upregulated in different human lung cancer cell lines. Knocking-down ANO1 by small hairpin RNAs inhibited proliferation, migration and invasion of GLC82 and NCI-H520 cancel cells evaluated by CCK-8, would-healing, transwell and 3D soft agar assays. ANO1 protein is overexpressed in 77.3% cases of human lung adenocarcinoma tissues detected by immunohistochemistry. Furthermore, the tumor growth in nude mice implanted with GLC82 cells was significantly suppressed by ANO1 silencing. Taken together, our findings provide evidence that ANO1 overexpression contributes to tumor growth and invasion of lung cancer; and suppressing ANO1 overexpression may have therapeutic potential in lung cancer therapy.

  2. Tumor-Derived Exosomes and Their Role in Cancer Progression.

    Science.gov (United States)

    Whiteside, Theresa L

    2016-01-01

    Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation. © 2016 Elsevier Inc. All rights reserved.

  3. Social Hierarchy and Depression: The Role of Emotion Suppression

    OpenAIRE

    Langner, Carrie A.; Epel, Elissa; Matthews, Karen; Moskowitz, Judith T.; Adler, Nancy

    2012-01-01

    Position in the social hierarchy is a major determinant of health outcomes. We examined the associations between aspects of social hierarchy and depressive symptoms with a specific focus on one potential psychological mechanism: emotion suppression. Suppressing negative emotion has mental health costs, but individuals with low social power and low social status may use these strategies to avoid conflict. Study 1 assessed perceived social power, tendency to suppress negative emotion, and depre...

  4. CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma.

    Science.gov (United States)

    Su, Juan; Gao, Tianyuan; Jiang, Minghao; Wu, Lisha; Zeng, Weiqi; Zhao, Shuang; Peng, Cong; Chen, Xiang

    2016-10-04

    Melanoma is a very malignant disease and there are still no effective treatments. CD147 participates in the carcinogenesis of multiple human cancers and GLUT-1, as a glucose transporter, is associated with tumor growth. However, the function of CD147 and GLUT-1 in melanoma have not been completely understood. Thus, in this study we investigated the expression of CD147 and GLUT-1 in melanoma tissue, which were overexpressed compared with that in nevus tissue. In addition, CD147 and GLUT-1 were co-localized in the cytoplasm of human melanoma A375 cells. Immunoprecipitation proved that CD147 interacted with GLUT-1 at D105-199. Silencing CD147 by specific siRNA could downregulate GLUT-1 level via inhibiting PI3K/Akt signaling and decrease glucose uptake in A375 cells. In vivo experiments also supported that CD147 knockdown suppressed the tumor growth in melanoma subcutaneous mice model, observed by micro PET/CT. Our results could help validate CD147 as a new therapeutic target for treating melanoma.

  5. Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis.

    Science.gov (United States)

    Dang, Qiang; Song, Wenbin; Xu, Defeng; Ma, Yanmin; Li, Feng; Zeng, Jin; Zhu, Guodong; Wang, Xinyang; Chang, Luke S; He, Dalin; Li, Lei

    2015-09-01

    The effects of the flavonoid compound, kaempferol, which is an inhibitor of cancer cell proliferation and an inducer of cell apoptosis have been shown in various cancers, including lung, pancreatic, and ovarian, but its effect has never been studied in bladder cancer. Here, we investigated the effects of kaempferol on bladder cancer using multiple in vitro cell lines and in vivo mice studies. The MTT assay results on various bladder cancer cell lines showed that kaempferol enhanced bladder cancer cell cytotoxicity. In contrast, when analyzed by the flow cytometric analysis, DNA ladder experiment, and TUNEL assay, kaempferol significantly was shown to induce apoptosis and cell cycle arrest. These in vitro results were confirmed in in vivo mice studies using subcutaneous xenografted mouse models. Consistent with the in vitro results, we found that treating mice with kaempferol significant suppression in tumor growth compared to the control group mice. Tumor tissue staining results showed decreased expressions of the growth related markers, yet increased expressions in apoptosis markers in the kaempferol treated group mice tissues compared to the control group mice. In addition, our in vitro and in vivo data showed kaempferol can also inhibit bladder cancer invasion and metastasis. Further mechanism dissection studies showed that significant down-regulation of the c-Met/p38 signaling pathway is responsible for the kaempferol mediated cell proliferation inhibition. All these findings suggest kaempferol might be an effective and novel chemotherapeutic drug to apply for the future therapeutic agent to combat bladder cancer. © 2014 Wiley Periodicals, Inc.

  6. Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment.

    Science.gov (United States)

    Ito, Koichi; Stannard, Kimberley; Gabutero, Elwyn; Clark, Amanda M; Neo, Shi-Yong; Onturk, Selda; Blanchard, Helen; Ralph, Stephen J

    2012-12-01

    The microenvironment of a tumor is a highly complex milieu, primarily characterized by immunosuppression, abnormal angiogenesis, and hypoxic regions. These features promote tumor progression and metastasis, resulting in poor prognosis and greater resistance to existing cancer therapies. Galectin-1 is a β-galactoside binding protein that is abundantly secreted by almost all types of malignant tumor cells. The expression of galectin-1 is regulated by hypoxia-inducible factor-1 (HIF-1) and it plays vital pro-tumorigenic roles within the tumor microenvironment. In particular, galectin-1 suppresses T cell-mediated cytotoxic immune responses and promotes tumor angiogenesis. However, since galectin-1 displays many different activities by binding to a number of diverse N- or O-glycan modified target proteins, it has been difficult to fully understand how galectin-1 supports tumor growth and metastasis. This review explores the importance of galectin-1 and glycan expression patterns in the tumor microenvironment and the potential effects of inhibiting galectin-1 as a therapeutic target for cancer treatment.

  7. Tubulin binding cofactor C (TBCC) suppresses tumor growth and enhances chemosensitivity in human breast cancer cells

    International Nuclear Information System (INIS)

    Hage-Sleiman, Rouba; Herveau, Stéphanie; Matera, Eva-Laure; Laurier, Jean-Fabien; Dumontet, Charles

    2010-01-01

    Microtubules are considered major therapeutic targets in patients with breast cancer. In spite of their essential role in biological functions including cell motility, cell division and intracellular transport, microtubules have not yet been considered as critical actors influencing tumor cell aggressivity. To evaluate the impact of microtubule mass and dynamics on the phenotype and sensitivity of breast cancer cells, we have targeted tubulin binding cofactor C (TBCC), a crucial protein for the proper folding of α and β tubulins into polymerization-competent tubulin heterodimers. We developed variants of human breast cancer cells with increased content of TBCC. Analysis of proliferation, cell cycle distribution and mitotic durations were assayed to investigate the influence of TBCC on the cell phenotype. In vivo growth of tumors was monitored in mice xenografted with breast cancer cells. The microtubule dynamics and the different fractions of tubulins were studied by time-lapse microscopy and lysate fractionation, respectively. In vitro sensitivity to antimicrotubule agents was studied by flow cytometry. In vivo chemosensitivity was assayed by treatment of mice implanted with tumor cells. TBCC overexpression influenced tubulin fraction distribution, with higher content of nonpolymerizable tubulins and lower content of polymerizable dimers and microtubules. Microtubule dynamicity was reduced in cells overexpressing TBCC. Cell cycle distribution was altered in cells containing larger amounts of TBCC with higher percentage of cells in G2-M phase and lower percentage in S-phase, along with slower passage into mitosis. While increased content of TBCC had little effect on cell proliferation in vitro, we observed a significant delay in tumor growth with respect to controls when TBCC overexpressing cells were implanted as xenografts in vivo. TBCC overexpressing variants displayed enhanced sensitivity to antimicrotubule agents both in vitro and in xenografts. These

  8. Gleditsia Saponin C Induces A549 Cell Apoptosis via Caspase-Dependent Cascade and Suppresses Tumor Growth on Xenografts Tumor Animal Model

    Directory of Open Access Journals (Sweden)

    Ye Cheng

    2018-01-01

    Full Text Available Saponins are natural compounds and possess the most promising anti-cancer function. Here, a saponin gleditsia saponin C (GSC, extracted from gleditsiae fructus abnormalis, could induce apoptosis of lung tumor cell line A549 via caspase dependent cascade and this effect could be prevented by the caspase inhibitors. In addition, GSC induced cell death companied with an increase ratio of Bax:Bcl-2 and inhibition of ERK and Akt signaling pathways. Meanwhile, GSC suppressed TNFα inducing NF-κB activation and increased the susceptibility of lung cancer cell to TNFα induced apoptosis. Furthermore, on mouse xenograft model, GSC significantly suppressed tumor growth and induced cancer cell apoptosis, which validated the anti-tumor effect of GSC. Based on these results, GSC might be a promising drug candidate of anti-lung cancer for its potential clinical applications.

  9. Mast Cell, the Neglected Member of the Tumor Microenvironment: Role in Breast Cancer.

    Science.gov (United States)

    Aponte-López, Angélica; Fuentes-Pananá, Ezequiel M; Cortes-Muñoz, Daniel; Muñoz-Cruz, Samira

    2018-01-01

    Mast cells are unique tissue-resident immune cells that secrete a diverse array of biologically active compounds that can stimulate, modulate, or suppress the immune response. Although mounting evidence supports that mast cells are consistently infiltrating tumors, their role as either a driving or an opposite force for cancer progression is still controversial. Particularly, in breast cancer, their function is still under discussion. While some studies have shown a protective role, recent evidence indicates that mast cells enhance blood and lymphatic vessel formation. Interestingly, one of the most important components of the mast cell cargo, the serine protease tryptase, is a potent angiogenic factor, and elevated serum tryptase levels correlate with bad prognosis in breast cancer patients. Likewise, histamine is known to induce tumor cell proliferation and tumor growth. In agreement, mast cell depletion reduces the size of mammary tumors and metastasis in murine models that spontaneously develop breast cancer. In this review, we will discuss the evidence supporting protumoral and antitumoral roles of mast cells, emphasizing recent findings placing mast cells as important drivers of tumor progression, as well as the potential use of these cells or their mediators as therapeutic targets.

  10. Social hierarchy and depression: the role of emotion suppression.

    Science.gov (United States)

    Langner, Carrie A; Epel, Elissa S; Matthews, Karen A; Moskowitz, Judith T; Adler, Nancy E

    2012-01-01

    Position in the social hierarchy is a major determinant of health outcomes. We examined the associations between aspects of social hierarchy and depressive symptoms with a specific focus on one potential psychological mechanism: emotion suppression. Suppressing negative emotion has mental health costs, but individuals with low social power and low social status may use these strategies to avoid conflict. Study 1 assessed perceived social power, tendency to suppress negative emotion, and depressive symptoms in a community sample of women. Low social power was related to greater depressive symptoms, and this relationship was partially mediated by emotion suppression. Study 2 examined education as a proxy for social hierarchy position, anger suppression, and depressive symptoms in a national, longitudinal cohort study (The coronary artery risk development in young adults [CARDIA] study; Cutter et al., 1991). Much as in study 1, low education levels were correlated with greater depressive symptoms, and this relationship was partially mediated by anger suppression. Further, suppression mediated the relationship between low education and subsequent depression up to 15 years later. These findings support the theory that social hierarchy affects mental health in part through a process of emotion suppression.

  11. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Yan, Jun-Hai; Zhao, Chun-Liu; Ding, Lan-Bao; Zhou, Xi

    2015-01-01

    The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

  12. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Jun-Hai; Zhao, Chun-Liu [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China); Ding, Lan-Bao [Department of Nuclear Medicine, Shanghai 10th People' s Hospital, Tongji University School of Medicine, Shanghai 200072 (China); Zhou, Xi, E-mail: modelmap@139.com [Department of Respiratory Medicine, Luwan Branch of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20020 (China)

    2015-10-09

    The transcription factor forkhead box D3 (FOXD3), widely studied as a transcriptional repressor in embryogenesis, participates in the carcinogenesis of many cancers. However, the expression pattern and role of FOXD3 in non-small cell lung cancer (NSCLC) have not been well characterized. We report that FOXD3 is significantly downregulated in NSCLC cell lines and clinical tissues. FOXD3 overexpression significantly inhibits cell growth and results in G1 cell cycle arrest in NSCLC A549 and H1299 cells. In a xenograft tumor model, FOXD3 overexpression inhibits tumor growth and angiogenesis. Remarkably, expression of vascular endothelial growth factor (VEGF) was reduced in FOXD3 overexpression models both in vitro and in vivo. These findings suggest that FOXD3 plays a potential tumor suppressor role in NSCLC progression and represents a promising clinical prognostic marker and therapeutic target for this disease. - Highlights: • FOXD3 is downregulated in NSCLC cell lines and tissues. • FOXD3 overexpression inhibited cell proliferation in NSCLC cells. • FOXD3 overexpression led to decreased angiogenesis in NSCLC cells in vitro and in vivo.

  13. Possible role of reassortment in tumor therapy

    International Nuclear Information System (INIS)

    Terashima, Toyozo

    1976-01-01

    On the basis of age-dependent response pattern of cultured mammalian cells, various exogenous agents, such as x-ray, antimetabolites, and antitumor drugs, were classified into two groups, i.e., x-ray type (A) and hydroxyurea type (B). Each type of agent was specific not only for the pattern of survival response during the cell cycle but also for the inhibition of progression. The treatment of cycling cell population with either type of agent results in the reassortment of cells in relation to cell age, thereby providing a chance for successive administrations of either type of agent. Taking advantage of such specific effects of agents on the tumor cell cycle, possible schedules for efficient cell sterilization were suggested: B.X(simultaneous administration) and A-X, X-B(two successive administrations at a scheduled interval) were found promissing. Finally, it was emphasized that much more information must be collected to formulate the cellular response of cycling and non-cycling fractions of the tumor to various exogenous agents. (J.P.N.)

  14. Metallothioneins in human tumors and potential roles in carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

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

    2003-12-10

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

  15. Metallothioneins in human tumors and potential roles in carcinogenesis

    International Nuclear Information System (INIS)

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

    2003-01-01

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

  16. A Novel Type of Non-coding RNA, nc886, Implicated in Tumor Sensing and Suppression

    Directory of Open Access Journals (Sweden)

    Yong Sun Lee

    2015-06-01

    Full Text Available nc886 (=vtRNA2-1, pre-miR-886, or CBL3 is a newly identified non-coding RNA (ncRNA that represses the activity of protein kinase R (PKR. nc886 is transcribed by RNA polymerase III (Pol III and is intriguingly the first case of a Pol III gene whose expression is silenced by CpG DNA hypermethylation in several types of cancer. PKR is a sensor protein that recognizes evading viruses and induces apoptosis to eliminate infected cells. Like viral infection, nc886 silencing activates PKR and induces apoptosis. Thus, the significance of the nc886:PKR pathway in cancer is to sense and eliminate pre-malignant cells, which is analogous to PKR's role in cellular innate immunity. Beyond this tumor sensing role, nc886 plays a putative tumor suppressor role as supported by experimental evidence. Collectively, nc886 provides a novel example how epigenetic silencing of a ncRNA contributes to tumorigenesis by controlling the activity of its protein ligand.

  17. Role of immune system in tumor progression and carcinogenesis.

    Science.gov (United States)

    Upadhyay, Shishir; Sharma, Nidhi; Gupta, Kunj Bihari; Dhiman, Monisha

    2018-01-12

    Tumor micro-environment has potential to customize the behavior of the immune cell according to their need. In immune-eliminating phase, immune cells eliminate transformed cells but after tumor establishment innate and adaptive immune cells synergistically provide shelter as well as fulfill their requirement that helps in progression. In between eliminating and establishment phase, equilibrium and escaping phase regulate the immune cells response. During immune-escaping, (1) the antigenic response generated is either inadequate, or focused entirely on tolerance, and (2) immune response generated is specific and effective, but the tumor skips immune recognition. In this review, we are discussing the critical role of immune cells and their cytokines before and after the establishment of tumor which might play a critical role during immunotherapy. © 2018 Wiley Periodicals, Inc.

  18. Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung cancer.

    Science.gov (United States)

    Yi, Fuming; Amarasinghe, Baru; Dang, Thao P

    2013-01-01

    Notch signaling plays an essential role in development as well as cancer. We have previously shown that Notch3 is important for lung cancer growth and survival. Notch receptors are activated through the interaction with their ligands, resulting in proteolytic cleavage of the receptors. This interaction is modulated by Fringe, a family of fucose-specific β1,3 N-acetylglucosaminyltransferases that modify the extracellular subunit of Notch receptors. Studies in developmental models showed that Fringe enhances Notch's response to Delta ligands at the expense of Jagged ligands. We observed that Manic Fringe expression is down-regulated in lung cancer. Since Jagged1, a known ligand for Notch3, is often over-expressed in lung cancer, we hypothesized that Fringe negatively regulates Notch3 activation. In this study, we show that re-expression of Manic Fringe down-regulates Notch3 target genes HES1 and HeyL and reduces tumor phenotype in vitro and in vivo. The mechanism for this phenomenon appears to be related to modulation of Notch3 protein stability. Proteasome inhibition reverses Manic Fringe-induced protein turnover. Taken together, our data provide the first evidence that Manic Fringe functions as a tumor suppressor in the lung and that the mechanism of its anti-tumor activity is mediated by inhibition of Notch3 activation.

  19. The role of the immune system in neurofibromatosis type 1-associated nervous system tumors.

    Science.gov (United States)

    Karmakar, Souvik; Reilly, Karlyne M

    2017-01-01

    With the recent development of new anticancer therapies targeting the immune system, it is important to understand which immune cell types and cytokines play critical roles in suppressing or promoting tumorigenesis. The role of mast cells in promoting neurofibroma growth in neurofibromatosis type 1 (NF1) patients was hypothesized decades ago. More recent experiments in mouse models have demonstrated the causal role of mast cells in neurofibroma development and of microglia in optic pathway glioma development. We review here what is known about the role of NF1 mutation in immune cell function and the role of immune cells in promoting tumorigenesis in NF1. We also review the therapies targeting immune cell pathways and their promise in NF1 tumors.

  20. Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice.

    Science.gov (United States)

    Weng, Mao-Chi; Wang, Mei-Hui; Tsai, Jai-Jen; Kuo, Yu-Cheng; Liu, Yu-Chang; Hsu, Fei-Ting; Wang, Hsin-Ell

    2018-03-13

    Regorafenib has been demonstrated in our previous study to trigger apoptosis through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) activation in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro However, the effect of regorafenib on NF-κB-modulated tumor progression in HCC in vivo is ambiguous. The aim of the present study is to investigate the effect of regorafenib on NF-κB-modulated tumor progression in HCC bearing mouse model. pGL4.50 luciferase reporter vector transfected SK-Hep1 (SK-Hep1/ luc2 ) and Hep3B 2.1-7 tumor bearing mice were established and used for this study. Mice were treated with vehicle or regorafenib (20 mg/kg/day by gavage) for 14 days. Effects of regorafenib on tumor growth and protein expression together with toxicity of regorafenib were evaluated with digital caliper and bioluminescence imaging (BLI), ex vivo Western blotting immunohistochemistry (IHC) staining, and measurement of body weight and pathological examination of liver tissue, respectively, in SK-Hep1/ luc2 and Hep3B 2.1-7 tumor bearing mice. The results indicated regorafenib significantly reduced tumor growth and expression of phosphorylated ERK, NF-κB p65 (Ser536), phosphorylated AKT and tumor progression-associated proteins. In addition, we found regorafenib induced both extrinsic and intrinsic apoptotic pathways. Body weight and liver morphology were not affected by regorafenib treatment. Our findings present the mechanism of tumor progression inhibition by regorafenib is linked to suppression of ERK/NF-κB signaling in SK-Hep1/ luc2 and Hep3B 2.1-7 tumor-bearing mice. ©2018 The Author(s).

  1. Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.

    Science.gov (United States)

    Lyu, Junfang; Yang, Eun Ju; Head, Sarah A; Ai, Nana; Zhang, Baoyuan; Wu, Changjie; Li, Ruo-Jing; Liu, Yifan; Yang, Chen; Dang, Yongjun; Kwon, Ho Jeong; Ge, Wei; Liu, Jun O; Shim, Joong Sup

    2017-11-28

    Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells

    International Nuclear Information System (INIS)

    Yasmin, Tania; Takahashi-Yanaga, Fumi; Mori, Jun; Miwa, Yoshikazu; Hirata, Masato; Watanabe, Yutaka; Morimoto, Sachio; Sasaguri, Toshiyuki

    2005-01-01

    To determine the mechanism by which differentiation-inducing factor-1 (DIF-1), a morphogen of Dictyostelium discoideum, inhibits tumor cell proliferation, we examined the effect of DIF-1 on the gene expression of cyclin D1. DIF-1 strongly reduced the expression of cyclin D1 mRNA and correspondingly decreased the amount of β-catenin in HeLa cells and squamous cell carcinoma cells. DIF-1 activated glycogen synthase kinase-3β (GSK-3β) and inhibition of GSK-3β attenuated the DIF-1-induced β-catenin degradation, indicating the involvement of GSK-3β in this effect. Moreover, DIF-1 reduced the activities of T-cell factor (TCF)/lymphoid enhancer factor (LEF) reporter plasmid and a reporter gene driven by the human cyclin D1 promoter. Eliminating the TCF/LEF consensus site from the cyclin D1 promoter diminished the effect of DIF-1. These results suggest that DIF-1 inhibits Wnt/β-catenin signaling, resulting in the suppression of cyclin D1 promoter activity

  3. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

    International Nuclear Information System (INIS)

    Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie; Oakley, Gregory G.; Wahl, James K.; Simpson, Melanie A.

    2011-01-01

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and β-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  4. Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma.

    Science.gov (United States)

    Liu, Tongxin; Sun, Quanquan; Li, Qi; Yang, Hua; Zhang, Yuqin; Wang, Rong; Lin, Xiaoshan; Xiao, Dong; Yuan, Yawei; Chen, Longhua; Wang, Wei

    2015-02-01

    Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual γ-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2-M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. ©2014 American Association for Cancer Research.

  5. The Pleiotropic Role of L1CAM in Tumor Vasculature

    Directory of Open Access Journals (Sweden)

    Francesca Angiolini

    2017-01-01

    Full Text Available Angiogenesis, the formation of new vessels, is a key step in the development, invasion, and dissemination of solid tumors and, therefore, represents a viable target in the context of antitumor therapy. Indeed, antiangiogenic approaches have given promising results in preclinical models and entered the clinical practice. However, in patients, the results obtained so far with antiangiogenic drugs have not completely fulfilled expectations, especially because their effect has been transient with tumors developing resistance and evasion mechanisms. A better understanding of the mechanisms that underlie tumor vascularization and the functional regulation of cancer vessels is a prerequisite for the development of novel and alternative antiangiogenic treatments. The L1 cell adhesion molecule (L1CAM, a cell surface glycoprotein previously implicated in the development and plasticity of the nervous system, is aberrantly expressed in the vasculature of various cancer types. L1CAM plays multiple pro-angiogenic roles in the endothelial cells of tumor-associated vessels, thus emerging as a potential therapeutic target. In addition, L1CAM prevents the maturation of cancer vasculature and its inhibition promotes vessel normalization, a process that is thought to improve the therapeutic response of tumors to cytotoxic drugs. We here provide an overview on tumor angiogenesis and antiangiogenic therapies and summarize the current knowledge on the biological role of L1CAM in cancer vasculature. Finally, we highlight the clinical implications of targeting L1CAM as a novel antiangiogenic and vessel-normalizing approach.

  6. MR imaging of gestational trophoblastic tumor: role of gadolinium enhancement

    International Nuclear Information System (INIS)

    Choi, Si Young; Byun, Jae Young; Kim, Bum Su; Yun, Young Hyun; Mun, Kyung Mi; Park, Kyung Sin; Kim, Byung Kee; Bae, Seog Nyeon; Shinn, Kyung Sub.

    1997-01-01

    The purpose of this study is to investigate the role of gadolinium enhanced MR imaging in the evaluation of gestational trophoblastic tumors (invasive mole and choriocarcinoma). Pre-enhanced T1-and T2-weighted images and gadolinium enhanced T1-weighted images of 34 gestational trophoblastic tumors (15 choriocarcinomas, 19 invasive moles) were retrospectively evaluated and enhancement patterns were analyzed. Morphologica differences and structural characteristics were analyzed by the evaluation of tumor margin, patterns of hemorrhagic necroses, the development of intratumoral vascularity, and molar villi. Graded scores of MR findings between pre- and gadolinium enhanced images were based on the following criteria : 1) visualization of tumor margin 2) distinction between tumor necrosis and zone of trophoblastic proliferation ; and 3) molar villi. Statistical differences between graded scores of pre- and post-enhanced images were analyzed. Gadolinium enhanced MR imaging was helpful for the visualization of tumor characteristics in gestational trophoblastic tumors and in differential diagnosis between invasive mole and choriocarcinoma. (author). 16 refs., 4 tabs., 4 figs

  7. Both p53-PUMA/NOXA-Bax-mitochondrion and p53-p21cip1 pathways are involved in the CDglyTK-mediated tumor cell suppression

    International Nuclear Information System (INIS)

    Yu, Zhendong; Wang, Hao; Zhang, Libin; Tang, Aifa; Zhai, Qinna; Wen, Jianxiang; Yao, Li; Li, Pengfei

    2009-01-01

    CDglyTK fusion suicide gene has been well characterized to effectively kill tumor cells. However, the exact mechanism and downstream target genes are not fully understood. In our study, we found that CDglyTK/prodrug treatment works more efficiently in p53 wild-type (HONE1) cells than in p53 mutant (CNE1) cells. We then used adenovirus-mediated gene delivery system to either knockdown or overexpress p53 and its target genes in these cells. Consistent results showed that both p53-PUMA/NOXA/Bcl2-Bax and p53-p21 pathways contribute to the CDglyTK induced tumor cell suppression. Our work for the first time addressed the role of p53 related genes in the CDglyTK/prodrug system.

  8. Both p53-PUMA/NOXA-Bax-mitochondrion and p53-p21cip1 pathways are involved in the CDglyTK-mediated tumor cell suppression

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Zhendong, E-mail: zdyu@hotmail.com [Department of Clinical laboratory, Peking University Shenzhen Hospital, Guangdong (China); Wang, Hao [Department of pathology, The Chinese University of Hong Kong, Hong Kong (China); Zhang, Libin; Tang, Aifa; Zhai, Qinna; Wen, Jianxiang; Yao, Li [Department of Clinical laboratory, Peking University Shenzhen Hospital, Guangdong (China); Li, Pengfei, E-mail: lipengfei@cuhk.edu.hk [Department of pathology, The Chinese University of Hong Kong, Hong Kong (China)

    2009-09-04

    CDglyTK fusion suicide gene has been well characterized to effectively kill tumor cells. However, the exact mechanism and downstream target genes are not fully understood. In our study, we found that CDglyTK/prodrug treatment works more efficiently in p53 wild-type (HONE1) cells than in p53 mutant (CNE1) cells. We then used adenovirus-mediated gene delivery system to either knockdown or overexpress p53 and its target genes in these cells. Consistent results showed that both p53-PUMA/NOXA/Bcl2-Bax and p53-p21 pathways contribute to the CDglyTK induced tumor cell suppression. Our work for the first time addressed the role of p53 related genes in the CDglyTK/prodrug system.

  9. PET measurements of hyperthermia-induced suppression of protein synthesis in tumors in relation to effects on tumor growth

    International Nuclear Information System (INIS)

    Daemen, B.J.; Elsinga, P.H.; Mooibroek, J.; Paans, A.M.; Wieringa, A.R.; Konings, A.W.; Vaalburg, W.

    1991-01-01

    Hyperthermia-induced metabolic changes in tumor tissue have been monitored by PET. Uptake of L-[1-11C]tyrosine in rhabdomyosarcoma tissue of Wag/Rij rats was dose-dependently reduced after local hyperthermia treatment at 42, 45, or 47 degrees C. Tumor blood flow, as measured by PET with 13NH3, appeared to be unchanged. The L-[1-11C]tyrosine uptake data were compared to uptake data of L-[1-14C]tyrosine and with data on the incorporation of L-[1-14C]tyrosine into tumor proteins. After intravenous injection, the 14C data were obtained from dissected tumor tissue. Heat-induced inhibition of the incorporation of L-[1-14C]tyrosine into tumor proteins tallied with the L-[1-11C]tyrosine uptake data. Heat-induced inhibition of amino acid uptake in the tumor correlated well with regression of tumor growth. It is concluded that PET using L-[1-11C]tyrosine is eligible for monitoring the effect of hyperthermia on tumor growth

  10. Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice.

    Science.gov (United States)

    Carr, Michael I; Roderick, Justine E; Zhang, Hong; Woda, Bruce A; Kelliher, Michelle A; Jones, Stephen N

    2016-12-27

    The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2 S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present study, we have generated an Mdm2 mutant mouse (Mdm2 Y393F ) to determine whether c-Abl phosphorylation of Mdm2 regulates the p53-mediated DNA damage response or p53 tumor suppression in vivo. The Mdm2 Y393F mice develop accelerated spontaneous and oncogene-induced tumors, yet display no defects in p53 stabilization and activity following acute genotoxic stress. Although apoptosis is unaltered in these mice, they recover more rapidly from radiation-induced bone marrow ablation and are more resistant to whole-body radiation-induced lethality. These data reveal an in vivo role for c-Abl phosphorylation of Mdm2 in regulation of p53 tumor suppression and bone marrow failure. However, c-Abl phosphorylation of Mdm2 Tyr393 appears to play a lesser role in governing Mdm2-p53 signaling than ATM phosphorylation of Mdm2 Ser394. Furthermore, the effects of these phosphorylation events on p53 regulation are not additive, as Mdm2 Y393F/S394A mice and Mdm2 S394A mice display similar phenotypes.

  11. Role of T lymphocytes in tumor response to radiotherapy

    Directory of Open Access Journals (Sweden)

    Sandra eDemaria

    2012-08-01

    Full Text Available Over thirty years ago, Helen Stone and colleagues compared the effects of local tumor irradiation in immunocompetent and T-cell deficient mice, providing the first evidence that tumor response to radiotherapy is impaired in the absence of a normal T cell repertoire. In the following three decades there has been an exponential growth in understanding T cells and the complex molecular mechanisms that regulate their activation, migration to tumors and effector functions. We now also know that tumor progression is intrinsically linked to the development of multiple immunosuppressive mechanisms that allow cancer cells to escape immune control. Recent evidence about the role of T cells in determining the prognosis and outcome of patients at any clinical stages of cancer has been instrumental in re-directing the concept of immunosurveillance and immunoediting from the realm of preclinical models to the reality of clinical observations. Importantly, cell death induced by standard anti-cancer therapies like chemotherapy and radiation has demonstrated to involve the immune system and, in certain specific settings, enable a specific immune response. It is, therefore, not surprising that the last few years have seen an increase in investigations exploring how to harness the ability of radiation to induce anti-tumor immune responses. We will review here the experimental evidence that anti-tumor T cells are key players in tumor control achieved by radiotherapy. The effects of radiation on the tumor that have been shown to enhance the priming and effector phases of anti-tumor immunity will be discussed. Finally, we will highlight promising combinations of immune response modifiers that enhance T cell function with radiotherapy that are being tested in the clinic.

  12. Role of T lymphocytes in tumor response to radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Demaria, Sandra [Department of Pathology, New York University School of Medicine and NYU Langone Medical Center, New York, NY (United States); Formenti, Silvia C., E-mail: sandra.demaria@nyumc.org [Department of Radiation Oncology, New York University School of Medicine and NYU Langone Medical Center, New York, NY (United States)

    2012-08-24

    Over thirty years ago, Helen Stone and colleagues compared the effects of local tumor irradiation in immunocompetent and T cell deficient mice, providing the first evidence that tumor response to radiotherapy is impaired in the absence of a normal T cell repertoire. In the following three decades there has been an exponential growth in understanding T cells and the complex molecular mechanisms that regulate their activation, migration to tumors and effector functions. We now also know that tumor progression is intrinsically linked to the development of multiple immunosuppressive mechanisms that allow cancer cells to escape immune control. Recent evidence about the role of T cells in determining the prognosis and outcome of patients at any clinical stages of cancer has been instrumental in re-directing the concept of immunosurveillance and immunoediting from the realm of preclinical models to the reality of clinical observations. Importantly, cell death induced by standard anti-cancer therapies like chemotherapy and radiation has been demonstrated to involve the immune system and, in certain specific settings, enable a specific immune response. It is, therefore, not surprising that the last few years have seen an increase in investigations exploring how to harness the ability of radiation to induce anti-tumor immune responses. We will review here the experimental evidence that anti-tumor T cells are key players in tumor control achieved by radiotherapy. The effects of radiation on the tumor that have been shown to enhance the priming and effector phases of anti-tumor immunity will be discussed. Finally, we will highlight promising combinations of immune response modifiers that enhance T cell function with radiotherapy which are being tested in the clinic.

  13. Role of T lymphocytes in tumor response to radiotherapy

    International Nuclear Information System (INIS)

    Demaria, Sandra; Formenti, Silvia C.

    2012-01-01

    Over thirty years ago, Helen Stone and colleagues compared the effects of local tumor irradiation in immunocompetent and T cell deficient mice, providing the first evidence that tumor response to radiotherapy is impaired in the absence of a normal T cell repertoire. In the following three decades there has been an exponential growth in understanding T cells and the complex molecular mechanisms that regulate their activation, migration to tumors and effector functions. We now also know that tumor progression is intrinsically linked to the development of multiple immunosuppressive mechanisms that allow cancer cells to escape immune control. Recent evidence about the role of T cells in determining the prognosis and outcome of patients at any clinical stages of cancer has been instrumental in re-directing the concept of immunosurveillance and immunoediting from the realm of preclinical models to the reality of clinical observations. Importantly, cell death induced by standard anti-cancer therapies like chemotherapy and radiation has been demonstrated to involve the immune system and, in certain specific settings, enable a specific immune response. It is, therefore, not surprising that the last few years have seen an increase in investigations exploring how to harness the ability of radiation to induce anti-tumor immune responses. We will review here the experimental evidence that anti-tumor T cells are key players in tumor control achieved by radiotherapy. The effects of radiation on the tumor that have been shown to enhance the priming and effector phases of anti-tumor immunity will be discussed. Finally, we will highlight promising combinations of immune response modifiers that enhance T cell function with radiotherapy which are being tested in the clinic.

  14. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    International Nuclear Information System (INIS)

    Guo, Jia; Liu, Xiuheng; Wang, Min

    2015-01-01

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo

  15. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jia; Liu, Xiuheng, E-mail: l_xiuheng@163.com; Wang, Min

    2015-09-04

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.

  16. Tumor-Suppressing Effect of MiR-4458 on Human Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Dan Tang

    2015-03-01

    Full Text Available Background: Besides multiple genetic and epigenetic changes of protein coding genes in hepatocellular carcinoma (HCC, growing evidence indicate that deregulation of miRNAs contribute to HCC development by influencing cell growth, apoptosis, migration, or invasion. IKBKE is amplified and over-expressed in a large percentage of human breast tumors and identified as an oncogene of human breast tumor. Microarray analysis showed that miR-4458 was down-regulated in HCC tissues. Methods: The level of miR-4458 was up-regulated by miR-4458 mimics transfection, or down-regulated by miR-4458 ASO transfection. Cell proliferation was assayed by MTT analysis. MiRNAs and mRNA expression were assayed by qRT-PCR. These potential targeted genes of miR-4458 were predicted by bioinformatic algorithms. Dual luciferase reporter assay system was used to analyze the interaction between miR-4458 and IKBKE. IKBKE protein level was assayed by Western blot. The role of miR-4458 or IKBKE in the survival of HCC patients were revealed by Kaplan-Meier plot of overall survival. Results: Lower miR-4458 expression level or higher IKBKE level in HCC tissues correlated with worse prognosis of HCC patients. Overexpression of miR-4458 inhibited the HCC cells growth and vice versa. MiR-4458 played its role via targeting 3'UTR of IKBKE. Conclusions: MiR-4458 or IKBKE may be potential predictors of HCC prognosis. Restoration of miR-4458 or inhibition of IKBKE could be a prospective therapeutic approach for HCC.

  17. Stage dependent expression and tumor suppressive function of FAM134B (JK1) in colon cancer.

    Science.gov (United States)

    Islam, Farhadul; Gopalan, Vinod; Wahab, Riajul; Smith, Robert A; Qiao, Bin; Lam, Alfred King-Yin

    2017-01-01

    The aims of the present study are to investigate sub-cellular location, differential expression in different cancer stages and functional role of FAM134B in colon cancer development. FAM134B expression was studied and quantified at protein and mRNA levels in cell lines using immunocytochemistry, Western blot and real-time PCR. In vitro functional assays and an in vivo xenotransplantation mouse models were used to investigate the molecular role of FAM134B in cancer cell biology in response to FAM134B silencing with shRNA lentiviral particles. FAM134B protein was noted in both cytoplasm and nuclei of cancer cells. In cancer cells derived from stage IV colon cancer, FAM134B expression was remarkably reduced when compared to non-cancer colon cells and cancer cells derived from stage II colon cancer. FAM134B knockdown significantly (P colon cancer cells following lentiviral transfection. Furthermore, FAM134B suppression significantly increased (34-52%; P cancer suppressor gene in colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Suppression of tumor growth and angiogenesis by a specific antagonist of the cell-surface expressed nucleolin.

    Directory of Open Access Journals (Sweden)

    Damien Destouches

    Full Text Available BACKGROUND: Emerging evidences suggest that nucleolin expressed on the cell surface is implicated in growth of tumor cells and angiogenesis. Nucleolin is one of the major proteins of the nucleolus, but it is also expressed on the cell surface where is serves as a binding protein for variety of ligands implicated in cell proliferation, differentiation, adhesion, mitogenesis and angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, here we show that the growth of tumor cells and angiogenesis are suppressed in various in vitro and in vivo experimental models. HB-19 inhibited colony formation in soft agar of tumor cell lines, impaired migration of endothelial cells and formation of capillary-like structures in collagen gel, and reduced blood vessel branching in the chick embryo chorioallantoic membrane. In athymic nude mice, HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in nude mice, and in some cases eliminated measurable tumors while displaying no toxicity to normal tissue. This potent antitumoral effect is attributed to the direct inhibitory action of HB-19 on both tumor and endothelial cells by blocking and down regulating surface nucleolin, but without any apparent effect on nucleolar nucleolin. CONCLUSION/SIGNIFICANCE: Our results illustrate the dual inhibitory action of HB-19 on the tumor development and the neovascularization process, thus validating the cell-surface expressed nucleolin as a strategic target for an effective cancer drug. Consequently, the HB-19 pseudopeptide provides a unique candidate to consider for innovative cancer therapy.

  19. Targeting of GIT1 by miR-149* in breast cancer suppresses cell proliferation and metastasis in vitro and tumor growth in vivo

    Directory of Open Access Journals (Sweden)

    Dong Y

    2017-12-01

    the tumor growth, while restored GIT1 accelerated the tumor growth in nude mice after 35 days of tumor xenograft. Collectively, these findings concluded that miR-149* might exert a tumor suppressive role in breast cancer by targeting GIT1. Keywords: microRNA 149*, miR-149*, G protein-coupled receptor kinase interacting protein 1, GIT1, tumor suppressive role, breast cancer

  20. Suppression of human breast tumors in NOD/SCID mice by CD44 shRNA gene therapy combined with doxorubicin treatment

    Directory of Open Access Journals (Sweden)

    Pham PV

    2012-05-01

    Full Text Available Phuc Van Pham1, Ngoc Bich Vu1, Thuy Thanh Duong1, Tam Thanh Nguyen1, Nhung Hai Truong1, Nhan Lu Chinh Phan1, Tue Gia Vuong1, Viet Quoc Pham1, Hoang Minh Nguyen1, Kha The Nguyen1, Nhung Thi Nguyen1, Khue Gia Nguyen1, Lam Tan Khat1, Dong Van Le2, Kiet Dinh Truong1, Ngoc Kim Phan11Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, HCM City, 2Military Medical University, Ha Noi, VietnamBackground: Breast cancer stem cells with a CD44+CD24- phenotype are the origin of breast tumors. Strong CD44 expression in this population indicates its important role in maintaining the stem cell phenotype. Previous studies show that CD44 down-regulation causes CD44+CD24- breast cancer stem cells to differentiate into non-stem cells that are sensitive to antitumor drugs and lose many characteristics of the original cells. In this study, we determined tumor suppression in non-obese severe combined immunodeficiency mice using CD44 shRNA therapy combined with doxorubicin treatment.Methods: Tumor-bearing non-obese severe combined immunodeficiency mice were established by injection of CD44+CD24- cells. To track CD44+CD24- cells, green fluorescence protein was stably transduced using a lentiviral vector prior to injection into mice. The amount of CD44 shRNA lentiviral vector used for transduction was based on CD44 down-regulation by in vitro CD44 shRNA transduction. Mice were treated with direct injection of CD44 shRNA lentiviral vector into tumors followed by doxorubicin administration after 48 hours. The effect was evaluated by changes in the size and weight of tumors compared with that of the control.Results: The combination of CD44 down-regulation and doxorubicin strongly suppressed tumor growth with significant differences in tumor sizes and weights compared with that of CD44 down-regulation or doxorubicin treatment alone. In the combination of CD44 down-regulation and doxorubicin group, the tumor weight was

  1. A limited role for suppression in the central field of individuals with strabismic amblyopia.

    Science.gov (United States)

    Barrett, Brendan T; Panesar, Gurvinder K; Scally, Andrew J; Pacey, Ian E

    2012-01-01

    Although their eyes are pointing in different directions, people with long-standing strabismic amblyopia typically do not experience double-vision or indeed any visual symptoms arising from their condition. It is generally believed that the phenomenon of suppression plays a major role in dealing with the consequences of amblyopia and strabismus, by preventing images from the weaker/deviating eye from reaching conscious awareness. Suppression is thus a highly sophisticated coping mechanism. Although suppression has been studied for over 100 years the literature is equivocal in relation to the extent of the retina that is suppressed, though the method used to investigate suppression is crucial to the outcome. There is growing evidence that some measurement methods lead to artefactual claims that suppression exists when it does not. Here we present the results of an experiment conducted with a new method to examine the prevalence, depth and extent of suppression in ten individuals with strabismic amblyopia. Seven subjects (70%) showed no evidence whatsoever for suppression and in the three individuals who did (30%), the depth and extent of suppression was small. Suppression may play a much smaller role in dealing with the negative consequences of strabismic amblyopia than previously thought. Whereas recent claims of this nature have been made only in those with micro-strabismus our results show extremely limited evidence for suppression across the central visual field in strabismic amblyopes more generally. Instead of suppressing the image from the weaker/deviating eye, we suggest the visual system of individuals with strabismic amblyopia may act to maximise the possibilities for binocular co-operation. This is consistent with recent evidence from strabismic and amblyopic individuals that their binocular mechanisms are intact, and that, just as in visual normals, performance with two eyes is better than with the better eye alone in these individuals.

  2. A limited role for suppression in the central field of individuals with strabismic amblyopia.

    Directory of Open Access Journals (Sweden)

    Brendan T Barrett

    Full Text Available BACKGROUND: Although their eyes are pointing in different directions, people with long-standing strabismic amblyopia typically do not experience double-vision or indeed any visual symptoms arising from their condition. It is generally believed that the phenomenon of suppression plays a major role in dealing with the consequences of amblyopia and strabismus, by preventing images from the weaker/deviating eye from reaching conscious awareness. Suppression is thus a highly sophisticated coping mechanism. Although suppression has been studied for over 100 years the literature is equivocal in relation to the extent of the retina that is suppressed, though the method used to investigate suppression is crucial to the outcome. There is growing evidence that some measurement methods lead to artefactual claims that suppression exists when it does not. METHODOLOGY/RESULTS: Here we present the results of an experiment conducted with a new method to examine the prevalence, depth and extent of suppression in ten individuals with strabismic amblyopia. Seven subjects (70% showed no evidence whatsoever for suppression and in the three individuals who did (30%, the depth and extent of suppression was small. CONCLUSIONS: Suppression may play a much smaller role in dealing with the negative consequences of strabismic amblyopia than previously thought. Whereas recent claims of this nature have been made only in those with micro-strabismus our results show extremely limited evidence for suppression across the central visual field in strabismic amblyopes more generally. Instead of suppressing the image from the weaker/deviating eye, we suggest the visual system of individuals with strabismic amblyopia may act to maximise the possibilities for binocular co-operation. This is consistent with recent evidence from strabismic and amblyopic individuals that their binocular mechanisms are intact, and that, just as in visual normals, performance with two eyes is better than

  3. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model.

    Science.gov (United States)

    Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

    2010-02-01

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the alpha-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the alpha5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer.

  4. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model

    International Nuclear Information System (INIS)

    Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

    2010-01-01

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the α-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the α5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer

  5. Wortmannin efficiently suppresses the recovery from radiation-induced damage in pimonidazole-unlabeled quiescent tumor cell population

    International Nuclear Information System (INIS)

    Masunaga, Shin-ichiro; Suzuki, Minoru; Kondo, Natsuko; Narabayashi, Masaru; Ono, Koji; Sakurai, Yoshinori; Tanaka, Hiroki; Maruhashi, Akira

    2013-01-01

    Labeling of proliferating (P) cells in mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2'-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after pimonidazole administration followed by caffeine or wortmannin treatment. Twenty-four hours later, assessment of the responses of quiescent (Q) and total (=P+Q) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using an assay performed 24 hours after irradiation, was more clearly observed in Q cells than total cells. In both the pimonidazole-unlabeled and the whole cell fractions, wortmannin efficiently suppressed the reduction in sensitivity due to delayed assay. Wortmannin combined with γ-ray irradiation is useful for suppressing the recovery from radiation-induced damage especially in the pimonidazole-unlabeled cell fraction within the total and Q tumor cell populations. (author)

  6. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    likely to be mechanistic drivers behind the observed tumor growth suppression. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.

    Directory of Open Access Journals (Sweden)

    Sathidpak Nantasanti

    Full Text Available The tumor suppressors Retinoblastoma (Rb and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC. DDC is metabolized mainly by cytochrome P450 (Cyp3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.

  8. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution

    DEFF Research Database (Denmark)

    Pedersen, Line; Idorn, Manja; Olofsson, Gitte H.

    2016-01-01

    Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models....... Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed...

  9. Emerging Role of the Unfolded Protein Response in Tumor Immunosurveillance.

    Science.gov (United States)

    Vanacker, Hélène; Vetters, Jessica; Moudombi, Lyvia; Caux, Christophe; Janssens, Sophie; Michallet, Marie-Cécile

    2017-07-01

    Disruption of endoplasmic reticulum (ER) homeostasis results in ER stress and activation of the unfolded protein response (UPR). This response alleviates cell stress, and is activated in both tumor cells and tumor infiltrating immune cells. The UPR plays a dual function in cancer biology, acting as a barrier to tumorigenesis at the premalignant stage, while fostering cancer maintenance in established tumors. In infiltrating immune cells, the UPR has been involved in both immunosurveillance and immunosuppressive functions. This review aims to decipher the role of the UPR at different stages of tumorigenesis and how the UPR shapes the balance between immunosurveillance and immune escape. This knowledge may improve existing UPR-targeted therapies and the design of novel strategies for cancer treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. miR-106a suppresses tumor cells death in colorectal cancer through targeting ATG7.

    Science.gov (United States)

    Hao, Haibin; Xia, Guangfeng; Wang, Chao; Zhong, Fuping; Liu, Laipeng; Zhang, Dong

    2017-06-01

    Autophagy-related gene 7 (ATG7) and miR-106a play an important role in cancer cell autophagy and apoptosis, but the outcome of ATG7 and miR-106a in colorectal cancer (CRC) still remains not clear. In this study, we found that ATG7 and miR-106a expression were mutually related with cell death and prognosis in CRC patients. In addition, we also showed that ATG7 and miR-106a expression were changeable in colorectal cancer cell lines when compared with normal cell lines, but ATG7 and miR-106a mRNA level was negatively correlated. Furthermore, ATG7 protein and mRNA levels decreased after over-expression of miR-106a, whereas the suppression of ATG7 had the opposite effect. We confirmed that miR-106a down-regulated ATG7 mRNA level by binding the specific sequence of ATG7 mRNA 3'UTR region. Moreover, the over-expression of ATG7 induced CRC cells death both in vitro and in vivo. Taken together, our study data demonstrated that ATG7 aggravated the cell death of CRC, which was inhibited by miR-106a.

  11. Role of Tumor-Derived Chemokines in Osteolytic Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Salvatore J. Coniglio

    2018-06-01

    Full Text Available Metastasis is the primary cause of mortality and morbidity in cancer patients. The bone marrow is a common destination for many malignant cancers, including breast carcinoma (BC, prostate carcinoma, multiple myeloma, lung carcinoma, uterine cancer, thyroid cancer, bladder cancer, and neuroblastoma. The molecular mechanism by which metastatic cancer are able to recognize, infiltrate, and colonize bone are still unclear. Chemokines are small soluble proteins which under normal physiological conditions mediate chemotactic trafficking of leukocytes to specific tissues in the body. In the context of metastasis, the best characterized role for the chemokine system is in the regulation of primary tumor growth, survival, invasion, and homing to specific secondary sites. However, there is ample evidence that metastatic tumors exploit chemokines to modulate the metastatic niche within bone which ultimately results in osteolytic bone disease. In this review, we examine the role of chemokines in metastatic tumor growth within bone. In particular, the chemokines CCL2, CCL3, IL-8/CXCL8, and CXCL12 are consistently involved in promoting osteoclastogenesis and tumor growth. We will also evaluate the suitability of chemokines as targets for chemotherapy with the use of neutralizing antibodies and chemokine receptor-specific antagonists.

  12. Explicit hypoxia targeting with tumor suppression by creating an "obligate" anaerobic Salmonella Typhimurium strain.

    Science.gov (United States)

    Yu, Bin; Yang, Mei; Shi, Lei; Yao, Yandan; Jiang, Qinqin; Li, Xuefei; Tang, Lei-Han; Zheng, Bo-Jian; Yuen, Kwok-Yung; Smith, David K; Song, Erwei; Huang, Jian-Dong

    2012-01-01

    Using bacteria as therapeutic agents against solid tumors is emerging as an area of great potential in the treatment of cancer. Obligate and facultative anaerobic bacteria have been shown to infiltrate the hypoxic regions of solid tumors, thereby reducing their growth rate or causing regression. However, a major challenge for bacterial therapy of cancer with facultative anaerobes is avoiding damage to normal tissues. Consequently the virulence of bacteria must be adequately attenuated for therapeutic use. By placing an essential gene under a hypoxia conditioned promoter, SalmonellaTyphimurium strain SL7207 was engineered to survive only in anaerobic conditions (strain YB1) without otherwise affecting its functions. In breast tumor bearing nude mice, YB1 grew within the tumor, retarding its growth, while being rapidly eliminated from normal tissues. YB1 provides a safe bacterial vector for anti-tumor therapies without compromising the other functions or tumor fitness of the bacterium as attenuation methods normally do.

  13. Explicit hypoxia targeting with tumor suppression by creating an “obligate” anaerobic Salmonella Typhimurium strain

    Science.gov (United States)

    Yu, Bin; Yang, Mei; Shi, Lei; Yao, Yandan; Jiang, Qinqin; Li, Xuefei; Tang, Lei-Han; Zheng, Bo-Jian; Yuen, Kwok-Yung; Smith, David K.; Song, Erwei; Huang, Jian-Dong

    2012-01-01

    Using bacteria as therapeutic agents against solid tumors is emerging as an area of great potential in the treatment of cancer. Obligate and facultative anaerobic bacteria have been shown to infiltrate the hypoxic regions of solid tumors, thereby reducing their growth rate or causing regression. However, a major challenge for bacterial therapy of cancer with facultative anaerobes is avoiding damage to normal tissues. Consequently the virulence of bacteria must be adequately attenuated for therapeutic use. By placing an essential gene under a hypoxia conditioned promoter, Salmonella Typhimurium strain SL7207 was engineered to survive only in anaerobic conditions (strain YB1) without otherwise affecting its functions. In breast tumor bearing nude mice, YB1 grew within the tumor, retarding its growth, while being rapidly eliminated from normal tissues. YB1 provides a safe bacterial vector for anti-tumor therapies without compromising the other functions or tumor fitness of the bacterium as attenuation methods normally do. PMID:22666539

  14. [The role of endoscopy in gastroenteropancreatic neuroendocrine tumors].

    Science.gov (United States)

    Magno, L; Sivero, L; Napolitano, V; Ruggiero, S; Fontanarosa, G; Massa, S

    2010-01-01

    Versione italiana Riassunto: Il ruolo dell'endoscopia nei tumori neuroendocrini gastroenteropancreatici. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa I tumori neuroendocrini (NET) gastro-entero-pancreatici (GEP) sono neoplasie rare che originano dalle cellule neuroendocrine del tubo digerente e del pancreas. L'endoscopia digestiva e l'ecoendoscopia rivestono un ruolo importante nella diagnosi, stadiazione e sorveglianza dei pazienti con NET. Inoltre, in casi selezionati, le tecniche endoscopiche operative consentono il trattamento di queste neoplasie in fase precoce. English version Summary: The role of endoscopy in gastroenteropancreatic neuroendocrine tumors. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa Gastroenteropancreatic (GEP) neuroendocrine tumors (NET) are rare neoplasia arisen from neuroendocrine cells present in the gut mucosa and pancreas. Digestive endoscopy and endoscopic ultrasonography play a relevant role in NET diagnosis, stadiation and surveillance. Moreover, in selected patients, surgical endoscopy allows the tratment of these cancers at an early stage.

  15. Emerging Roles for Eosinophils in the Tumor Microenvironment.

    Science.gov (United States)

    Reichman, Hadar; Karo-Atar, Danielle; Munitz, Ariel

    2016-11-01

    Eosinophils are evolutionary conserved cells largely studied in the context of allergy. Although eosinophils were first described in tumors more than 120 years ago, their roles in cancer are often overlooked. This is puzzling given their potent immune modulatory, cytotoxic, and/or tissue repair capabilities, and recent studies demonstrating key roles for eosinophils in contexts far beyond their 'classical' field (e.g., metabolism, thermogenesis, and tissue regeneration). Recent data suggest that this frequently ignored cell is emerging as a potent immune effector and immune modulator in the tumor microenvironment. This review discusses the relevance of eosinophils to tumorigenesis and the potential to harness their function in cancer therapies. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Prolonged oxidative stress down-regulates Early B cell factor 1 with inhibition of its tumor suppressive function against cholangiocarcinoma genesis

    Directory of Open Access Journals (Sweden)

    Napat Armartmuntree

    2018-04-01

    Full Text Available Early B cell factor 1 (EBF1 is a transcription factor involved in the differentiation of several stem cell lineages and it is a negative regulator of estrogen receptors. EBF1 is down-regulated in many tumors, and is believed to play suppressive roles in cancer promotion and progression. However, the functional roles of EBF1 in carcinogenesis are unclear. Liver fluke-infection-associated cholangiocarcinoma (CCA is an oxidative stress-driven cancer of bile duct epithelium. In this study, we investigated EBF1 expression in tissues from CCA patients, CCA cell lines (KKU-213, KKU-214 and KKU-156, cholangiocyte (MMNK1 and its oxidative stress-resistant (ox-MMNK1-L cell lines. The formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG was used as an oxidative stress marker. Our results revealed that EBF1 expression was suppressed in cancer cells compared with the individual normal bile duct cells at tumor adjacent areas of CCA tissues. CCA patients with low EBF1 expression and high formation of 8-oxodG were shown to correlate with poor survival. Moreover, EBF1 was suppressed in the oxidative stress-resistant cell line and all of CCA cell lines compared to the cholangiocyte cell line. This suggests that prolonged oxidative stress suppressed EBF1 expression and the reduced EBF1 level may facilitate CCA genesis. To elucidate the significance of EBF1 suppression in CCA genesis, EBF1 expression of the MMNK1 cell line was down-regulated by siRNA technique, and its effects on stem cell properties (CD133 and Oct3/4 expressions, tumorigenic properties (cell proliferation, wound healing and cell migration, estrogen responsive gene (TFF1, estrogen-stimulated wound healing, and cell migration were examined. The results showed that CD133, Oct3/4 and TFF1 expression levels, wound healing, and cell migration of EBF1 knockdown-MMNK1 cells were significantly increased. Also, cell migration of EBF1-knockdown cells was significantly enhanced after 17

  17. Ruxolitinib combined with vorinostat suppresses tumor growth and alters metabolic phenotype in hematological diseases.

    Science.gov (United States)

    Civallero, Monica; Cosenza, Maria; Pozzi, Samantha; Sacchi, Stefano

    2017-11-28

    JAK-2 dysregulation plays an important role as an oncogenic driver, and is thus a promising therapeutic target in hematological malignancies. Ruxolitinib is a pyrrolo[2.3-d]pyrimidine derivative with inhibitory activity against JAK1 and JAK2, moderate activity against TYK2, and minor activity against JAK3. Vorinostat is an HDAC inhibitor that reduces JAK-2 expression, thus affecting JAK-2 mRNA expression and increasing JAK-2 proteasomal deterioration. Here we hypothesized that the combination of ruxolitinib and vorinostat could have synergistic effects against hematological disease. We tested combinations of low doses of ruxolitinib and vorinostat in 12 cell lines, and observed highly synergistic cytotoxic action in six cell lines, which was maintained for up to 120 h in the presence of stromal cells. The sensitivity of the six cell lines may be explained by the broad effects of the drug combination, which can affect various targets. Treatment with the combination of ruxolitinib and vorinostat appeared to induce a possible reversal of the Warburg effect, with associated ROS production, apoptotic events, and growth inhibition. Decreased glucose metabolism may have markedly sensitized the six more susceptible cell lines to combined treatment. Therapeutic inhibition of the JAK/STAT pathway seems to offer substantial anti-tumor benefit, and combined therapy with ruxolitinib and vorinostat may represent a promising novel therapeutic modality for hematological neoplasms.

  18. EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression.

    Science.gov (United States)

    Gu, Jian-Wei; Makey, Kristina L; Tucker, Kevan B; Chinchar, Edmund; Mao, Xiaowen; Pei, Ivy; Thomas, Emily Y; Miele, Lucio

    2013-05-02

    The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood. The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1α and NFκB, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer progression. Sixteen eight-wk-old female mice (C57BL/6 J) were inoculated with 10^6 E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight mice received EGCG at 50-100 mg/kg/d in drinking water for 4 weeks. 8 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, heart and limb muscles were collected for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. EGCG treatment significantly reduced tumor weight over the control (0.37 ± 0.15 vs. 1.16 ± 0.30 g; P < 0.01), tumor CD (109 ± 20 vs. 156 ± 12 capillary #/mm^2; P < 0.01), tumor VEGF expression (45.72 ± 1.4 vs. 59.03 ± 3.8 pg/mg; P < 0.01), respectively. But, it has no effects on the body weight, heart weight, angiogenesis and VEGF expression in the heart and skeletal muscle of mice. EGCG at 50 μg/ml significantly inhibited the activation of HIF-1α and NFκB as well as VEGF expression in cultured E0771 cells, compared to the control, respectively. These findings support the hypothesis that EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1α and NFκB activation as well as VEGF expression.

  19. A reason for intermittent fasting to suppress the awakening of dormant breast tumors.

    Science.gov (United States)

    Lankelma, Jan; Kooi, Bob; Krab, Klaas; Dorsman, Josephine C; Joenje, Hans; Westerhoff, Hans V

    2015-01-01

    For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors will contain anoxic living tumor cells. These cells are dangerous, because they are capable of inducing angiogenesis, which will "wake up" the tumor. Anoxic cells are dependent on anaerobic glucose breakdown for ATP generation. The local extracellular glucose concentration gradient is determined by the blood glucose concentration and by consumption by cells closer to the nearest blood vessel. The blood glucose concentration can be lowered by 20-40% during fasting. We calculated that glucose supply to the potentially hazardous anoxic cells can thereby be reduced significantly, resulting in cell death specifically of the anoxic tumor cells. We hypothesize that intermittent fasting will help to reduce the incidence of tumor relapse via reducing the number of anoxic tumor cells and tumor awakening. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. A reason for intermittent fasting to suppress the awakening of dormant breast tumors.

    NARCIS (Netherlands)

    Lankelma, J.; Kooi, B.W.; Krab, K.; Dorsman, J.C.; Joenje, H.; Westerhoff, H.V.

    2015-01-01

    For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors

  1. A reason for intermittent fasting to suppress the awakening of dormant breast tumors

    NARCIS (Netherlands)

    Lankelma, J.; Kooi, B.; Krab, K.; Dorsman, J.C.; Joenje, H.; Westerhoff, H.V.

    2015-01-01

    For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors

  2. A Limited Role for Suppression in the Central Field of Individuals with Strabismic Amblyopia

    OpenAIRE

    Barrett, Brendan T.; Panesar, Gurvinder K.; Scally, Andrew J.; Pacey, Ian E.

    2012-01-01

    BACKGROUND: Although their eyes are pointing in different directions, people with long-standing strabismic amblyopia typically do not experience double-vision or indeed any visual symptoms arising from their condition. It is generally believed that the phenomenon of suppression plays a major role in dealing with the consequences of amblyopia and strabismus, by preventing images from the weaker/deviating eye from reaching conscious awareness. Suppression is thus a highly sophisticated coping m...

  3. The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.

    Science.gov (United States)

    Bennewith, Kevin L; Huang, Xin; Ham, Christine M; Graves, Edward E; Erler, Janine T; Kambham, Neeraja; Feazell, Jonathan; Yang, George P; Koong, Albert; Giaccia, Amato J

    2009-02-01

    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 s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography 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 colocalization 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.

  4. Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway.

    Science.gov (United States)

    Pramanik, Kartick C; Kudugunti, Shashi K; Fofaria, Neel M; Moridani, Majid Y; Srivastava, Sanjay K

    2013-09-01

    Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE

  5. Trehalose Liposomes Suppress the Growth of Tumors on Human Lung Carcinoma-bearing Mice by Induction of Apoptosis In Vivo.

    Science.gov (United States)

    Ichihara, Hideaki; Kuwabara, Keiji; Matsumoto, Yoko

    2017-11-01

    Previous evidence demonstrates that trehalose liposomes (DMTreC14) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and α-D-glycopyranosyl-α-D-glucopyranoside monomyristate (TreC14) inhibit proliferation and invasion on lung carcinoma (A549 cells) in vitro. Here, we aimed to investigate suppressive effects of DMTreC14 on the growth of tumor on human lung carcinoma bearing mice. DMTreC14 composed of 30 mol% DMPC and 70 mol% TreC14 were prepared by the sonication method. Anti-tumor activities of DMTreC14 using the subcutaneous and orthotopic graft-bearing mice of A549 cells were investigated in vivo. The remarkable reduction of volume and weight in subcutaneous tumors on subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were obtained. Apoptotic-positive cells in the subcutaneous tumor slice of subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were observed using TUNEL staining. Lung weights on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 were markedly decreased compared to those of the control group. Remarkable decrease in dimensions of tumor area of lung on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 was obtained in histological analysis using the hematoxylin and eosin staining. Remarkably high anti-tumor activities of DMTreC14 for the subcutaneous and orthotopic graft-bearing mice of lung carcinoma accompanied with apoptosis were revealed for the first time in vivo. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  6. Injury Signals Cooperate with Nf1 Loss to Relieve the Tumor-Suppressive Environment of Adult Peripheral Nerve

    Directory of Open Access Journals (Sweden)

    Sara Ribeiro

    2013-10-01

    Full Text Available Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1−/− mSCs redifferentiate normally, whereas at the wound site Nf1−/− mSCs give rise to neurofibromas in both Nf1+/+ and Nf1+/− backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.

  7. Immune Suppression in Tumors as a Surmountable Obstacle to Clinical Efficacy of Cancer Vaccines

    International Nuclear Information System (INIS)

    Wieërs, Grégoire; Demotte, Nathalie; Godelaine, Danièle; Bruggen, Pierre van der

    2011-01-01

    Human tumors are usually not spontaneously eliminated by the immune system and therapeutic vaccination of cancer patients with defined antigens is followed by tumor regressions only in a small minority of the patients. The poor vaccination effectiveness could be explained by an immunosuppressive tumor microenvironment. Because T cells that infiltrate tumor metastases have an impaired ability to lyse target cells or to secrete cytokine, many researchers are trying to decipher the underlying immunosuppressive mechanisms. We will review these here, in particular those considered as potential therapeutic targets. A special attention will be given to galectins, a family of carbohydrate binding proteins. These lectins have often been implicated in inflammation and cancer and may be useful targets for the development of new anti-cancer therapies

  8. Tumor Suppression and Sensitization to Taxol Induced Apoptosis of E1A in Breast Cancer Cells

    National Research Council Canada - National Science Library

    Liao, Yong

    2002-01-01

    The purpose of this project is to study the molecular mechanisms underlying ElA's proapoptotic effect and anti-tumor activity and to dissect the functional domains of ElA that are critical for its antitumor activity...

  9. Tumor Suppression and Sensitization to Taxol Induces Apoptosis of EIA in Breast Cancer Cells

    National Research Council Canada - National Science Library

    Liao, Yong

    2005-01-01

    The purpose of this project is to study the molecular mechanisms underlying ElA's proapoptotic effect and anti-tumor activity and to dissect the functional domains of ElA that are critical for its antitumor activity...

  10. Mechanism of immune suppression by ultraviolet irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology

    International Nuclear Information System (INIS)

    De Fabo, E.C.; Noonan, F.P.

    1983-01-01

    UV irradiation of mice causes a systemic immune alteration that can be detected either by suppression of the immunologic rejection of UV-induced tumors, or by suppression of contact hypersensitivity (CHS). Suppression of these two immunologic responses has similar photobiologic characteristics and in both cases is associated with the generation of antigen-specific suppressor T cells. To identify whether a specific photoreceptor for this effect exists, the relative wavelength effectiveness (action spectrum) was determined for the UV-induced suppression of CHS. Narrow bands of UV (half bandwidth 3 nm) were used at 10 wavelengths from 250 to 320 nm to obtain dose-response curves. The action spectrum derived from the dose-response curves has a maximum between 260 and 270 nm, a shoulder at 280-290 nm, and declines steadily to approximately 3% of maximum at 320 nm. The finding of such a clearly defined wavelength dependence implies the presence of a specific photoreceptor for this effect. Removing the stratum corneum by tape stripping before UV irradiation prevented the suppression of CHS using 254-nm radiation, suggesting the photoreceptor is superficially located in the skin. The hypothesis is advanced that the photoreceptor for systemic UV-induced immunosuppression of contact hypersensitivity may be urocanic acid. As such, it may also play a role in UV-induced carcinogenesis via the production of tumor-specific suppressor cells

  11. The role of inducer cells in mediating in vitro suppression of feline immunodeficiency virus replication

    International Nuclear Information System (INIS)

    Phadke, Anagha P.; Choi, In-Soo; Li Zhongxia; Weaver, Eric; Collisson, Ellen W.

    2004-01-01

    CD8 + T-cell-mediated suppression of feline immunodeficiency virus (FIV) replication has been described by several groups, although the mechanisms of activation and conditions for viral suppression vary with the methodologies. We have previously reported that CD8 + T-cell-mediated suppression of FIV replication required inducer cell stimulation of the effector cells. The focus of the present study was to examine the essential role of inducer cells required for the induction of this soluble anti-FIV activity. Both FIV-PPR-infected T cells and feline skin fibroblasts (FSF) infected with an alphavirus vector expressing FIV capsid or the irrelevant antigen lacZ, stimulated autologous or heterologous effector cells to produce supernatants that suppressed FIV replication. Thus, induction of this suppression of FIV replication did not strictly require autologous inducer cells and did not require the presence of FIV antigen. Anti-viral activity correlated with the presence of CD8 + T cells. Suppression was maximal when the inducer cells and the effector cells were in contact with each other, because separation of the inducer and effector cells by a 0.45-μm membrane reduced FIV suppression by approximately 50%. These findings emphasize the importance for membrane antigen interactions and cytokines in the optimal induction of effector cell synthesis of the soluble anti-FIV activity

  12. Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

    Directory of Open Access Journals (Sweden)

    Kathrin Rupertus

    2012-01-01

    Full Text Available Background. Mobilization of c-Kit+ hematopoietic cells (HCs contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy. Methods. BALB/c mice (=16 were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals (=8 additionally received a neutralizing anti-SDF-1 antibody. Animals (=8 treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis. Results. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration. Conclusion. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

  13. Melatonin exerts anti-oral cancer effect via suppressing LSD1 in patient-derived tumor xenograft models

    Science.gov (United States)

    Yang, Cheng-Yu; Lin, Chih-Kung; Tsao, Chang-Huei; Hsieh, Cheng-Chih; Lin, Gu-Jiun; Ma, Kuo-Hsing; Shieh, Yi-Shing; Sytwu, Huey-Kang; Chen, Yuan-Wu

    2017-01-01

    Aberrant activation of histone lysine-specific demethylase (LSD1) increases tumorigenicity; hence, LSD1 is considered a therapeutic target for various human cancers. Although melatonin, an endogenously produced molecule, may defend against various cancers, the precise mechanism involved in its anti-oral cancer effect remains unclear. Patient-derived tumor xenograft (PDTX) models are preclinical models that can more accurately reflect human tumor biology compared with cell line xenograft models. Here, we evaluated the anticancer activity of melatonin by using LSD1-overexpressing oral cancer PDTX models. By assessing oral squamous cell carcinoma (OSCC) tissue arrays through immunohistochemistry, we examined whether aberrant LSD1 overexpression in OSCC is associated with poor prognosis. We also evaluated the action mechanism of melatonin against OSCC with lymphatic metastases by using the PDTX models. Our results indicated that melatonin, at pharmacological concentrations, significantly suppresses cell proliferation in a dose- and time-dependent manner. The observed suppression of proliferation was accompanied by the melatonin-mediated inhibition of LSD1 in oral cancer PDTXs and oral cancer cell lines. In conclusion, we determined that the beneficial effects of melatonin in reducing oral cancer cell proliferation are associated with reduced LSD1 expression in vivo and in vitro. PMID:28422711

  14. RNAi screening of subtracted transcriptomes reveals tumor suppression by taurine-activated GABAA receptors involved in volume regulation

    Science.gov (United States)

    van Nierop, Pim; Vormer, Tinke L.; Foijer, Floris; Verheij, Joanne; Lodder, Johannes C.; Andersen, Jesper B.; Mansvelder, Huibert D.; te Riele, Hein

    2018-01-01

    To identify coding and non-coding suppressor genes of anchorage-independent proliferation by efficient loss-of-function screening, we have developed a method for enzymatic production of low complexity shRNA libraries from subtracted transcriptomes. We produced and screened two LEGO (Low-complexity by Enrichment for Genes shut Off) shRNA libraries that were enriched for shRNA vectors targeting coding and non-coding polyadenylated transcripts that were reduced in transformed Mouse Embryonic Fibroblasts (MEFs). The LEGO shRNA libraries included ~25 shRNA vectors per transcript which limited off-target artifacts. Our method identified 79 coding and non-coding suppressor transcripts. We found that taurine-responsive GABAA receptor subunits, including GABRA5 and GABRB3, were induced during the arrest of non-transformed anchor-deprived MEFs and prevented anchorless proliferation. We show that taurine activates chloride currents through GABAA receptors on MEFs, causing seclusion of cell volume in large membrane protrusions. Volume seclusion from cells by taurine correlated with reduced proliferation and, conversely, suppression of this pathway allowed anchorage-independent proliferation. In human cholangiocarcinomas, we found that several proteins involved in taurine signaling via GABAA receptors were repressed. Low GABRA5 expression typified hyperproliferative tumors, and loss of taurine signaling correlated with reduced patient survival, suggesting this tumor suppressive mechanism operates in vivo. PMID:29787571

  15. The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration

    Science.gov (United States)

    Hesse, Robert G; Kouklis, Gayle K; Ahituv, Nadav; Pomerantz, Jason H

    2015-01-01

    The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species’ regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF –p53 axis activation. DOI: http://dx.doi.org/10.7554/eLife.07702.001 PMID:26575287

  16. Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression

    International Nuclear Information System (INIS)

    Ramos, Gerardo; Kazimi, Nasser; Nghiem, Dat X.; Walterscheid, Jeffrey P.; Ullrich, Stephen E.

    2004-01-01

    Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependant manner. The release of biological response modifiers, particularly prostaglandin E 2 (PGE 2 ), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE 2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE 2 secretion. Jet fuel-induced PGE 2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin

  17. Cooperation of Ad-hING4 and 125I seed in tumor-suppression on human pancreatic cancer xenograft in nude mice

    International Nuclear Information System (INIS)

    Zhai Hongyan; Fa Yihua; Su Chenghai; Yang Jicheng; Sheng Weihua; Xie Yufeng

    2009-01-01

    This work is to investigate the combined tumor-suppression effect of Adenovirus-mediated human ING4 (Ad-hING4) and 125 I seed on human pancreatic cancer xenograft and the possible mechanisms. Ad-hING4 recombinant adenovirus vector was transected into QBI-293A cells and high titre adenovirus was obtained. Subcutaneous tumor models were established with 25 nude mice with human pancreatic cancer cell line PANC-1. They were randomly divided into 5 groups: PBS control group, Ad carrier group, 125 I seed brachytherapy group, Ad-hING4 gene treatment group, combined 125 I seed and Ad-hING4 group. The tumor volumes were measured every 5 days after treatment, and were sacrificed on the 20th day. The tumors were measured and weighed to determine the ratio of tumor-suppression and Jin-Shi q value. Morphological changes of tumor cells,the tissue injury and apoptotic index AI were examined on pathological sections. MVD, Survivin and Caspase3 were tested in immunohistochemistry. The results show that the tumor-suppressive ratio of the 125 I seed group, Ad-hING4 group, combined treatment group were,respectively, 34.19%(P 0.05). It can be concluded that 125 I seed and Ad-hING4 inhibit the growth of PANC-1 pancreatic cancer on nude mice significantly. These indicate a synergy of the combined treatments in tumor-suppression and Ad-hING4 is a promising novel radiosensitizer. The mechanisms of tumor-suppressive may be multi-pathways such as down-regulation the expression of Survivin and up-regulation the expression of Caspase3 to induce apoptosis and inhibit angiogenesis. (authors)

  18. Role of scrape cytology in the intraoperative diagnosis of tumor

    Directory of Open Access Journals (Sweden)

    Kolte Sachin

    2010-01-01

    Full Text Available Background : Rapid diagnosis of surgically removed specimens has created many controversies and a single completely reliable method has not yet been developed. Histopathology of a paraffin section remains the ultimate gold standard in tissue diagnosis. Frozen section is routinely used by the surgical pathology laboratories for intraoperative diagnosis. The use of either frozen section or cytological examination alone has an acceptable rate (93-97% of correct diagnosis, with regard to interpretation of benign versus malignant. Aim : To evaluate the utility of scrape cytology for the rapid diagnosis of surgically removed tumors and its utilisation for learning cytopathology. Materials and Methods : 75 surgically removed specimens from various organs and systems were studied. Scrapings were taken from each specimen before formalin fixation and stained by modified rapid Papanicolaou staining. Results : Of the 75 cases studied, 73 could be correctly differentiated into benign and malignant tumors, with an accuracy rate of 97.3%. Conclusions : Intraoperative scrape cytology is useful for intraoperative diagnosis of tumor, where facilities for frozen section are not available. The skill and expertise developed by routinely practicing intraoperative cytology can be applied to the interpretation of fine needle aspirate smears. Thus, apart from its diagnostic role, intraoperative cytology can become a very useful learning tool in the field of cytopathology.

  19. Combination of Bifunctional Alkylating Agent and Arsenic Trioxide Synergistically Suppresses the Growth of Drug-Resistant Tumor Cells

    Directory of Open Access Journals (Sweden)

    Pei-Chih Lee

    2010-05-01

    Full Text Available Drug resistance is a crucial factor in the failure of cancer chemotherapy. In this study, we explored the effect of combining alkylating agents and arsenic trioxide (ATO on the suppression of tumor cells with inherited or acquired resistance to therapeutic agents. Our results showed that combining ATO and a synthetic derivative of 3a-aza-cyclopenta[a]indenes (BO-1012, a bifunctional alkylating agent causing DNA interstrand cross-links, was more effective in killing human cancer cell lines (H460, H1299, and PC3 than combining ATO and melphalan or thiotepa. We further demonstrated that the combination treatment of H460 cells with BO-1012 and ATO resulted in severe G2/M arrest and apoptosis. In a xenograft mouse model, the combination treatment with BO-1012 and ATO synergistically reduced tumor volumes in nude mice inoculated with H460 cells. Similarly, the combination of BO-1012 and ATO effectively reduced the growth of cisplatin-resistant NTUB1/P human bladder carcinoma cells. Furthermore, the repair of BO-1012-induced DNA interstrand cross-links was significantly inhibited by ATO, and consequently, γH2AX was remarkably increased and formed nuclear foci in H460 cells treated with this drug combination. In addition, Rad51 was activated by translocating and forming foci in nuclei on treatment with BO-1012, whereas its activation was significantly suppressed by ATO. We further revealed that ATO might mediate through the suppression of AKT activity to inactivate Rad51. Taken together, the present study reveals that a combination of bifunctional alkylating agents and ATO may be a rational strategy for treating cancers with inherited or acquired drug resistance.

  20. Role of Axumin PET Scan in Germ Cell Tumor

    Science.gov (United States)

    2018-05-01

    Testis Cancer; Germ Cell Tumor; Testicular Cancer; Germ Cell Tumor of Testis; Germ Cell Tumor, Testicular, Childhood; Testicular Neoplasms; Testicular Germ Cell Tumor; Testicular Yolk Sac Tumor; Testicular Choriocarcinoma; Testicular Diseases; Germ Cell Cancer Metastatic; Germ Cell Neoplasm of Retroperitoneum; Germ Cell Cancer, Nos

  1. Why expressive suppression does not pay? Cognitive costs of negative emotion suppression: The mediating role of subjective tense-arousal

    Directory of Open Access Journals (Sweden)

    Szczygieł Dorota

    2015-09-01

    Full Text Available The aim of this paper was to contribute to a broader understanding of the cognitive consequences of expressive suppression. Specifically, we examined whether the deteriorating effect of expressive suppression on cognitive functioning is caused by tense arousal enhanced by suppression. Two experiments were performed in order to test this prediction. In both studies we tested the effect of expressive suppression on working memory, as measured with a backwards digit-span task (Study 1, N = 43 and anagram problem-solving task (Study 2, N = 60. In addition, in Study 2 we tested whether expressive suppression degrades memory of the events that emerged during the period of expressive suppression. Both studies were conducted in a similar design: Participants watched a film clip which evoked negative emotions (i.e. disgust in Study 1 and a combination of sadness and anxiety in Study 2 under the instruction to suppress those negative emotions or (in the control condition to simply watch the film. The results of these experiments lead to three conclusions. First, the results reveal that expressive suppression degrades memory of the events that emerged during the period of expressive suppression and leads to poorer performance on working memory tasks, as measured with a backwards digit-span task and anagram problem-solving task. Second, the results indicate that expressive suppression leads to a significant increase in subjective tense arousal. Third, the results support our prediction that expressive suppression decreases cognitive performance through its effects on subjective tense arousal. The results of the Study 1 show that tense arousal activated during expressive suppression of disgust fully mediates the negative effect of suppression on working memory as measured with a backwards digit-span task. The results of Study 2 reveal that subjective tense arousal elicited while suppressing sadness and anxiety mediates both the effect of suppression on

  2. Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells.

    Science.gov (United States)

    Kato, Taigo; Inoue, Hiroyuki; Imoto, Seiya; Tamada, Yoshinori; Miyamoto, Takashi; Matsuo, Yo; Nakamura, Yusuke; Park, Jae-Hyun

    2016-04-05

    T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects.

  3. Resveratrol (trans-3,5,4'-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB.

    Science.gov (United States)

    Singh, Narendra P; Singh, Udai P; Hegde, Venkatesh L; Guan, Hongbing; Hofseth, Lorne; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2011-08-01

    Understanding the molecular mechanisms through which natural products and dietary supplements exhibit anticancer properties is crucial and can lead to drug discovery and chemoprevention. The current study sheds new light on the mode of action of resveratrol (RES), a plant-derived polyphenolic compound, against EL-4 lymphoma growth. Immuno-compromised NOD/SCID mice injected with EL-4 tumor cells and treated with RES (100 mg/kg body weight) showed delayed development and progression of tumor growth and increased mean survival time. RES caused apoptosis in EL4 cells through activation of aryl hydrocarbon receptor (AhR) and upregulation of Fas and FasL expression in vitro. Blocking of RES-induced apoptosis in EL4 cells by FasL mAb, cleavage of caspases and PARP, and release of cytochorme c, demonstrated the participation of both extrinsic and intrinsic pathways of apoptosis. RES also induced upregulation of silent mating type information regulation 2 homolog, 1 (SIRT1) and downregulation of nuclear factor kappa B (NF-κB) in EL4 cells. siRNA-mediated downregulation of SIRT1 in EL4 cells increased the activation of NF-κB but decreased RES-mediated apoptosis, indicating the critical role of SIRT1 in apoptosis via blocking activation of NF-κB. These data suggest that RES-induced SIRT1 upregulation promotes tumor cell apoptosis through negative regulation of NF-κB, leading to suppression of tumor growth. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Tumor suppressor roles of CENP-E and Nsl1 in Drosophila epithelial tissues.

    Science.gov (United States)

    Clemente-Ruiz, Marta; Muzzopappa, Mariana; Milán, Marco

    2014-01-01

    Depletion of spindle assembly checkpoint (SAC) genes in Drosophila epithelial tissues leads to JNK-dependent programmed cell death and additional blockade of the apoptotic program drives tumorigenesis. A recent report proposes that chromosomal instability (CIN) is not the driving force in the tumorigenic response of the SAC-deficient tissue, and that checkpoint proteins exert a SAC-independent tumor suppressor role. This notion is based on observations that the depletion of CENP-E levels or prevention of Bub3 from binding to the kinetochore in Drosophila tissues unable to activate the apoptotic program induces CIN but does not cause hyperproliferation. Here we re-examined this proposal. In contrast to the previous report, we observed that depletion of CENP-E or Nsl1-the latter mediating kinetochore targeting of Bub3-in epithelial tissues unable to activate the apoptotic program induces significant levels of aneuploidy and drives tumor-like growth. The induction of the JNK transcriptional targets Wingless, a mitogenic molecule, and MMP1, a matrix metaloproteinase 1 involved in basement membrane degradation was also observed in these tumors. An identical response of the tissue was previously detected upon depletion of several SAC genes or genes involved in spindle assembly, chromatin condensation, and cytokinesis, all of which have been described to cause CIN. All together, these results reinforce the role of CIN in driving tumorigenesis in Drosophila epithelial tissues and question the proposed SAC-independent roles of checkpoint proteins in suppressing tumorigenesis. Differences in aneuploidy rates might explain the discrepancy between the previous report and our results.

  5. Role of TPS in 125I brachytherapy for orbital tumors

    International Nuclear Information System (INIS)

    Ren Ling; Dai Haojie; Li Quan

    2012-01-01

    Objective: To investigate the role of TPS in 125 I brachytherapy for orbital tumors. Methods: Sixty-six patients with orbital tumor treated with 125 I seeds from 2005 to 2009 were retrospectively analyzed. Forty-three patients were treated using TPS guided brachytherapy and the prescribed dose was 140 Gy. Other 23 patients were treated without TPS but simply implanted with 125 I seeds at 1 cm intervals in parallel with each other intraoperatively. CT and TPS quality verification were performed postoperatively in all patients. Also, CT and (or) MRI examination were performed at 3, 6, 12 and 24 months after brachytherapy for follow-up. χ 2 test and Kaplan-Meier survival analysis with log-rank significance test were used with SPSS 17.0. Results: A total of 1070 125 I seeds were implanted in 66 cases, on average, (16.2 ± 7.3) seeds for each patient. The satisfaction rates of postoperative quality verification in patients with and without TPS pre-plans were 79.07% (34/43) and 43.48% (10/23) respectively (χ 2 =8.542, P=0.003). Ten patients were lost in follow-up. Local recurrence rates in patients with favorable postoperative quality verification were 0 (0/37) in 3 months, 6.25% (2/32) in 6 months, 13.64% (3/22) in 12 months and 3/9 in 24 months respectively, which were significantly different from those (5.26% (1/19), 16.67% (3/18), 30.77% (4/13), 6/6) in the patients with inferior postoperative quality verification (χ 2 =9.017, P=0.0003). Conclusions: TPS plays an important role in 125 I brachytherapy for orbital tumors. Also, postoperative quality verification by TPS may help predict the local recurrence after brachytherapy. (authors)

  6. Tumor-suppressive function of miR-139-5p in esophageal squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Ran Liu

    Full Text Available Recent studies have demonstrated the possible function of miR-139-5p in tumorigenesis. However, the exact mechanism of miR-139-5p in cancer remains unclear. In this study, the association of miR-139-5p expression with esophageal squamous cell carcinoma (ESCC was evaluated in 106 pairs of esophageal cancer and adjacent non-cancerous tissue from ESCC patients. The tumor suppressive features of miR-139-5p were measured by evaluating cell proliferation and cell cycle state, migratory activity and invasion capability, as well as apoptosis. Luciferase reporter assay and Western blot analysis were performed to determine the target gene regulated by miR-139-5p. The mRNA level of NR5A2, the target gene of miR-139-5p, was determined in ESCC patients. Results showed that reduced miR-139-5p level was associated with lymph node metastases of ESCC. MiR-139-5p was investigated to induce cell cycle arrest in the G0/G1 phase and to suppress the invasive capability of esophageal carcinoma cells by targeting the 3'UTR of oncogenic NR5A2. Cyclin E1 and MMP9 were confirmed to participate in cell cycle arrest and invasive suppression induced by NR5A2, respectively. Pearson correlation analysis further confirmed the significantly negative correlation between miR-139-5p and NR5A2 expression. The results suggest that miR-139-5p exerts a growth- and invasiveness-suppressing function in human ESCCs, which demonstrates that miR-139-5p is a potential biomarker for early diagnosis and prognosis and is a therapeutic target for ESCC.

  7. p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

    DEFF Research Database (Denmark)

    Tschaharganeh, Darjus F; Xue, Wen; Calvisi, Diego F

    2014-01-01

    The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protei...... by p53 restricts cellular plasticity and tumorigenesis in liver cancer....

  8. Anti-SEMA3A Antibody: A Novel Therapeutic Agent to Suppress GBM Tumor Growth.

    Science.gov (United States)

    Lee, Jaehyun; Shin, Yong Jae; Lee, Kyoungmin; Cho, Hee Jin; Sa, Jason K; Lee, Sang-Yun; Kim, Seok-Hyung; Lee, Jeongwu; Yoon, Yeup; Nam, Do-Hyun

    2017-11-10

    Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression. We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3A mRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo. By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell-line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment. In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.

  9. Suppression of Peroxiredoxin 4 in Glioblastoma Cells Increases Apoptosis and Reduces Tumor Growth

    Science.gov (United States)

    Kim, Tae Hyong; Song, Jieun; Alcantara Llaguno, Sheila R.; Murnan, Eric; Liyanarachchi, Sandya; Palanichamy, Kamalakannan; Yi, Ji-Yeun; Viapiano, Mariano Sebastian; Nakano, Ichiro; Yoon, Sung Ok; Wu, Hong; Parada, Luis F.; Kwon, Chang-Hyuk

    2012-01-01

    Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future. PMID:22916164

  10. Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth.

    Directory of Open Access Journals (Sweden)

    Tae Hyong Kim

    Full Text Available Glioblastoma multiforme (GBM, the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4 is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.

  11. Local administration of siRNA through Microneedle: Optimization, Bio-distribution, Tumor Suppression and Toxicity

    Science.gov (United States)

    Tang, Tao; Deng, Yan; Chen, Jiao; Zhao, Yi; Yue, Ruifeng; Choy, Kwong Wai; Wang, Chi Chiu; Du, Quan; Xu, Yan; Han, Linxiao; Chung, Tony Kwok Hung

    2016-07-01

    Although RNA interference may become a novel therapeutic approach for cancer treatment, target-site accumulation of siRNA to achieve therapeutic dosage will be a major problem. Microneedle represents a better way to deliver siRNAs and we have evaluated for the first time the capability of a silicon microneedle array for delivery of Gapdh siRNA to the skin in vivo and the results showed that the microneedle arrays could effectively deliver siRNA to relevant regions of the skin noninvasively. For the further study in this field, we evaluated the efficacy of the injectable microneedle device for local delivery of siRNA to the mouse xenograft. The results presented here indicate that local administration of siRNA through injectable microneedle could effectively deliver siRNA into the tumor region, and inhibit tumor progression without major adverse effects.

  12. Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans

    Czech Academy of Sciences Publication Activity Database

    Stapelberg, M.; Zobalová, Renata; Nguyen, M.N.; Walker, T.; Stantic, M.; Goodwin, J.; Pasdar, E.A.; Thai, T.; Prokopová, Kateřina; Yan, B.; Hall, S.; de Pennington, N.; Thomas, S.R.; Grant, G.; Štursa, Jan; Bajziková, Martina; Meedeniya, A.C.B.; Truksa, Jaroslav; Ralph, S. J.; Ansorge, O.; Dong, L.-F.; Neužil, Jiří

    2014-01-01

    Roč. 67, FEB (2014), s. 41-50 ISSN 0891-5849 R&D Projects: GA ČR(CZ) GAP301/10/1937; GA ČR GAP305/12/1708 Institutional support: RVO:86652036 ; RVO:61388963 Keywords : IDO * Tumor-initiating cells * Mitocans * Mitochondrially targeted vitamin E succinate Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.736, year: 2014

  13. Determination of the lysosomal role in tumor accumulation of 67Ga by dual-tracer studies

    International Nuclear Information System (INIS)

    Ando, Atsushi; Ando, Itsuko; Hiraki, Tatsunosuke; Yamada, Norihisa; Hisada, Kinichi

    1989-01-01

    The lysosomal role in tumor accumulation of 67 Ga was determined by dual-tracer( 67 Ga and 46 Sc) studies. It became clear that 67 Ga essentially did not accumulate in the tumor lysosome, and that the lysosome did not play a major role in tumor accumulation of 67 Ga. In addition, it was revealed that tumor lysosome was hardly disrupted at all in some phases of fractionation procedures. (author)

  14. A Catalytic Role for Proangiogenic Marrow-Derived Cells in Tumor Neovascularization

    Science.gov (United States)

    Seandel, Marco; Butler, Jason; Lyden, David; Rafii, Shahin

    2010-01-01

    Small numbers of proangiogenic bone marrow-derived cells (BMDCs) can play pivotal roles in tumor progression. In this issue of Cancer Cell, two papers, utilizing different tumor angiogenesis models, both find that activated MMP-9 delivered by BMDCs modulates neovessel remodeling, thereby promoting tumor growth. The changes in microvascular anatomy induced by MMP-9-expressing BMDCs are strikingly different between the preirradiated tumor vascular bed model employed by Ahn and Brown and the invasive glioblastoma model utilized by Du et al., likely mirroring the complexity of the real tumor microenvironment and the intricacy of roles of different BMDC populations in mediating tumor neoangiogenesis. PMID:18328420

  15. The role of epidermal cytokines in the generation of cutaneous immune reactions and ultraviolet radiation-induced immune suppression

    International Nuclear Information System (INIS)

    Ullrich, S.E.

    1995-01-01

    The immune suppression generated by UV exposure is a major risk factor for skin cancer patients. This finding has fuelled efforts to understand the mechanisms involved in the immune suppression induced by exposure to UV radiation. This article reviews the recent findings on the role of epidermal cytokines in the generation of an immune response and their role in the induction of immune suppression induced by UV exposure. (UK)

  16. Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin.

    Science.gov (United States)

    Nair, Jayasree S; Musi, Elgilda; Schwartz, Gary K

    2017-08-01

    Purpose: Selinexor, a small molecule that inhibits nuclear export protein XPO1, has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few, and hence the need to identify novel targets and strategic therapies is of utmost importance. Experimental Design: The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines in vitro and few in xenograft mouse models were investigated. Results: Selinexor induced IκB nuclear localization as a single agent, and the effect was enhanced by stabilization of IκB when pretreated with the proteasome inhibitor carfilzomib. This stabilization and retention of IκB in the nucleus resulted in inhibition of NFκB and transcriptional suppression of the critical antiapoptotic protein, survivin. Treatment of carfilzomib followed by selinexor caused selinexor-sensitive and selinexor-resistant cell lines to be more sensitive to selinexor as determined by an increase in apoptosis. This was successfully demonstrated in the MPNST xenograft model with enhanced tumor suppression. Conclusions: The subcellular distributions of IκB and NFκB are indicative of carcinogenesis. Inhibition of XPO1 results in intranuclear retention of IκB, which inhibits NFκB and thereby provides a novel mechanism for drug therapy in sarcoma. This effect can be further enhanced in relatively selinexor-resistant sarcoma cell lines by pretreatment with the proteasome inhibitor carfilzomib. Because of these results, a human clinical trial with selinexor in combination with a proteasome inhibitor is planned for the treatment of sarcoma. Clin Cancer Res; 23(15); 4301-11. ©2017 AACR . ©2017 American Association for Cancer Research.

  17. Epigenetic inactivation of SPINT2 is associated with tumor suppressive function in esophageal squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Yue, Dongli [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); The Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Fan, Qingxia [The Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Chen, Xinfeng; Li, Feng [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Wang, Liping [The Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Huang, Lan [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Dong, Wenjie; Chen, Xiaoqi [The Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Zhang, Zhen [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Liu, Jinyan; Wang, Fei [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); The School of Life Sciences, Zhengzhou University, Zhengzhou 450052, Henan (China); Wang, Meng [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); The Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Zhang, Bin [The Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); The Department of Hematology/Oncology, School of Medicine, Northwestern University, Chicago 60611 (United States); and others

    2014-03-10

    Hepatocyte growth factor activator inhibitor type 2 (SPINT2), a Kunitz-type serine proteinase inhibitor, has been identified as a putative tumor suppressor gene silenced by promoter methylation. We aimed to investigate whether SPINT2 might act as an esophageal squamous cell carcinoma (ESCC) tumor suppressor gene. Four ESCC cell lines, Fifty-two ESCC tissues and twenty-nine neighboring non-cancerous tissues were included in this study. The expression of SPINT2 was monitored by real time PCR. Bisulfite genomic sequencing and methylation-specific PCR were used to analyze methylation status. The effect of SPINT2 on cell proliferation and apoptosis in EC109 and EC9706 cells was observed by CCK-8 assay and flow cytometric analysis. We found that silencing of SPINT2 was associated with promoter methylation in ESCC cell lines. The densely methylated SPINT2 promoter region was confirmed by bisulfite genomic sequencing. Ectopic expression of SPINT2 inhibited cell proliferation through inducing cell apoptosis in vitro. Furthermore, methylation-specific PCR analysis revealed that SPINT2 promoter methylation was prominent in carcinoma tissues (52.08%) compared with neighboring non-cancerous tissues (22.58%). Kaplan–Meier analysis showed that patients with SPINT2 hypermethylation had shorter survival time. The tumor suppressor gene of SPINT2 is commonly silenced by promoter hypermethylation in human ESCC and SPINT2 hypermethylation is correlated with poor overall survival, implicating SPINT2 is an underlying prognostic marker for human ESCC. - Highlights: • We firstly found SPINT2 gene may be transcriptionally repressed by promoter hypermethylation in ESCC cells. • SPINT2 overexpressing cells induced proliferation inhibition through promoting apoptosis. • mRNA expression of SPINT2 was significantly higher in ESCC tissues than in neighboring non-cancerous tissues. • Promoter hypermethylation of SPINT2 is significantly linked to TNM stage and poor overall survival.

  18. Treatment Combining X-Irradiation and a Ribonucleoside Anticancer Drug, TAS106, Effectively Suppresses the Growth of Tumor Cells Transplanted in Mice

    International Nuclear Information System (INIS)

    Yasui, Hironobu; Inanami, Osamu; Asanuma, Taketoshi; Iizuka, Daisuke; Nakajima, Takayuki; Kon, Yasuhiro; Matsuda, Akira; Kuwabara, Mikinori

    2007-01-01

    Purpose: To examine the in vivo antitumor efficacy of X-irradiation combined with administration of a ribonucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd), to tumor cell-transplanted mice. Methods and Materials: Colon26 murine rectum adenocarcinoma cells and MKN45 human gastric adenocarcinoma cells were inoculated into the footpad in BALB/c mice and severe combined immunodeficient mice, respectively. They were treated with a relatively low dose of X-irradiation (2 Gy) and low amounts of TAS106 (0.1 mg/kg and 0.5 mg/kg). The tumor growth was monitored by measuring the tumor volume from Day 5 to Day 16 for Colon26 and from Day 7 to Day 20 for MKN45. Histologic analyses for proliferative and apoptotic cells in the tumors were performed using Ki-67 immunohistochemical and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. The expression of survivin, a key molecule related to tumor survival, was assessed by quantitative polymerase chain reaction and immunohistochemical analysis. Results: When X-irradiation and TAS106 treatment were combined, significant inhibition of tumor growth was observed in both types of tumors compared with mice treated with X-irradiation or TAS106 alone. Marked inhibition of tumor growth was observed in half of the mice that received the combined treatment three times at 2-day intervals. Parallel to these phenomena, the suppression of survivin expression and appearance of Ki-67-negative and apoptotic cells were observed. Conclusions: X-irradiation and TAS106 effectively suppress tumor growth in mice. The inhibition of survivin expression by TAS106 is thought to mainly contribute to the suppression of the tumor growth

  19. The role of radiotherapy in the management of desmoid tumors

    International Nuclear Information System (INIS)

    Kirschner, M.J.; Sauer, R.

    1993-01-01

    698 published cases are reviewed and analysed with respect to the previous surgery and the therapeutic impact of postoperative radiotherapy. After an R1 surgical resection radiotherapy significantly decreases the risk for loco-regional relapse in about 40%. Radiotherapy is also recommended after an R0 surgical resection with safety margins less than 2 cm. A total radiotherapy dose of 50 Gy seems to be sufficient, whereas radiotherapy doses beyond 60 Gy provide no additional control. Following an R2 resection up to 28% of these tumors may not progress or even show a complete remission. A wait-and-see policy is justified for R1-2-resected lesions in the abdominal wall, especially if severe treatment sequelae have to be expected. The role of chemotherapy still remains questionable. (orig./MM) [de

  20. Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest

    International Nuclear Information System (INIS)

    Dan, Shingo; Yoshimi, Hisashi; Okamura, Mutsumi; Mukai, Yumiko; Yamori, Takao

    2009-01-01

    Phosphoinositide 3-kinase (PI3K) is a potential target in cancer therapy. Inhibition of PI3K is believed to induce apoptosis. We recently developed a novel PI3K inhibitor ZSTK474 with antitumor efficacy. In this study, we have examined the underlying mode of action by which ZSTK474 exerts its antitumor efficacy. In vivo, ZSTK474 effectively inhibited the growth of human cancer xenografts. In parallel, ZSTK474 treatment suppressed the expression of phospho-Akt, suggesting effective PI3K inhibition, and also suppressed the expression of nuclear cyclin D1 and Ki67, both of which are hallmarks of proliferation. However, ZSTK474 treatment did not increase TUNEL-positive apoptotic cells. In vitro, ZSTK474 induced marked G 0 /G 1 arrest, but did not increase the subdiploid cells or activate caspase, both of which are hallmarks of apoptosis. These results clearly indicated that inhibition of PI3K by ZSTK474 did not induce apoptosis but rather induced strong G 0 /G 1 arrest, which might cause its efficacy in tumor cells.

  1. Cancer-Associated Fibroblasts from lung tumors maintain their immuno-suppressive abilities after high-dose irradiation

    Directory of Open Access Journals (Sweden)

    Laia eGorchs

    2015-05-01

    Full Text Available Accumulating evidence supports the notion that high-dose (>5 Gy radiotherapy (RT regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study we have investigated the effects of high-dose irradiation (HD-RT on the immunomodulating functions of cancer-associated fibroblasts (CAFs. Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays and T-cell cytokine production. Additionally, CAF-secreted immuno-regulatory factors were studied by multiplex protein arrays, ELISAs and by LC-MS/MS proteomics. In all functional assays we observed a powerful immuno-suppressive effect exerted by CAF-conditioned medium on activated T-cells (p>0,001, and this effect was sustained after a single radiation dose of 18 Gy. Relevant immuno-suppressive molecules such as prostaglandin E2, interleukin-6 and -10, or transforming growth factor-β were found in CAF conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immuno-suppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

  2. Andrographolide Suppress Tumor Growth by Inhibiting TLR4/NF-κB Signaling Activation in Insulinoma

    Science.gov (United States)

    Zhang, Qian-Qian; Ding, Yi; Lei, Yan; Qi, Cui-Ling; He, Xiao-Dong; Lan, Tian; Li, Jiang-Chao; Gong, Ping; Yang, Xuesong; Geng, Jian-Guo; Wang, Li-Jing

    2014-01-01

    Insulinomas are rare tumors, and approximately 10% of insulinomas are malignant. Accumulating evidence has implicated that we still lack effective therapy to treat the patients who are diagnosed with rare malignant insulinoma. Previous studies have reported that Andrographolide (Andro) could inhibit cell cycle progression, reduce cell invasion and induce cell apoptosis in many common cancer cells. However, the effects of andro are cell type-dependent. So we emplored the β-TC-6 cells and the RIP1-Tag2 transgenic mouse model of endogenously growing insulinoma model to elucidate the possible anti-cancer effect of Andro on insulinoma, an uncommon type of malignant cancers in this study. Our experiments revealed that Andro significantly inhibited tumor growth at both the early-stage and the advanced-stage of insulinoma through targeting the TLR4/NF-κB signaling pathway. This work initially provides the evidence that the TLR4/NF-κB signaling pathway might be vital as a potential therapeutic target, and also indispensable in Andro-mediated anti-cancer effect in insulinoma. PMID:24719558

  3. A Multi-targeted Approach to Suppress Tumor-Promoting Inflammation

    Science.gov (United States)

    Samadi, Abbas K.; Georgakilas, Alexandros G.; Amedei, Amedeo; Amin, Amr; Bishayee, Anupam; Lokeshwar, Bal L.; Grue, Brendan; Panis, Carolina; Boosani, Chandra S.; Poudyal, Deepak; Stafforini, Diana M.; Bhakta, Dipita; Niccolai, Elena; Guha, Gunjan; Rupasinghe, H.P. Vasantha; Fujii, Hiromasa; Honoki, Kanya; Mehta, Kapil; Aquilano, Katia; Lowe, Leroy; Hofseth, Lorne J.; Ricciardiello, Luigi; Ciriolo, Maria Rosa; Singh, Neetu; Whelan, Richard L.; Chaturvedi, Rupesh; Ashraf, S. Salman; Kumara, HMC Shantha; Nowsheen, Somaira; Mohammed, Sulma I.; Helferich, William G.; Yang, Xujuan

    2015-01-01

    Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-kappaB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes. PMID:25951989

  4. siRNA-mediated Erc gene silencing suppresses tumor growth in Tsc2 mutant renal carcinoma model.

    Science.gov (United States)

    Imamura, Osamu; Okada, Hiroaki; Takashima, Yuuki; Zhang, Danqing; Kobayashi, Toshiyuki; Hino, Okio

    2008-09-18

    Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery of siRNAs for stable treatment except short hairpin RNAs (shRNAs). On the other hand, there are many reports of systemic delivery of siRNAs for transient treatment using liposome carriers and others. With regard to shRNAs, a report showed fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Therefore, we decided to use original siRNA microspheres instead of shRNA for stable treatment of disease. In this study, we designed rat-specific siRNA sequences for Erc/mesothelin, which is a tumor-specific gene expressed in the Eker (Tsc2 mutant) rat model of hereditary renal cancer and confirmed the efficacy of gene silencing in vitro. Then, by using siRNA microspheres, we found that the suppression of Erc/mesothelin caused growth inhibition of Tsc2 mutant renal carcinoma cells in tumor implantation experiments in mice.

  5. Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression.

    Science.gov (United States)

    Hartford, Suzanne A; Luo, Yunhai; Southard, Teresa L; Min, Irene M; Lis, John T; Schimenti, John C

    2011-10-25

    Effective DNA replication is critical to the health and reproductive success of organisms. The six MCM2-7 proteins, which form the replicative helicase, are essential for high-fidelity replication of the genome. Many eukaryotes have a divergent paralog, MCM9, that was reported to be essential for loading MCM2-7 onto replication origins in the Xenopus oocyte extract system. To address the in vivo role of mammalian MCM9, we created and analyzed the phenotypes of mice with various mutations in Mcm9 and an intronic DNA replication-related gene Asf1a. Ablation of Mcm9 was compatible with cell proliferation and mouse viability, showing that it is nonessential for MCM2-7 loading or DNA replication. Mcm9 mutants underwent p53-independent embryonic germ-cell depletion in both sexes, with males also exhibiting defective spermatogonial stem-cell renewal. MCM9-deficient cells had elevated genomic instability and defective cell cycle reentry following replication stress, and mutant animals were prone to sex-specific cancers, most notably hepatocellular carcinoma in males. The phenotypes of mutant mice and cells suggest that MCM9 evolved a specialized but nonessential role in DNA replication or replication-linked quality-control mechanisms that are especially important for germ-line stem cells, and also for tumor suppression and genome maintenance in the soma.

  6. Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts

    International Nuclear Information System (INIS)

    Tsang, Chi Man; Cheung, Yuk Chun; Lui, Vivian Wai-Yan; Yip, Yim Ling; Zhang, Guitao; Lin, Victor Weitao; Cheung, Kenneth Chat-Pan; Feng, Yibin; Tsao, Sai Wah

    2013-01-01

    Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented. In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models. Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R. Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC

  7. MicroRNAs-449a and -449b exhibit tumor suppressive effects in retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Alissa [Division of Hematology, Oncology, and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611 (United States); Jones, Aunica [Cancer Biology and Epigenomics Program, Ann and Robert H. Lurie Children’s Hospital of Chicago Research Center, Chicago, IL 60611 (United States); Bryar, Paul J. [Departments of Ophthalmology and Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 (United States); Mets, Marilyn [Division of Ophthalmology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611 (United States); Department of Ophthalmology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611 (United States); Weinstein, Joanna [Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611 (United States); Division of Hematology, Oncology, and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611 (United States); Zhang, Gang [Biostatistics Research Core, Ann and Robert H. Lurie Children’s Hospital of Chicago Research Center, Chicago, IL 60611 (United States); Laurie, Nikia A., E-mail: n-laurie@northwestern.edu [Cancer Biology and Epigenomics Program, Ann and Robert H. Lurie Children’s Hospital of Chicago Research Center, Chicago, IL 60611 (United States); Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611 (United States)

    2013-11-01

    Highlights: •We validate miR-449a/b expression in primary human retinoblastomas and cell lines. •Exogenous miRs-449a/b inhibited proliferation in retinoblastoma cell lines. •Exogenous miRs-449a/b increased apoptosis in retinoblastoma cell lines. •miRs-449a/b could serve as viable therapeutic targets for retinoblastoma treatment. -- Abstract: Retinoblastoma is the most common pediatric cancer of the eye. Currently, the chemotherapeutic treatments for retinoblastoma are broad-based drugs such as vincristine, carboplatin, or etoposide. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. The purpose of our study is to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. We are the first to confirm an inhibitory effect of miR-449a and -449b in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when these miRNAs are overexpressed. This study suggests that these miRNAs could serve as viable therapeutic targets for retinoblastoma treatment.

  8. Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

    Directory of Open Access Journals (Sweden)

    Youn Kyung Choi

    2014-01-01

    Full Text Available Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.

  9. 3-bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth.

    Science.gov (United States)

    Wang, Ting-An; Zhang, Xiao-Dong; Guo, Xing-Yu; Xian, Shu-Lin; Lu, Yun-Fei

    2016-03-01

    Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.

  10. Role of tumor necrosis factor in flavone acetic acid-induced tumor vasculature shutdown

    International Nuclear Information System (INIS)

    Mahadevan, V.; Malik, S.T.; Meager, A.; Fiers, W.; Lewis, G.P.; Hart, I.R.

    1990-01-01

    Flavone acetic acid (FAA), a novel investigational antitumor agent, has been shown to cause early vascular shutdown in several experimental murine tumors, and this phenomenon is believed to be crucial to FAA's antitumor effects. However, the basis of this FAA-induced tumor vascular shutdown is unknown. In this study a radioactive tracer-clearance technique has been used as an objective indication of tumor blood flow to show that i.p. administered FAA induces a progressive and sustained reduction in blood flow in a colon 26 tumor growing s.c. in syngeneic mice. As early as 1 h after administration, there was a significant increase in the t1/2 clearance value for intratumorally injected 133Xe, reaching a peak at 3 h (117.3 +/- 36.4 versus 7.8 +/- 0.85 min for controls). Significant inhibition of blood flow was still apparent 48 h after a single injection of drug. This FAA-induced vascular shutdown was virtually abolished in tumor-bearing mice pretreated with an antiserum against tumor necrosis factor, while no such effect was observed in controls pretreated with nonimmune serum (t1/2 of 10.8 +/- 1.2 versus 65.6 +/- 8.0 min for controls). Furthermore, in vitro FAA was seen to induce tumor necrosis factor secretion from murine peritoneal cells and splenocytes. These studies suggest that FAA-induced tumor vascular shutdown in the colon 26 tumor is mediated by tumor necrosis factor

  11. Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

    Science.gov (United States)

    Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

    2014-12-01

    Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  12. The role of computed tomography in diagnosis of ovarian tumors

    International Nuclear Information System (INIS)

    Yasuda, Yukihiko; Kohchiyama, Masahiko; Tsuru, Hiroshi; Shirai, Shigeo; Kikuchi, Shigeru; Koganemaru, Michihiko; Ohtake, Hisashi

    1985-01-01

    CT is useful in the diagnosis of pelvic tumors. CT can differenciate solid from cystic, and benign from malignant tumors and further provide important diagnostic informations for differential diagnosis. Twenty cases of ovarian tumors have been studied at Kurume University Hospital. This included 3 cystadenomas, 7 cystadenocarcinomas, 5 cystic teratomas, 2 endometriosis cysts and 3 metastatic ovarian cancers. CT was very valuable in differenciation of benign from malignant lesions on the basis of contrast enhancement, presence of ascites and adheison as well as irregularity of the cyst walls. It was difficult to differenciate ovarian tumors on the basis of the density of the tumor or calcification in the wall of the tumor. Cystic teratomas were diagnosed quite accurately in all cases because of its specific CT findings. Differenciation of endometriosis cysts of the ovary was difficult from degenerated uterine myoma. (author)

  13. The tumor suppressor role of miR-124 in osteosarcoma.

    Directory of Open Access Journals (Sweden)

    Shuo Geng

    Full Text Available MicroRNAs have crucial roles in development and progression of human cancers, including osteosarcoma. Recent studies have shown that miR-124 was down-regulated in many cancers; however, the role of miR-124 in osteosarcoma development is unknown. In this study, we demonstrate that expression of miR-124 is significantly downregulated in osteosarcoma tissues and cell lines, compared to the adjacent tissues. The expression of miR-124 in the metastases osteosarcoma tissues was lower than that in non- metastases tissues. We identified and confirmed Rac1 as a novel, direct target of miR-124 using prediction algorithms and luciferase reporter gene assays. Overexpression of miR-124 suppressed Rac1 protein expression and attenuated cell proliferation, migration, and invasion and induced apoptosis in MG-63 and U2OS in vitro. Moreover, overexpression of Rac1 in miR-124-transfected osteosarcoma cells effectively rescued the inhibition of cell invasion caused by miR-124. Therefore, our results demonstrate that miR-124 is a tumor suppressor miRNA and suggest that this miRNA could be a potential target for the treatment of osteosarcoma in future.

  14. Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling.

    Science.gov (United States)

    Moon, Seungtae; Lee, Yong-Kyu; Lee, Sang-Wang; Um, Soo-Jong

    2017-10-07

    BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. The role of telomeres in Etoposide induced tumor cell death.

    Science.gov (United States)

    Jeyapalan, Jessie; Leake, Alan; Ahmed, Shaheda; Saretzki, Gabriele; Tilby, Michael; von Zglinicki, Thomas

    2004-09-01

    Etoposide, a topoisomerase II poison is used in the treatment of a number of solid tumors. Contradictory data exist on the role of the telomere/telomerase complex in etoposide induced apoptosis. Therefore we examined the effects of etoposide treatment in the neuroblastoma cell line SHSY5Y, with very short telomeres and the acute lymphoblastic T cell line 1301, which displays extremely long telomeres. Both short-term and continuous exposure to the drug were examined. Etoposide induced widespread DNA damage followed by DNA damage foci formation and ultimately growth arrest and apoptosis in a concentration-dependent manner. However, length of telomeres and of single stranded telomeric G rich overhangs did not change significantly under the treatments in any cell line. There was no significant induction of single-strand breaks in the G-rich strand of telomeres. Telomerase activity was transiently upregulated under low concentrations of etoposide, while high concentrations resulted in decreased telomerase activity only after onset of apoptosis. Telomerase overexpression protected against etoposide induced apoptosis in fibroblasts. The data suggest that telomeres are not major signal transducers towards growth arrest or apoptosis after etoposide treatment. However, upregulation of telomerase might be part of an attempted adaptative response, which protects cells by a mechanism that might be independent of telomere length maintenance.

  16. Sox4 Links Tumor Suppression to Accelerated Aging in Mice by Modulating Stem Cell Activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2014-07-01

    Full Text Available Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display accelerated aging and reduced cancer incidence. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and resistance to chemical carcinogenesis concomitantly with downregulation of cell cycle, DNA repair, and activated hair follicle stem cell pathways. Altogether, these findings highlight the importance of Sox4 in regulating adult tissue homeostasis and cancer.

  17. Differential expression of miR-1, a putative tumor suppressing microRNA, in cancer resistant and cancer susceptible mice

    Directory of Open Access Journals (Sweden)

    Jessica L. Fleming

    2013-04-01

    Full Text Available Mus spretus mice are highly resistant to several types of cancer compared to Mus musculus mice. To determine whether differences in microRNA (miRNA expression account for some of the differences in observed skin cancer susceptibility between the strains, we performed miRNA expression profiling of skin RNA for over 300 miRNAs. Five miRNAs, miR-1, miR-124a-3, miR-133a, miR-134, miR-206, were differentially expressed by array and/or qPCR. miR-1 was previously shown to have tumor suppressing abilities in multiple tumor types. We found miR-1 expression to be lower in mouse cutaneous squamous cell carcinomas (cSCCs compared to normal skin. Based on the literature and our expression data, we performed detailed studies on predicted miR-1 targets and evaluated the effect of miR-1 expression on two murine cSCC cell lines, A5 and B9. Following transfection of miR-1, we found decreased mRNA expression of three validated miR-1 targets, Met, Twf1 and Ets1 and one novel target Bag4. Decreased expression of Ets1 was confirmed by Western analysis and by 3’ reporter luciferase assays containing wildtype and mutated Ets1 3’UTR. We evaluated the effect of miR-1 on multiple tumor phenotypes including apoptosis, proliferation, cell cycle and migration. In A5 cells, expression of miR-1 led to decreased proliferation compared to a control miR. miR-1 expression also led to increased apoptosis at later time points (72 and 96 h and to a decrease in cells in S-phase. In summary, we identified five miRNAs with differential expression between cancer resistant and cancer susceptible mice and found that miR-1, a candidate tumor suppressor, has targets with defined roles in tumorigenesis.

  18. Iron Handling in Tumor-Associated Macrophages—Is There a New Role for Lipocalin-2?

    Directory of Open Access Journals (Sweden)

    Michaela Jung

    2017-09-01

    Full Text Available Carcinogenesis is a multistep process. Besides somatic mutations in tumor cells, stroma-associated immunity is a major regulator of tumor growth. Tumor cells produce and secrete diverse mediators to create a local microenvironment that supports their own survival and growth. It is becoming apparent that iron acquisition, storage, and release in tumor cells is different from healthy counterparts. It is also appreciated that macrophages in the tumor microenvironment acquire a tumor-supportive, anti-inflammatory phenotype that promotes tumor cell proliferation, angiogenesis, and metastasis. Apparently, this behavior is attributed, at least in part, to the ability of macrophages to support tumor cells with iron. Polarization of macrophages by apoptotic tumor cells shifts the profile of genes involved in iron metabolism from an iron sequestering to an iron-release phenotype. Iron release from macrophages is supposed to be facilitated by ferroportin. However, lipid mediators such as sphingosine-1-phosphate, released form apoptotic tumor cells, upregulate lipocalin-2 (Lcn-2 in macrophages. This protein is known to bind siderophore-complexed iron and thus, may participate in iron transport in the tumor microenvironment. We describe how macrophages handle iron in the tumor microenvironment, discuss the relevance of an iron-release macrophage phenotype for tumor progression, and propose a new role for Lcn-2 in tumor-associated macrophages.

  19. Cytoplasmic transfer of heritable elements other than mtDNA from SAMP1 mice into mouse tumor cells suppresses their ability to form tumors in C57BL6 mice.

    Science.gov (United States)

    Shimizu, Akinori; Tani, Haruna; Takibuchi, Gaku; Ishikawa, Kaori; Sakurazawa, Ryota; Inoue, Takafumi; Hashimoto, Tetsuo; Nakada, Kazuto; Takenaga, Keizo; Hayashi, Jun-Ichi

    2017-11-04

    In a previous study, we generated transmitochondrial P29mtSAMP1 cybrids, which had nuclear DNA from the C57BL6 (referred to as B6) mouse strain-derived P29 tumor cells and mitochondrial DNA (mtDNA) exogenously-transferred from the allogeneic strain SAMP1. Because P29mtSAMP1 cybrids did not form tumors in syngeneic B6 mice, we proposed that allogeneic SAMP1 mtDNA suppressed tumor formation of P29mtSAMP1 cybrids. To test this hypothesis, current study generated P29mt(sp)B6 cybrids carrying all genomes (nuclear DNA and mtDNA) from syngeneic B6 mice by eliminating SAMP1 mtDNA from P29mtSAMP1 cybrids and reintroducing B6 mtDNA. However, the P29mt(sp)B6 cybrids did not form tumors in B6 mice, even though they had no SAMP1 mtDNA, suggesting that SAMP1 mtDNA is not involved in tumor suppression. Then, we examined another possibility of whether SAMP1 mtDNA fragments potentially integrated into the nuclear DNA of P29mtSAMP1 cybrids are responsible for tumor suppression. We generated P29 H (sp)B6 cybrids by eliminating nuclear DNA from P29mt(sp)B6 cybrids and reintroducing nuclear DNA with no integrated SAMP1 mtDNA fragment from mtDNA-less P29 cells resistant to hygromycin in selection medium containing hygromycin. However, the P29 H (sp)B6 cybrids did not form tumors in B6 mice, even though they carried neither SAMP1 mtDNA nor nuclear DNA with integrated SAMP1 mtDNA fragments. Moreover, overproduction of reactive oxygen species (ROS) and bacterial infection were not involved in tumor suppression. These observations suggest that tumor suppression was caused not by mtDNA with polymorphic mutations or infection of cytozoic bacteria but by hypothetical heritable cytoplasmic elements other than mtDNA from SAMP1 mice. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. The role of CT in diagnosing small hepatic tumors

    International Nuclear Information System (INIS)

    Usuki, Noriaki; Daikokuya, Hideo; Fukuda, Haruyuki; Saiwai, Shigeo; Nakajima, Hideyuki; Miyamoto, Takeshi; Kudo, Masatoshi

    1992-01-01

    Twenty-seven cases of small hepatic tumors were examined by MRI and CT (ICT). MRI was more sensitive than plain and contrast CT. But ICT could detect more small lesions than MRI. CT is not more superior modality than MRI untill ICT is performed. It is concluded ICT should be done when diagnosing small hepatic tumors by CT. (author)

  1. The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses breast cell proliferation.

    Science.gov (United States)

    Zhao, Dong; Zheng, Han-Qiu; Zhou, Zhongmei; Chen, Ceshi

    2010-06-01

    Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes breast cell proliferation and tumorigenesis through upregulating FGF-BP. The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCF(Fbw7)) targets KLF5 for ubiquitin-mediated degradation in a GSK3beta-mediated KLF5 phosphorylation-dependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif ((303)SPPSS) abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and breast cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits breast cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for breast cancer and other cancers. Copyright 2010 AACR.

  2. PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells.

    Science.gov (United States)

    Raab, Monika; Sanhaji, Mourad; Matthess, Yves; Hörlin, Albrecht; Lorenz, Ioana; Dötsch, Christina; Habbe, Nils; Waidmann, Oliver; Kurunci-Csacsko, Elisabeth; Firestein, Ron; Becker, Sven; Strebhardt, Klaus

    2018-03-16

    The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.

  3. Docosahexaenoic Acid Inhibits Tumor Promoter-Induced Urokinase-Type Plasminogen Activator Receptor by Suppressing PKCδ- and MAPKs-Mediated Pathways in ECV304 Human Endothelial Cells.

    Directory of Open Access Journals (Sweden)

    Sen Lian

    Full Text Available The overexpression of urokinase-type plasminogen activator receptor (uPAR is associated with inflammation and virtually all human cancers. Despite the fact that docosahexaenoic acid (DHA has been reported to possess anti-inflammatory and anti-tumor properties, the negative regulation of uPAR by DHA is still undefined. Here, we investigated the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA-induced uPAR expression and the underlying molecular mechanisms in ECV304 human endothelial cells. DHA concentration-dependently inhibited TPA-induced uPAR. Specific inhibitors and mutagenesis studies showed that PKCδ, JNK1/2, Erk1/2, NF-κB, and AP-1 were critical for TPA-induced uPAR expression. Application of DHA suppressed TPA-induced translocation of PKCδ, activation of the JNK1/2 and Erk1/2 signaling pathways, and subsequent AP-1 and NF-κB transactivation. In conclusion, these observations suggest a novel role for DHA in reducing uPAR expression and cell invasion by inhibition of PKCδ, JNK1/2, and Erk1/2, and the reduction of AP-1 and NF-κB activation in ECV304 human endothelial cells.

  4. Differential roles of resistance to proactive interference and suppression of prepotent responses in overgeneral memory.

    Science.gov (United States)

    Comas, Michelle; Valentino, Kristin; Johnson, Anne F; Gibson, Bradley S; Taylor, Courtney

    2018-06-12

    Overgeneral memory (OGM), difficulty in retrieving specific autobiographical memories, is a robust phenomenon related to the onset and course of depressive and posttraumatic stress disorders. Inhibitory mechanisms are theorized to underlie OGM; however, empirical support for this link is equivocal. The current study examines the differential roles of two aspects of inhibitory control in association with OGM: suppression of prepotent responses and resistance to proactive interference (PI). Only resistance to PI was expected to be negatively related to OGM, whereby individuals with greater ability to resist PI would have reduced OGM. Participants (n = 49) completed a self-report measure of depressive symptoms and engaged in two tasks aimed at assessing resistance to PI and suppression of prepotent responses. Participants also completed a task assessing overgeneral autobiographical memory. As hypothesized, resistance to PI, but not suppression of prepotent responses negatively predicted OGM above and beyond the influence of depressive symptoms. Because a double dissociation was not examined, we cannot address the potential independence of the submechanisms of inhibitory control that we assessed. Results exemplify the differential associations of two components of inhibition and OGM, suggesting that resistance to PI, in particular, may contribute to the development and/or maintenance of OGM and associated depressive disorders. Directions for future research are discussed. Copyright © 2018. Published by Elsevier Ltd.

  5. Roles of F-box proteins in human digestive system tumors (Review).

    Science.gov (United States)

    Gong, Jian; Lv, Liang; Huo, Jirong

    2014-12-01

    F-box proteins (FBPs), the substrate-recognition subunit of E3 ubiquitin (Ub) ligase, are the important components of Ub proteasome system (UPS). FBPs are involved in multiple cellular processes through ubiquitylation and subsequent degradation of their target proteins. Many studies have described the roles of FBPs in human cancers. Digestive system tumors account for a large proportion of all the tumors, and their mortality is very high. This review summarizes for the first time the roles of FBPs in digestive system tumorige-nesis and tumor progression, aiming at finding new routes for the rational design of targeted anticancer therapies in digestive system tumors.

  6. Role of tumor size in radiotherapy using modifiers

    International Nuclear Information System (INIS)

    Kozin, S.V.; Furmanchuk, A.V.

    1990-01-01

    Consideration is given to present-day knowledge about changes, taking place in malignant tumor tissues during their growth, important for results of radiotherapy, using modifiers, from a radiobiological viewpoint. It is shown that hypertermia (HT) is the most effective adjuvant of radiotherapy for medium - and large-size tumors. The combined application of artificial hyperglycemia (AH) and HT is investigated as the method for increasing efficiency of radiotherapy. Efficiency of using radioprotectors and electron-acceptor compounds (metronidazole, misonidazole) for large-size malignant tumors in combinations-metronidazole with AH and misonidazole with HT-is noted. Analysis of these data on radiotherapy efficiency depending on size of irradiated tumors will enable an evaluation of radiotherapy potential in different cases in determining the advisability of modifier application

  7. Rosmarinic acid inhibits inflammation and angiogenesis of hepatocellular carcinoma by suppression of NF-κB signaling in H22 tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Wen Cao

    2016-10-01

    Full Text Available The aim of this study was to explore the anti-tumor effect and therapeutic potential of rosmarinic acid (RA in the treatment of hepatocellular carcinoma (HCC. RA at 75, 150 and 300 mg/kg was given to H22 tumor-bearing mice by intragastric administration once daily for 10 consecutive days. Levels of inflammatory and angiogenic factors, including interleukin-1β (IL-1β, interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, vascular endothelial growth factor (VEGF, and transforming growth factor-β (TGF-β were measured by enzyme linked immunosorbent assays (ELISA. Protein levels of phosphorylated NF-κB p65 and p65 were detected by western blot. mRNA level of NF-κB p65 was analyzed by qRT-PCR. The results showed that RA could effectively suppress tumor growth with fewer toxic effects by regulating the secretion of cytokines associated with inflammation and angiogenesis, and suppressing the expression of NF-κB p65 in the xenograft microenvironment. Our findings unveil the possible anti-tumor mechanisms of RA and support RA as a potential drug for the treatment of HCC.

  8. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer.

    Science.gov (United States)

    Martey, Orleans; Nimick, Mhairi; Taurin, Sebastien; Sundararajan, Vignesh; Greish, Khaled; Rosengren, Rhonda J

    2017-01-01

    Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks) also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg) for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles.

  9. Thioredoxin and Cancer: A Role for Thioredoxin in all States of Tumor Oxygenation

    International Nuclear Information System (INIS)

    Karlenius, Therese Christina; Tonissen, Kathryn Fay

    2010-01-01

    Thioredoxin is a small redox-regulating protein, which plays crucial roles in maintaining cellular redox homeostasis and cell survival and is highly expressed in many cancers. The tumor environment is usually under either oxidative or hypoxic stress and both stresses are known up-regulators of thioredoxin expression. These environments exist in tumors because their abnormal vascular networks result in an unstable oxygen delivery. Therefore, the oxygenation patterns in human tumors are complex, leading to hypoxia/re-oxygenation cycling. During carcinogenesis, tumor cells often become more resistant to hypoxia or oxidative stress-induced cell death and most studies on tumor oxygenation have focused on these two tumor environments. However, recent investigations suggest that the hypoxic cycling occurring within tumors plays a larger role in the contribution to tumor cell survival than either oxidative stress or hypoxia alone. Thioredoxin is known to have important roles in both these cellular responses and several studies implicate thioredoxin as a contributor to cancer progression. However, only a few studies exist that investigate the regulation of thioredoxin in the hypoxic and cycling hypoxic response in cancers. This review focuses on the role of thioredoxin in the various states of tumor oxygenation

  10. Modeling and analysis of the impacts of jet lag on circadian rhythm and its role in tumor growth

    Directory of Open Access Journals (Sweden)

    Azka Hassan

    2018-06-01

    Full Text Available Circadian rhythms maintain a 24 h oscillation pattern in metabolic, physiological and behavioral processes in all living organisms. Circadian rhythms are organized as biochemical networks located in hypothalamus and peripheral tissues. Rhythmicity in the expression of circadian clock genes plays a vital role in regulating the process of cell division and DNA damage control. The oncogenic protein, MYC and the tumor suppressor, p53 are directly influenced by the circadian clock. Jet lag and altered sleep/wake schedules prominently affect the expression of molecular clock genes. This study is focused on developing a Petri net model to analyze the impacts of long term jet lag on the circadian clock and its probable role in tumor progression. The results depict that jet lag disrupts the normal rhythmic behavior and expression of the circadian clock proteins. This disruption leads to persistent expression of MYC and suppressed expression of p53. Thus, it is inferred that jet lag altered circadian clock negatively affects the expressions of cell cycle regulatory genes and contribute in uncontrolled proliferation of tumor cells.

  11. Salinomycin inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cell in vitro and suppresses tumor growth in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Danxin; Zhang, Yu; Huang, Jie; Fan, Zirong; Shi, Fengrong; Wang, Senming, E-mail: wsenming@126.com

    2014-01-10

    Highlight: •We first evaluated the effect of salinomycin on nasopharyngeal carcinoma (NPC). •Salinomycin could inhibit Wnt/β-catenin signaling and induce apoptosis in NPC. •So salinomycin may be a good potential candidate for the chemotherapy of NPC. -- Abstract: Salinomycin (Sal) is a polyether ionophore antibiotic that has recently been shown to induce cell death in various human cancer cells. However, whether salinomycin plays a functional role in nasopharyngeal carcinoma (NPC) has not been determined to date. The present study investigated the chemotherapeutic efficacy of salinomycin and its molecular mechanisms of action in NPC cells. Salinomycin efficiently inhibited proliferation and invasion of 3 NPC cell lines (CNE-1, CNE-2, and CNE-2/DDP) and activated a extensive apoptotic process that is accompanied by activation of caspase-3 and caspase-9, and decreased mitochondrial membrane potential. Meanwhile, the protein expression level of the Wnt coreceptor lipoprotein receptor related protein 6 (LRP6) and β-catenin was down-regulated, which showed that the Wnt/β-catenin signaling was involved in salinomycin-induced apoptosis of NPC cells. In a nude mouse NPC xenograft model, the anti-tumor effect of salinomycin was associated with the downregulation of β-catenin expression. The present study demonstrated that salinomycin can effectively inhibit proliferation and invasion, and induce apoptosis of NPC cells in vitro and inhibit tumor growth in vivo, probably via the inhibition of Wnt/β-catenin signaling, suggesting salinomycin as a potential candidate for the chemotherapy of NPC.

  12. NF-κB Directly Regulates Fas Transcription to Modulate Fas-mediated Apoptosis and Tumor Suppression*

    Science.gov (United States)

    Liu, Feiyan; Bardhan, Kankana; Yang, Dafeng; Thangaraju, Muthusamy; Ganapathy, Vadivel; Waller, Jennifer L.; Liles, Georgia B.; Lee, Jeffrey R.; Liu, Kebin

    2012-01-01

    Fas is a member of the death receptor family. Stimulation of Fas leads to induction of apoptotic signals, such as caspase 8 activation, as well as “non-apoptotic” cellular responses, notably NF-κB activation. Convincing experimental data have identified NF-κB as a critical promoter of cancer development, creating a solid rationale for the development of antitumor therapy that suppresses NF-κB activity. On the other hand, compelling data have also shown that NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence. Furthermore, although stimulation of Fas activates NF-κB, the function of NF-κB in the Fas-mediated apoptosis pathway remains largely undefined. In this study, we observed that deficiency of either Fas or FasL resulted in significantly increased incidence of 3-methylcholanthrene-induced spontaneous sarcoma development in mice. Furthermore, Fas-deficient mice also exhibited significantly greater incidence of azoxymethane and dextran sodium sulfate-induced colon carcinoma. In addition, human colorectal cancer patients with high Fas protein in their tumor cells had a longer time before recurrence occurred. Engagement of Fas with FasL triggered NF-κB activation. Interestingly, canonical NF-κB was found to directly bind to the FAS promoter. Blocking canonical NF-κB activation diminished Fas expression, whereas blocking alternate NF-κB increased Fas expression in human carcinoma cells. Moreover, although canonical NF-κB protected mouse embryo fibroblast (MEF) cells from TNFα-induced apoptosis, knocking out p65 diminished Fas expression in MEF cells, resulting in inhibition of FasL-induced caspase 8 activation and apoptosis. In contrast, knocking out p52 increased Fas expression in MEF cells. Our observations suggest that canonical NF-κB is a Fas transcription activator and alternate NF-κB is a Fas transcription repressor, and Fas functions as a suppressor of spontaneous sarcoma and colon carcinoma. PMID:22669972

  13. Carnosine inhibits carbonic anhydrase IX-mediated extracellular acidosis and suppresses growth of HeLa tumor xenografts

    International Nuclear Information System (INIS)

    Ditte, Zuzana; Ditte, Peter; Labudova, Martina; Simko, Veronika; Iuliano, Filippo; Zatovicova, Miriam; Csaderova, Lucia; Pastorekova, Silvia; Pastorek, Jaromir

    2014-01-01

    Carbonic anhydrase IX (CA IX) is a transmembrane enzyme that is present in many types of solid tumors. Expression of CA IX is driven predominantly by the hypoxia-inducible factor (HIF) pathway and helps to maintain intracellular pH homeostasis under hypoxic conditions, resulting in acidification of the tumor microenvironment. Carnosine (β-alanyl-L-histidine) is an anti-tumorigenic agent that inhibits the proliferation of cancer cells. In this study, we investigated the role of CA IX in carnosine-mediated antitumor activity and whether the underlying mechanism involves transcriptional and translational modulation of HIF-1α and CA IX and/or altered CA IX function. The effect of carnosine was studied using two-dimensional cell monolayers of several cell lines with endogenous CA IX expression as well as Madin Darby canine kidney transfectants, three-dimensional HeLa spheroids, and an in vivo model of HeLa xenografts in nude mice. mRNA and protein expression and protein localization were analyzed by real-time PCR, western blot analysis, and immunofluorescence staining, respectively. Cell viability was measured by a flow cytometric assay. Expression of HIF-1α and CA IX in tumors was assessed by immunohistochemical staining. Real-time measurement of pH was performed using a sensor dish reader. Binding of CA IX to specific antibodies and metabolon partners was investigated by competitive ELISA and proximity ligation assays, respectively. Carnosine increased the expression levels of HIF-1α and HIF targets and increased the extracellular pH, suggesting an inhibitory effect on CA IX-mediated acidosis. Moreover, carnosine significantly inhibited the growth of three-dimensional spheroids and tumor xenografts compared with untreated controls. Competitive ELISA showed that carnosine disrupted binding between CA IX and antibodies specific for its catalytic domain. This finding was supported by reduced formation of the functional metabolon of CA IX and anion exchanger 2 in the

  14. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    International Nuclear Information System (INIS)

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-01-01

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: ► ATO and SAHA are therapeutic agents with different action modes. ► Combination of ATO and SAHA synergistically inhibits tumor cell growth. ► SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. ► ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  15. An efficient approach to suppress the negative role of contrarian oscillators in synchronization

    Science.gov (United States)

    Zhang, Xiyun; Ruan, Zhongyuan; Liu, Zonghua

    2013-09-01

    It has been found that contrarian oscillators usually take a negative role in the collective behaviors formed by conformist oscillators. However, experiments revealed that it is also possible to achieve a strong coherence even when there are contrarians in the system such as neuron networks with both excitable and inhibitory neurons. To understand the underlying mechanism of this abnormal phenomenon, we here consider a complex network of coupled Kuramoto oscillators with mixed positive and negative couplings and present an efficient approach, i.e., tit-for-tat strategy, to suppress the negative role of contrarian oscillators in synchronization and thus increase the order parameter of synchronization. Two classes of contrarian oscillators are numerically studied and a brief theoretical analysis is provided to explain the numerical results.

  16. Considering the role of radiation therapy for gastrointestinal stromal tumor

    Directory of Open Access Journals (Sweden)

    Corbin KS

    2014-05-01

    Full Text Available Kimberly S Corbin,1 Hedy L Kindler,2 Stanley L Liauw31Department of Radiation Oncology, Memorial Medical Center, Springfield, IL, USA; 2Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA; 3Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USAAbstract: Gastrointestinal stromal tumors (GISTs are rare mesenchymal tumors arising in the gastrointestinal tract. Over the last decade, the management and prognosis of GISTs has changed dramatically with molecular characterization of the c-kit mutation and the adoption of targeted systemic therapy. Currently, the standard of care for resectable tumors is surgery, followed by adjuvant imatinib for tumors at high risk for recurrence. Inoperable or metastatic tumors are treated primarily with imatinib. Despite excellent initial response rates, resistance to targeted therapy has emerged as a common clinical problem, with relatively few therapeutic solutions. While the treatment of GISTs does not commonly include radiotherapy, radiation therapy could be a valuable contributing modality. Several case reports indicate that radiation can control locally progressive, drug-resistant disease. Further study is necessary to define whether radiation could potentially prevent or delay the onset of drug resistance, or improve outcomes when given in combination with imatinib.Keywords: GIST, imatinib, radiotherapy

  17. Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway.

    Science.gov (United States)

    Tian, Binqiang; Zhao, Yingmei; Liang, Tao; Ye, Xuxiao; Li, Zuowei; Yan, Dongliang; Fu, Qiang; Li, Yonghui

    2017-08-01

    We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.

  18. The role of MRI for radiotherapy of brain tumors

    International Nuclear Information System (INIS)

    Aoki, Yoshiro; Ikehira, Hiroo; Fukuda, Nobuo; Tateno, Yukio

    1987-01-01

    Magnetic resonance imaging(MRI) was performed on 10 patients with intracranial tumors, before and after intravenous administration of gadolinium-DTPA(Gd-DTPA). After administration of Gd-DTPA(0.1 mmol/kg), increased signal intensity from the tumors was observed in all patients. T1 value(300/1000, matrix; 128 x 128) was measured in sequence after administration of Gd-DTPA, whose enhancement efficacy was examined by two exponential model. Two cases of pituitary adenoma were examined by this model before and after radiotherapy. The difference of the two exponential curve between these two cases were considered to indicate the changes of the capillary walls in the irradiated tumors. (author)

  19. Mangiferin, a novel nuclear factor kappa B-inducing kinase inhibitor, suppresses metastasis and tumor growth in a mouse metastatic melanoma model

    Energy Technology Data Exchange (ETDEWEB)

    Takeda, Tomoya; Tsubaki, Masanobu; Sakamoto, Kotaro; Ichimura, Eri; Enomoto, Aya; Suzuki, Yuri [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-, Osaka (Japan); Itoh, Tatsuki [Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Nara (Japan); Imano, Motohiro [Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka (Japan); Tanabe, Genzoh; Muraoka, Osamu [Laboratory of Pharmaceutical Organic Chemistry, School of Pharmacy, Kinki University, Kowakae, Higashi-, Osaka (Japan); Matsuda, Hideaki [Department of Natural Drugs Resources, Kinki University School of Pharmacy, Kowakae, Higashi-, Osaka (Japan); Satou, Takao [Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka (Japan); Nishida, Shozo, E-mail: nishida@phar.kindai.ac.jp [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-, Osaka (Japan)

    2016-09-01

    Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa B kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma. - Highlights: • Mangiferin prolongs survival in mice by inhibiting metastasis and tumor growth • Mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation • Mangiferin regulates the expression of MMPs, VLAs, and apoptosis regulatory proteins.

  20. The role of imaging for translational research in bone tumors

    International Nuclear Information System (INIS)

    Benassi, Maria Serena; Rimondi, Eugenio; Balladelli, Alba; Ghinelli, Cristina; Magagnoli, Giovanna; Vanel, Daniel

    2013-01-01

    Sarcomas are a heterogeneous group of rare connective tissue tumors, representing 1% of adult and 15% of childhood cancers for which biological and pathological information is still incomplete. In bone tumors patients with metastatic disease at onset, those who relapse and those with post-surgical secondary lesions still have a dismal outcome because of poor response to current therapies. Different molecular biology approaches have identified activated cell signalling pathways or specific molecular endpoints that may be considered potential drug targets or markers useful for diagnosis/prognosis in musculoskeletal pathology. Recently, advances in the field of molecular imaging allow visualization of cell and metabolic functions with the use of targets that include cell membrane receptors, enzymes of intracellular transport. Moreover advanced non-invasive newer imaging techniques like 18-FDG PET, quantitative dynamic-contrast MR imaging, diffusion weighted imaging have all shown a potential in distinguish malignant from benign lesions, in revealing the efficacy of therapy in tumors, the onset of recurrence and a good reliability in reckoning the percentage of necrosis in Ewing sarcoma and osteosarcoma. Thus, in vivo detection of imaging cancer biomarkers may be useful to better characterize those complex pathologic processes, such as apoptosis, proliferation and angiogenesis that determine tumor aggressiveness, providing not only complementary information of prognostic metabolic indicators, but also data in real-time on the efficacy of the treatment through the modulation of the cell metabolism

  1. The role of imaging for translational research in bone tumors

    Energy Technology Data Exchange (ETDEWEB)

    Benassi, Maria Serena, E-mail: mariaserena.benassi@ior.it [Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna (Italy); Rimondi, Eugenio, E-mail: eugenio.rimondi@ior.it [Radiology, Istituto Ortopedico Rizzoli, Bologna (Italy); Balladelli, Alba, E-mail: alba.balladelli@ior.it [Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna (Italy); Ghinelli, Cristina, E-mail: cristina.ghinelli@ior.it [Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna (Italy); Magagnoli, Giovanna, E-mail: giovanna.magagnoli@ior.it [Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna (Italy); Vanel, Daniel, E-mail: daniel.vanel@ior.it [Bone Tumor Center, Istituto Ortopedico Rizzoli, Bologna (Italy)

    2013-12-01

    Sarcomas are a heterogeneous group of rare connective tissue tumors, representing 1% of adult and 15% of childhood cancers for which biological and pathological information is still incomplete. In bone tumors patients with metastatic disease at onset, those who relapse and those with post-surgical secondary lesions still have a dismal outcome because of poor response to current therapies. Different molecular biology approaches have identified activated cell signalling pathways or specific molecular endpoints that may be considered potential drug targets or markers useful for diagnosis/prognosis in musculoskeletal pathology. Recently, advances in the field of molecular imaging allow visualization of cell and metabolic functions with the use of targets that include cell membrane receptors, enzymes of intracellular transport. Moreover advanced non-invasive newer imaging techniques like 18-FDG PET, quantitative dynamic-contrast MR imaging, diffusion weighted imaging have all shown a potential in distinguish malignant from benign lesions, in revealing the efficacy of therapy in tumors, the onset of recurrence and a good reliability in reckoning the percentage of necrosis in Ewing sarcoma and osteosarcoma. Thus, in vivo detection of imaging cancer biomarkers may be useful to better characterize those complex pathologic processes, such as apoptosis, proliferation and angiogenesis that determine tumor aggressiveness, providing not only complementary information of prognostic metabolic indicators, but also data in real-time on the efficacy of the treatment through the modulation of the cell metabolism.

  2. Conflicting Roles of Connexin43 in Tumor Invasion and Growth in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Miaki Uzu

    2018-04-01

    Full Text Available The tumor microenvironment is known to have increased levels of cytokines and metabolites, such as glutamate, due to their release from the surrounding cells. A normal cell around the tumor that responds to the inflammatory environment is likely to be subsequently altered. We discuss how these abnormalities will support tumor survival via the actions of gap junctions (GJs and hemichannels (HCs which are composed of hexamer of connexin43 (Cx43 protein. In particular, we discuss how GJ intercellular communication (GJIC in glioma cells, the primary brain tumor, is a regulatory factor and its attenuation leads to tumor invasion. In contrast, the astrocytes, which are normal cells around the glioma, are “hijacked” by tumor cells, either by receiving the transmission of malignant substances from the cancer cells via GJIC, or perhaps via astrocytic HC activity through the paracrine signaling which enable the delivery of these substances to the distal astrocytes. This astrocytic signaling would promote tumor expansion in the brain. In addition, brain metastasis from peripheral tissues has also been known to be facilitated by GJs formed between cerebral vascular endothelial cells and cancer cells. Astrocytes and microglia are generally thought to eliminate cancer cells at the blood–brain barrier. In contrast, some reports suggest they facilitate tumor progression as tumor cells take advantage of the normal functions of astrocytes that support the survival of the neurons by exchanging nutrients and metabolites. In summary, GJIC is essential for the normal physiological function of growth and allowing the diffusion of physiological substances. Therefore, whether GJIC is cancer promoting or suppressing may be dependent on what permeates through GJs, when it is active, and to which cells. The nature of GJs, which has been ambiguous in brain tumor progression, needs to be revisited and understood together with new findings on Cx proteins and HC

  3. The Potential Role of circRNA in Tumor Immunity Regulation and Immunotherapy

    OpenAIRE

    Xu, Zihao; Li, Peiyao; Fan, Li; Wu, Minghua

    2018-01-01

    Non-coding RNAs (ncRNAs) can be divided into circular non-coding RNAs (circRNAs) and linear ncRNAs. ncRNAs exist in different cell types, including normal cells, tumor cells and immunocytes. Linear ncRNAs, such as long ncRNAs and microRNAs, have been found to play important roles in the regulation of tumor immunity and immunotherapy; however, the functions of circRNAs in tumor immunity and immunotherapy are less known. Here, we review the current status of ncRNAs in the regulation of tumor im...

  4. Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605

    International Nuclear Information System (INIS)

    Pappano, William N; Sheppard, George S; Donawho, Cherrie; Buchanan, Fritz G; Davidsen, Steven K; Bell, Randy L; Wang, Jieyi; Jung, Paul M; Meulbroek, Jonathan A; Wang, Yi-Chun; Hubbard, Robert D; Zhang, Qian; Grudzien, Meagan M; Soni, Niru B; Johnson, Eric F

    2009-01-01

    The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation

  5. Hepatic Radiofrequency Ablation–induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition

    Science.gov (United States)

    Kumar, Gaurav; Moussa, Marwan; Wang, Yuanguo; Rozenblum, Nir; Galun, Eithan; Goldberg, S. Nahum

    2016-01-01

    Purpose To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways. Materials and Methods Rats were used in this institutional animal care and use committee–approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 3½ to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met–negative R3230 tumors for comparison with the native c-Met–positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests. Results After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor

  6. The Role of Neutrophil Myeloperoxidase in Models of Lung Tumor Development

    International Nuclear Information System (INIS)

    Rymaszewski, Amy L.; Tate, Everett; Yimbesalu, Joannes P.; Gelman, Andrew E.; Jarzembowski, Jason A.; Zhang, Hao; Pritchard, Kirkwood A. Jr.; Vikis, Haris G.

    2014-01-01

    Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA)-initiated, butylated hydroxytoluene (BHT)-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO) activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC), a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC) tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting

  7. The role of neutrophil myeloperoxidase in models of lung tumor development.

    Science.gov (United States)

    Rymaszewski, Amy L; Tate, Everett; Yimbesalu, Joannes P; Gelman, Andrew E; Jarzembowski, Jason A; Zhang, Hao; Pritchard, Kirkwood A; Vikis, Haris G

    2014-05-09

    Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA)-initiated, butylated hydroxytoluene (BHT)-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO) activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC), a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC) tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting.

  8. The Role of Neutrophil Myeloperoxidase in Models of Lung Tumor Development

    Energy Technology Data Exchange (ETDEWEB)

    Rymaszewski, Amy L.; Tate, Everett; Yimbesalu, Joannes P. [Department of Pharmacology and Toxicology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Gelman, Andrew E. [Department of Surgery, Washington University in St. Louis, St. Louis, MO 63130 (United States); Jarzembowski, Jason A. [Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Zhang, Hao; Pritchard, Kirkwood A. Jr. [Department of Surgery and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Vikis, Haris G., E-mail: hvikis@mcw.edu [Department of Pharmacology and Toxicology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226 (United States)

    2014-05-09

    Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA)-initiated, butylated hydroxytoluene (BHT)-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO) activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC), a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC) tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting.

  9. The Role of Neutrophil Myeloperoxidase in Models of Lung Tumor Development

    Directory of Open Access Journals (Sweden)

    Amy L. Rymaszewski

    2014-05-01

    Full Text Available Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA-initiated, butylated hydroxytoluene (BHT-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC, a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting.

  10. [Immune system and tumors].

    Science.gov (United States)

    Terme, Magali; Tanchot, Corinne

    2017-02-01

    Despite having been much debated, it is now well established that the immune system plays an essential role in the fight against cancer. In this article, we will highlight the implication of the immune system in the control of tumor growth and describe the major components of the immune system involved in the antitumoral immune response. The immune system, while exerting pressure on tumor cells, also will play a pro-tumoral role by sculpting the immunogenicity of tumors cells as they develop. Finally, we will illustrate the numerous mechanisms of immune suppression that take place within the tumoral microenvironment which allow tumor cells to escape control from the immune system. The increasingly precise knowledge of the brakes to an effective antitumor immune response allows the development of immunotherapy strategies more and more innovating and promising of hope. Copyright © 2016. Published by Elsevier Masson SAS.

  11. Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Xiaohong Wang

    2008-07-01

    Full Text Available MicroRNAs (miRNAs play important roles in cancer development. By cloning and sequencing of a HPV16(+ CaSki cell small RNA library, we isolated 174 miRNAs (including the novel miR-193c which could be grouped into 46 different miRNA species, with miR-21, miR-24, miR-27a, and miR-205 being most abundant. We chose for further study 10 miRNAs according to their cloning frequency and associated their levels in 10 cervical cancer- or cervical intraepithelial neoplasia-derived cell lines. No correlation was observed between their expression with the presence or absence of an integrated or episomal HPV genome. All cell lines examined contained no detectable miR-143 and miR-145. HPV-infected cell lines expressed a different set of miRNAs when grown in organotypic raft cultured as compared to monolayer cell culture, including expression of miR-143 and miR-145. This suggests a correlation between miRNA expression and tissue differentiation. Using miRNA array analyses for age-matched normal cervix and cervical cancer tissues, in combination with northern blot verification, we identified significantly deregulated miRNAs in cervical cancer tissues, with miR-126, miR-143, and miR-145 downregulation and miR-15b, miR-16, miR-146a, and miR-155 upregulation. Functional studies showed that both miR-143 and miR-145 are suppressive to cell growth. When introduced into cell lines, miR-146a was found to promote cell proliferation. Collectively, our data indicate that downregulation of miR-143 and miR-145 and upregulation of miR-146a play a role in cervical carcinogenesis.

  12. Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth.

    Science.gov (United States)

    Enderling, Heiko; Hlatky, Lynn; Hahnfeldt, Philip

    2012-07-28

    The role of the immune system in tumor progression has been a subject for discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression. We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response. Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step "immunoediting" concept - the modulation of tumor growth through inhibition, selection and promotion.

  13. Macrophage biology plays a central role during ionizing radiation-elicited tumor response

    Directory of Open Access Journals (Sweden)

    Qiuji Wu

    2017-08-01

    Full Text Available Radiation therapy is one of the major therapeutic modalities for most solid tumors. The anti-tumor effect of radiation therapy consists of the direct tumor cell killing, as well as the modulation of tumor microenvironment and the activation of immune response against tumors. Radiation therapy has been shown to promote immunogenic cells death, activate dendritic cells and enhance tumor antigen presentation and anti-tumor T cell activation. Radiation therapy also programs innate immune cells such as macrophages that leads to either radiosensitization or radioresistance, according to different tumors and different radiation regimen studied. The mechanisms underlying radiation-induced macrophage activation remain largely elusive. Various molecular players such as NF-κB, MAPKs, p53, reactive oxygen species, inflammasomes have been involved in these processes. The skewing to a pro-inflammatory phenotype thus results in the activation of anti-tumor immune response and enhanced radiotherapy effect. Therefore, a comprehensive understanding of the mechanism of radiation-induced macrophage activation and its role in tumor response to radiation therapy is crucial for the development of new therapeutic strategies to enhance radiation therapy efficacy.

  14. Worry, problem elaboration and suppression of imagery: the role of concreteness.

    Science.gov (United States)

    Stöber, J

    1998-01-01

    Both lay concept and scientific theory claim that worry may be helpful for defining and analyzing problems. Recent studies, however, indicate that worrisome problem elaborations are less concrete than worry-free problem elaborations. This challenges the problem solving view of worry because abstract problem analyses are unlikely to lead to concrete problem solutions. Instead the findings support the avoidance theory of worry which claims that worry suppresses aversive imagery. Following research findings in the dual-coding framework [Paivio, A. (1971). Imagery and verbal processes. New York: Holt, Rhinehart and Winston; Paivio, A. (1986). Mental representations: a dual coding approach. New York: Oxford University Press.], the present article proposes that reduced concreteness may play a central role in the understanding of worry. First, reduced concreteness can explain how worry reduces imagery. Second, it offers an explanation why worrisome problem analyses are unlikely to arrive at solutions. Third, it provides a key for the understanding of worry maintenance.

  15. Role for the Wilms tumor gene in genital development?

    International Nuclear Information System (INIS)

    van Heyningen, V.; Bickmore, W.A.; Seawright, A.; Fletcher, J.M.; Maule, J.; Hastie, N.D.; Fekete, G.; Gessler, M.; Bruns, G.A.P.; Huerre-Jeanpierre, C.; Junien, C.; Williams, B.R.G.

    1990-01-01

    Detailed molecular definition of the WAGR region at chromosome 11p13 has been achieved by chromosome breakpoint analysis and long-range restriction mapping. Here the authors describe the molecular detection of a cytogenetically invisible 1-megabase deletion in an individual with aniridia, cryptorchidism, and hypospadias but no Wilms tumor (WT). The region of overlap between this deletion and one associated with WT and similar genital anomalies but no aniridia covers a region of 350-400 kilobases, which is coincident with the extent of homozygous deletion detected in tumor tissue from a sporadic WT. A candidate WT gene located within this region has recently been isolated, suggesting nonpenetrance for tumor expression in the first individual. The inclusion within the overlap region of a gene for WT predisposition and a gene for the best-documented WT-associated genitourinary malformations leads to suggest that both of these anomalies result from a loss-of-function mutation at the same locus. This in turn implies that the WT gene exerts pleiotropic effect on both kidney and genitourinary development, a possibility supported by the observed expression pattern of the WT candidate gene in developing kidney and gonads

  16. Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage

    Science.gov (United States)

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin; Eggert, Tobias; Hawk, Nga; Kleiner, David E.; Korangy, Firouzeh; Greten, Tim F.

    2015-01-01

    Immune stimulatory monoclonal antibodies are currently evaluated as anti tumor agents. Although overall toxicity appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in liver and spleen, serum transaminases and liver histologies were analyzed after antibody administration. Nox2−/−, Cd40−/− as well as bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid derived suppressive cells was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras we demonstrated that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80 and CD40 positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14+HLA-DRlow PBMC from cancer patients reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced, myeloid cells, caused myeloid dependent hepatotoxicity and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggests that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. PMID:25637366

  17. Stereotactic body radiotherapy for stage I lung cancer and small lung metastasis: evaluation of an immobilization system for suppression of respiratory tumor movement and preliminary results

    Directory of Open Access Journals (Sweden)

    Ayakawa Shiho

    2009-05-01

    Full Text Available Abstract Background In stereotactic body radiotherapy (SBRT for lung tumors, reducing tumor movement is necessary. In this study, we evaluated changes in tumor movement and percutaneous oxygen saturation (SpO2 levels, and preliminary clinical results of SBRT using the BodyFIX immobilization system. Methods Between 2004 and 2006, 53 consecutive patients were treated for 55 lesions; 42 were stage I non-small cell lung cancer (NSCLC, 10 were metastatic lung cancers, and 3 were local recurrences of NSCLC. Tumor movement was measured with fluoroscopy under breath holding, free breathing on a couch, and free breathing in the BodyFIX system. SpO2 levels were measured with a finger pulseoximeter under each condition. The delivered dose was 44, 48 or 52 Gy, depending on tumor diameter, in 4 fractions over 10 or 11 days. Results By using the BodyFIX system, respiratory tumor movements were significantly reduced compared with the free-breathing condition in both craniocaudal and lateral directions, although the amplitude of reduction in the craniocaudal direction was 3 mm or more in only 27% of the patients. The average SpO2 did not decrease by using the system. At 3 years, the local control rate was 80% for all lesions. Overall survival was 76%, cause-specific survival was 92%, and local progression-free survival was 76% at 3 years in primary NSCLC patients. Grade 2 radiation pneumonitis developed in 7 patients. Conclusion Respiratory tumor movement was modestly suppressed by the BodyFIX system, while the SpO2 level did not decrease. It was considered a simple and effective method for SBRT of lung tumors. Preliminary results were encouraging.

  18. Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity.

    Science.gov (United States)

    Dwivedi, Mitesh; Kumar, Prasant; Laddha, Naresh C; Kemp, E Helen

    2016-04-01

    Regulatory T cells (Tregs) are comprised of a heterogeneous population of cells that play a vital role in suppressing inflammation and maintaining immune tolerance. Given the crucial role of Tregs in maintaining immune homeostasis, it is probably not surprising that many microbial species and their metabolites have the potential to induce Tregs. There is now great interest in the therapeutic potential of probiotics and prebiotics based strategies for a range of autoimmune disorders. This review will summarise recent findings concerning the role of probiotics and prebiotics in induction of Tregs to ameliorate the autoimmune conditions. In addition, the article is focused to explain the different mechanisms of Treg induction and function by these probiotics and prebiotics, based on the available studies till date. The article further proposes that induction of Tregs by probiotics and prebiotics could lead to the development of new therapeutic approach towards curbing the autoimmune response and as an alternative to detrimental immunosuppressive drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

    International Nuclear Information System (INIS)

    Klenke, Frank Michael; Gebhard, Martha-Maria; Ewerbeck, Volker; Abdollahi, Amir; Huber, Peter E; Sckell, Axel

    2006-01-01

    The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases

  20. A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors

    Directory of Open Access Journals (Sweden)

    Maria Isabel Carvalho

    2014-01-01

    Full Text Available Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.

  1. Styrene maleic acid-encapsulated RL71 micelles suppress tumor growth in a murine xenograft model of triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Martey O

    2017-10-01

    Full Text Available Orleans Martey,1 Mhairi Nimick,1 Sebastien Taurin,1 Vignesh Sundararajan,1 Khaled Greish,2 Rhonda J Rosengren1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene-1-methylpiperidine-4-one (RL71, that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles. Keywords: curcumin derivatives, nanomedicine, EGFR, biodistribution

  2. The role of radiation therapy in the management of desmoid tumors

    International Nuclear Information System (INIS)

    Schulz-Ertner, D.; Zierhut, D.; Mende, U.; Harms, W.; Branitzki, P.; Wannenmacher, M.

    2002-01-01

    Purpose: To investigate the role of radiation therapy (RT) in the management of desmoid tumors. Patients and Methods: Retrospective analysis was performed on 28 patients with desmoid tumors treated with radiation therapy between March 1989 and March 1999. Tumor site was intraabdominal in three, abdominal wall in three and extraabdominal in 22 patients. Median tumor dose was 48 Gy (range 36-60 Gy). Radiation therapy was delivered postoperatively in 26 of 28 patients, two patients received radiation therapy for unresectable recurrent tumors. Results: Median follow-up was 46 months (range 13-108 months). Actuarial 5-year control rate was 73%. We observed six recurrences, located within the radiation field in one patient, out of field in two and at the field margin in three patients. All patients with intraabdominal tumors have been controlled without severe side effects. Conclusions: Radiation therapy is an effective treatment after incomplete resection of desmoid tumors. We did not observe a benefit for tumor doses exceeding 50 Gy. In some patients with circumscribed intraabdominal desmoid tumors, radiation therapy might be a treatment option with low toxicity, if 3-D treatment planning is utilized. (orig.) [de

  3. The Role of BRCA1 in Suppressing Epithelial Mesenchymal Transition in Mammary Gland and Tumor Development

    Science.gov (United States)

    2016-11-01

    Berton D, Nicholls M, Srinivasan D, Raman R, Girshik S, Kigonya P, Alonso S, Sanbhadti R, Barletta S, Pot D, Sheth M, Demchok JA, Mills Shaw KR, Yang L...443:421–426. 8. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE. p16INK4a induces an age-dependent decline in

  4. Elucidating the Tumor-Suppressive Role of SLITs in Maintaining the Basal Cell Niche

    Science.gov (United States)

    2011-10-01

    used were as follows: CK-14 ( Covance ); E-cadherin (R&D Systems); p63 (Santa Cruz Biotechnology); ROBO1 (Abcam); Myc (9E10); tubulin (Sigma); GAPDH...AF64, Covance ), anti-SMA (1A4, Sigma), anti-Ki67 (Santa Cruz Biotechnology), anti-CXCR4 (Abcam), anti-SDF1 (Santa Cruz Biotechnology), anti-SLIT3

  5. The Role of BRCA1 Domains and Motifs in Tumor Suppression

    Science.gov (United States)

    2011-08-01

    George C. Prendergast Thomas Jefferson University Carol Prives Columbia University Martin Raff University College London E. Premkumar Reddy Temple...71] Taron, M.; Rosell, R.; Felip, E.; Mendez , P.; Souglakos, J.; Ronco, M.S.; Queralt, C.; Majo, J.; Sanchez, J.M.; Sanchez, J.J.; Maestre, J...Skrzypski, M.; Jassem, E.; Taron, M.; Bartolucci, R.; Sanchez, J.J.; Mendez , P.; Chaib, I.; Perez-Roca, L.; Szymanowska, A.; Rzyman, W.; Puma, F

  6. Peculiarities of tumor blood supply and their role in radiotherapy, hyperthermia and hyperglycemia

    International Nuclear Information System (INIS)

    Kozin, S.V.; Furmanchuk, A.V.

    1986-01-01

    Development regularities and functional peculiarities of tumor microcirculatory channel (MCC) are considered. The role of microcirculation changes under radiotherapy and it's combinations with hyperthermia and hyperglycemia is estimated. The conclusion is drawn, that MCC reactions play a substantial role in realization of hyperthermia and hyperglycemia radiomodifying action

  7. A Role for PPARβ/δ in Tumor Stroma and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Rolf Müller

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ is a transcription factor that is activated by endogenous fatty acid ligands and by synthetic agonists. Its role in the regulation of skeletal muscle fatty acid catabolism, glucose homeostasis, and cellular differentiation has been established in multiple studies. On the contrary, a role for PPARβ/δ in tumorigenesis is less clear because there are contradictory reports in the literature. However, the majority of these studies have not examined the role of PPARβ/δ in the tumor stroma. Recent evidence suggests that stromal PPARβ/δ regulates tumor endothelial cell proliferation and promotes differentiation leading to the properly orchestrated events required for tumor blood vessel formation. This review briefly summarizes the significance of these studies that may provide clues to help explain the reported discrepancies in the literature regarding the role of PPARβ/δ in tumorigenesis.

  8. The role of CT in the diagnosis of tumors in sellar area

    International Nuclear Information System (INIS)

    Li Wenxin

    2005-01-01

    Objective: To evaluate computed tomography (CT) in patients with tumors in sellar area. Methods: CT images of 33 patients with sellar area tumor's proved by surgery and pathology were analyzed retrospectively. Results: Pituitary adenomas (n=20), craniopharyngiomas (n=8) and meningiomas (n=3) had characteristic findings and were given a high rate of correct diagnosis. While astrocytoma (n=1) and germinoma (n=1) were solid lesions in sellar area and lack of diagnostic signs and the astrocytoma was misdiagnosed as craniopharyngioma. Conclusion: CT, especially 2-demision reconstructed (coronal and sagittal) images can demonstrate inner structure, pattern of growth, extension of invasion of tumors as well as the relationship between tumor and the adjacent vessels. CT plays an important role in the diagnosis of tumors in seliar area. (authors)

  9. EGCG Inhibits Proliferation, Invasiveness and Tumor Growth by Up-Regulation of Adhesion Molecules, Suppression of Gelatinases Activity, and Induction of Apoptosis in Nasopharyngeal Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Chih-Yeu Fang

    2015-01-01

    Full Text Available (−-Epigallocatechin-3-gallate (EGCG, a major green tea polyphenol, has been shown to inhibit the proliferation of a variety of tumor cells. Epidemiological studies have shown that drinking green tea can reduce the incidence of nasopharyngeal carcinoma (NPC, yet the underlying mechanism is not well understood. In this study, the inhibitory effect of EGCG was tested on a set of Epstein Barr virus-negative and -positive NPC cell lines. Treatment with EGCG inhibited the proliferation of NPC cells but did not affect the growth of a non-malignant nasopharyngeal cell line, NP460hTert. Moreover, EGCG treated cells had reduced migration and invasive properties. The expression of the cell adhesion molecules E-cadherin and β-catenin was found to be up-regulated by EGCG treatment, while the down-regulation of matrix metalloproteinases (MMP-2 and MMP-9 were found to be mediated by suppression of extracellular signal-regulated kinase (ERK phosphorylation and AP-1 and Sp1 transactivation. Spheroid formation by NPC cells in suspension was significantly inhibited by EGCG. Oral administration of EGCG was capable of suppressing tumor growth in xenografted mice bearing NPC tumors. Treatment with EGCG was found to elevate the expression of p53 and p21, and eventually led to apoptosis of NPC cells via caspase 3 activation. The nuclear translocation of NF-κB and β-catenin was also suppressed by EGCG treatment. These results indicate that EGCG can inhibit the proliferation and invasiveness, and induce apoptosis, of NPC cells, making it a promising agent for chemoprevention or adjuvant therapy of NPC.

  10. Rodlike Supramolecular Nanoassemblies of Degradable Poly(Aspartic Acid) Derivatives and Hydroxyl-Rich Polycations for Effective Delivery of Versatile Tumor-Suppressive ncRNAs.

    Science.gov (United States)

    Song, Hai-Qing; Pan, Wenting; Li, Rui-Quan; Yu, Bingran; Liu, Wenjuan; Yang, Ming; Xu, Fu-Jian

    2018-03-01

    The delivery of tumor-suppressive noncoding RNAs (ncRNAs) including short ncRNAs (i.e., miRNAs) and long ncRNAs (lncRNAs) is put forward to treat tumors. In this work, novel rodlike supramolecular nanoassemblies (CNC @CB[8] @ PGEA) of degradable poly(aspartic acid) (PAsp) derivatives-grafted cellulose nanocrystals (CNCs) and hydroxyl-rich polycations (ethanolamine-functionalized poly(glycidyl methacrylate), PGEA) are proposed via typical cucurbit[8]uril (CB[8])-based host-guest interactions for delivery of different ncRNAs to treat hepatocellular carcinoma (HCC). Spindly CNCs, one kind of natural polysaccharide nanoparticles, possess good biocompatibility and unique physico-chemical properties. PGEA with abundant hydroxyl groups is one promising gene carrier with low cytotoxicity. PAsp can benefit the disassembly and degradability of nanoassemblies within cells. CNC @ CB[8]@PGEA combines the different unique properties of CNC, PGEA, and PAsp. CNC @ CB[8] @ PGEA effectively complexes the expression constructs of miR-101 (plasmid pc3.0-miR-101) and lncRNA MEG3 (plasmid pc3.0-MEG3). CNC @ CB[8] @ PGEA produces much better transfection performances than PGEA-containing assembly units. In addition, the codelivery system of CNC @ CB[8] @ PGEA/(pc3.0-MEG3+pc3.0-miR-101) nanocomplexes demonstrates better efficacy in suppressing HCC than CNC @ CB[8] @ PGEA/pc3.0-MEG3 or CNC @ CB[8] @ PGEA/pc3.0-miR-101 nanocomplexes alone. Such rodlike supramolecular nanoassemblies will provide a promising means to produce efficient delivery vectors of versatile tumor-suppressive nucleic acids. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Analysis of the Role of Cortactin in Tumor Cell Invasion

    National Research Council Canada - National Science Library

    Zhan, Xi

    1999-01-01

    .... Studies have demonstrated that cortactin (also EMS1), a filamentous actin (F-actin) associated protein and a substrate of protein tyrosine kinase Src, plays an important role in the amplification...

  12. Chrysin inhibits tumor promoter-induced MMP-9 expression by blocking AP-1 via suppression of ERK and JNK pathways in gastric cancer cells.

    Directory of Open Access Journals (Sweden)

    Yong Xia

    Full Text Available Cell invasion is a crucial mechanism of cancer metastasis and malignancy. Matrix metalloproteinase-9 (MMP-9 is an important proteolytic enzyme involved in the cancer cell invasion process. High expression levels of MMP-9 in gastric cancer positively correlate with tumor aggressiveness and have a significant negative correlation with patients' survival times. Recently, mechanisms suppressing MMP-9 by phytochemicals have become increasingly investigated. Chrysin, a naturally occurring chemical in plants, has been reported to suppress tumor metastasis. However, the effects of chrysin on MMP-9 expression in gastric cancer have not been well studied. In the present study, we tested the effects of chrysin on MMP-9 expression in gastric cancer cells, and determined its underlying mechanism. We examined the effects of chrysin on MMP-9 expression and activity via RT-PCR, zymography, promoter study, and western blotting in human gastric cancer AGS cells. Chrysin inhibited phorbol-12-myristate 13-acetate (PMA-induced MMP-9 expression in a dose-dependent manner. Using AP-1 decoy oligodeoxynucleotides, we confirmed that AP-1 was the crucial transcriptional factor for MMP-9 expression. Chrysin blocked AP-1 via suppression of the phosphorylation of c-Jun and c-Fos through blocking the JNK1/2 and ERK1/2 pathways. Furthermore, AGS cells pretreated with PMA showed markedly enhanced invasiveness, which was partially abrogated by chrysin and MMP-9 antibody. Our results suggest that chrysin may exert at least part of its anticancer effect by controlling MMP-9 expression through suppression of AP-1 activity via a block of the JNK1/2 and ERK1/2 signaling pathways in gastric cancer AGS cells.

  13. MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

    DEFF Research Database (Denmark)

    Cogoi, Susanna; Zorzet, Sonia; Rapozzi, Valentina

    2013-01-01

    and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited...... cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased...

  14. Activated Natural Killer Cells Mediate the Suppressive Effect of Interleukin-4 on Tumor Development via STAT6 Activation in an Atopic Condition Melanoma Model

    OpenAIRE

    Dong Ju Son; Yu Yeon Jung; Mi Hee Park; Hye Lim Lee; Min Ji Song; Hwan-Soo Yoo; Dae Youn Hwang; Sang Bae Han; Jin Tae Hong

    2017-01-01

    A protective effect of allergy for cancer has been suggested, but the results are somewhat conflicting, and the mechanism remains elusive. Interleukin-4 (IL-4) signaling has been identified as a potentially important pathway in the development of allergies and the suppression of cancer development. To evaluate the allergy responses in IL-4?mediated tumor development, we compared the growth of B16F10 melanoma cells in 4% phthalic anhydride (PA)-treated IL-4/Luc/CNS-1 transgenic mice (IL-4 mice...

  15. Profile of patients with brain tumors and the role of nursing care

    OpenAIRE

    Magalhães, Kênia Cristina Soares Fonseca de; Vaz, Josiane Pinto Moreira; Gontijo, Pollyana Anicio Magalhaes; Carvalho, Gervásio Teles Cardoso de; Christo, Paulo Pereira; Simões, Renata Toscano; Silva, Karla Rona da

    2016-01-01

    ABSTRACT Objective: to describe the profile of 200 patients with central nervous system tumors (CNST), and the role of the nursing care. Method: prospective, quantitative and descriptive analysis of medical records of 200 patients with TSNC. Results: a total of 61% of our patients had benign CNST and 39% had malignant tumors. The extent of patient dependence, according to the Karnofsky Performance Status scale, was significantly greater for patients with malignant CNST (p < .05), indicatin...

  16. Natural killer cells and interleukin-1: a possible role in natural killer-tumor cell interaction

    Energy Technology Data Exchange (ETDEWEB)

    Traub, L M

    1986-01-01

    Effector cells with broad cytolytic reactivity against various tumor cell lines have been detected in the peripheral blood of normal individuals. This phenomenon, known as natural killing, appeared to be significantly depressed in a small group of patients with extensive primary hepatocellular carcinoma. These data, together with that of others showing depressed interleukin-1 (IL-1) production in these patients, were taken to indicate that IL-1 played a functional role in natural killer (NK) cell biology. The hypothesis was confirmed by the demonstration that preincubation of tumor target cells with IL-1 enhanced their susceptibility to NK cell killing. In this study tumor target cells were labelled with /sup 51/Cr.

  17. New and paradoxical roles of matrix metalloproteinases in the tumor microenvironment

    DEFF Research Database (Denmark)

    Noël, Agnès; Gutiérrez-Fernández, Ana; Sounni, Nor Eddine

    2012-01-01

    Processes such as cell proliferation, angiogenesis, apoptosis, or invasion are strongly influenced by the surrounding microenvironment of the tumor. Therefore, the ability to change these surroundings represents an important property through which tumor cells are able to acquire specific functions....... Despite the pro-tumorigenic function of certain metalloproteinases, recent studies have shown that other members of these families, such as MMP8 or MMP11, have a protective role against tumor growth and metastasis in animal models. These studies have been further expanded by large-scale genomic analysis...

  18. The role of apparent diffusion coefficient in the differentiation between benign and malignant bone tumors

    International Nuclear Information System (INIS)

    Liu Jicun; Cui Jianling; Li Shiling; Guo Zhiping; Ma Xiaohui

    2009-01-01

    Objective: To explore the role of apparent diffusion coefficient (ADC) value of diffusion-weighted imaging (DWI) in the differentiation between benign and malignant bone tumors. Methods: Echo planar imaging DWI was performed in 18 patients with benign tumor or tumorous lesion and 26 patients with malignant tumor of bone. Three b-values (0, 500 and 1000 s/mm 2 ) were applied. The lowest, highest, and whole ADC values were measured for each lesion, respectively. Results: The lowest ADC values of benign bone tumor [mean (1.28 ± 0.49)x10 -3 mm 2 /s] were significantly higher than that of malignant tumor [ mean (0.92 ± 0.35) x10 -3 mm 2 /s,t =2.839,P -3 mm 2 /s] were significantly higher than that of malignant tumor [ mean (1.21 ± 0.36)x10 -3 mm 2 /s, t =3.092, P -3 mm 2 /s] and malignant bone tumor [ mean (1.71 ± 0.65)x10 -3 mm 2 /s, t = 1.669, P > 0.05]. Excluding cases of bone cyst and aneurismal bone cyst, the lowest, highest, and whole ADC values of benign bone tumor waw (1.11 ± 0.31)x10 -3 mm 2 /s, (1.88 ± 0.49)x10 -3 mm 2 /s, and (1.45 ± 0.35)x10 -3 mm 2 /s, respectively. There was no significant difference for the lowest, highest, or whole ADC values between benign and malignant bone tumor (t =1.728, 0.964, and 2.012, respectively, P> 0.05). Conclusion: ADC value is useless for the differentiation between benign and malignant bone tumors. (authors)

  19. Role of Interleukin-6 in the Radiation Response of Liver Tumors

    International Nuclear Information System (INIS)

    Chen, Miao-Fen; Hsieh, Ching-Chuan; Chen, Wen-Cheng; Lai, Chia-Hsuan

    2012-01-01

    Purpose: To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. Methods and Materials: The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6–neutralizing antibody for 24 hours or stably transfected with IL-6–silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. Results: Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6–silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. Conclusion: These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.

  20. Expanding roles for CD4 T cells and their subpopulations in tumor immunity and therapy

    Directory of Open Access Journals (Sweden)

    Mark J Dobrzanski

    2013-03-01

    Full Text Available The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for "plasticity" and memory cell generation within the hostile tumor environment and their potentials in cancer treatment and adoptive immunotherapies.

  1. Targeting acceptance in the management of food craving: The mediating roles of eating styles and thought suppression.

    Science.gov (United States)

    Coffino, Jaime A; Heiss, Sydney; Hormes, Julia M

    2018-04-01

    Food craving is now widely considered to be a cognitively motivated state. Acceptance-based treatments are effective in reducing the adverse impact of food cravings on consumption, via a hypothesized decrease in experiential avoidance. The mechanisms that drive the success of acceptance-based management of craving remain to be empirically tested. This study examined the role of eating styles and thought suppression as mediators in the relationship between experiential avoidance and craving. Participants (n = 298, 51.5% female) completed the Food Craving Acceptance and Awareness Questionnaire (FAAQ), the Dutch Eating Behavior Questionnaire (DEBQ), the White Bear Suppression Inventory (WBSI; a measure of thought suppression), and the reduced version of the Food Craving Questionnaire- Trait (FCQ-T-r). Scores on the FAAQ were inversely associated with scores on the FCQ-T-r, DEBQ, and WBSI; FCQ-T-r scores were positively correlated with scores on the DEBQ and WBSI (all p styles and thought suppression, acceptance remained a significant predictor of craving. Results thus provide initial evidence that eating styles and thought suppression mediate the relationship between food-specific experiential avoidance and food craving. Findings lay the foundation for future study of the proximal antecedents of food cravings and lend preliminary support for targeting thought suppression and eating styles in acceptance-based approaches to the management of craving. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Blockade of A2b Adenosine Receptor Reduces Tumor Growth and Immune Suppression Mediated by Myeloid-Derived Suppressor Cells in a Mouse Model of Melanoma

    Directory of Open Access Journals (Sweden)

    Raffaella Iannone

    2013-12-01

    Full Text Available The A2b receptor (A2bR belongs to the adenosine receptor family. Emerging evidence suggest that A2bR is implicated in tumor progression in some murine tumor models, but the therapeutic potential of targeting A2bR in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A2bR agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL-10 and monocyte chemoattractant protein 1 (MCP-1 and accumulation of tumor-associated CD11b positive Gr1 positive cells (CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs. Depletion of CD11b+Gr1+ cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A2bR with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b+Gr1+ cell number in melanoma lesions. These effects were associated with higher frequency of tumor-infiltrating CD8 positive (CD8+ T cells and natural killer T (NKT cells and increased levels of T helper 1 (Th1-like cytokines. Adoptive transfer of CD11b+Gr1+ cells abrogated the antitumor activity of PSB1115. These data suggest that the antitumor activity of PSB1115 relies on its ability to lower accumulation of tumor-infiltrating MDSCs and restore an efficient antitumor T cell response. The antitumor effect of PSB1115 was not observed in melanoma-bearing nude mice. Furthermore, PSB1115 enhanced the antitumor efficacy of dacarbazine. These data indicate that A2bR antagonists such as PSB1115 should be investigated as adjuvants in the treatment of melanoma.

  3. Human Mut T Homolog 1 (MTH1): a roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS.

    Science.gov (United States)

    Rai, Priyamvada

    2012-01-01

    Oncogenic RAS-induced reactive oxygen species (ROS) trigger barriers to cell transformation and cancer progression through tumor-suppressive responses such as cellular senescence or cell death. We have recently shown that oncogenic RAS-induced DNA damage and attendant premature senescence can be prevented by overexpressing human MutT Homolog 1 (MTH1), the major mammalian detoxifier of the oxidized DNA precursor, 8-oxo-dGTP. Paradoxically, RAS-induced ROS are also able to participate in tumor progression via transformative processes such as mitogenic signaling, the epithelial-mesenchymal transition (EMT), anoikis inhibition, and PI3K/Akt-mediated survival signaling. Here we provide a preliminary insight into the influence of MTH1 levels on the EMT phenotype and Akt activation in RAS-transformed HMLE breast epithelial cells. Within this context, we will discuss the implications of MTH1 upregulation in oncogenic RAS-sustaining cells as a beneficial adaptive change that inhibits ROS-mediated cell senescence and participates in the maintenance of ROS-associated tumor-promoting mechanisms. Accordingly, targeting MTH1 in RAS-transformed tumor cells will not only induce proliferative defects but also potentially enhance therapeutic cytotoxicity by shifting cellular response away from pro-survival mechanisms.

  4. CO2 bubbling-based 'Nanobomb' System for Targetedly Suppressing Panc-1 Pancreatic Tumor via Low Intensity Ultrasound-activated Inertial Cavitation.

    Science.gov (United States)

    Zhang, Kun; Xu, Huixiong; Chen, Hangrong; Jia, Xiaoqing; Zheng, Shuguang; Cai, Xiaojun; Wang, Ronghui; Mou, Juan; Zheng, Yuanyi; Shi, Jianlin

    2015-01-01

    Noninvasive and targeted physical treatment is still desirable especially for those cancerous patients. Herein, we develop a new physical treatment protocol by employing CO2 bubbling-based 'nanobomb' system consisting of low-intensity ultrasound (1.0 W/cm(2)) and a well-constructed pH/temperature dual-responsive CO2 release system. Depending on the temperature elevation caused by exogenous low-intensity therapeutic ultrasound irradiation and the low pH caused by the endogenous acidic-environment around/within tumor, dual-responsive CO2 release system can quickly release CO2 bubbles, and afterwards, the generated CO2 bubbles waves will timely explode before dissolution due to triggering by therapeutic ultrasound waves. Related bio-effects (e.g., cavitation, mechanical, shock waves, etc) caused by CO2 bubbles' explosion effectively induce instant necrosis of panc-1 cells and blood vessel destruction within panc-1 tumor, and consequently inhibit the growth of panc-1 solid tumor, simultaneously minimizing the side effects to normal organs. This new physiotherapy employing CO2 bubbling-based 'nanobomb' system promises significant potentials in targetedly suppressing tumors, especially for those highly deadly cancers.

  5. Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo

    International Nuclear Information System (INIS)

    Tran, Phan LCHB; Kim, Soo-A; Choi, Hong Seok; Yoon, Jung-Hoon; Ahn, Sang-Gun

    2010-01-01

    Epigallocatechin-3-gallate (EGCG), one of the major catechins in green tea, is a potential chemopreventive agent for various cancers. The aim of this study was to examine the effect of EGCG on the expression of heat shock proteins (HSPs) and tumor suppression. Cell colony formation was evaluated by a soft agar assay. Transcriptional activity of HSP70 and HSP90 was determined by luciferase reporter assay. An EGCG-HSPs complex was prepared using EGCG attached to the cyanogen bromide (CNBr)-activated Sepharose 4B. In vivo effect of EGCG on tumor growth was examined in a xenograft model. Treatment with EGCG decreased cell proliferation and colony formation of MCF-7 human breast cancer cells. EGCG specifically inhibited the expression of HSP70 and HSP90 by inhibiting the promoter activity of HSP70 and HSP90. Pretreatment with EGCG increased the stress sensitivity of MCF-7 cells upon heat shock (44°C for 1 h) or oxidative stress (H 2 O 2 , 500 μM for 24 h). Moreover, treatment with EGCG (10 mg/kg) in a xenograft model resulted in delayed tumor incidence and reduced tumor size, as well as the inhibition of HSP70 and HSP90 expression. Overall, these findings demonstrate that HSP70 and HSP90 are potent molecular targets of EGCG and suggest EGCG as a drug candidate for the treatment of human cancer

  6. Tumor Suppression and Sensitization to Taxol-Induced Apoptosis of E1A in Breast Cancer Cells

    National Research Council Canada - National Science Library

    Liao, Yong

    2003-01-01

    The purpose of this project is to study the molecular mechanisms underlying ElA's proapoptotic effect and anti-tumor activity and to dissect the functional domains of ElA that are critical for its antitumor activity...

  7. Targeting gastrointestinal stromal tumors: the role of regorafenib

    Directory of Open Access Journals (Sweden)

    Schroeder B

    2016-05-01

    Full Text Available Brett Schroeder,1 Zula Li,2,3 Lee D Cranmer,2,3 Robin L Jones,4 Seth M Pollack2,3 1College of Human Medicine, Michigan State University, Grand Rapids, MI, 2Division of Medical Oncology, University of Washington, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 4Royal Marsden Hospital, Institute of Cancer Research, London, UK Abstract: Gastrointestinal stromal tumor (GIST is a devastating disease in the metastatic setting, but its natural history has been dramatically altered by the development of small molecule tyrosine kinase inhibitors, most notably imatinib. Although patients with advanced GIST live much longer today than they did in the past, imatinib-refractory disease remains a tremendous problem. For disease that is refractory to imatinib and sunitinib, regorafenib is an excellent option. In this review, we discuss the biology and clinical work establishing regorafenib as the standard of care for advanced GIST refractory to both imatinib and sunitinib. Keywords: regorafenib, GIST, refractory, imatinib

  8. Hypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells.

    LENUS (Irish Health Repository)

    Wang, Jiang Huai

    2012-02-03

    BACKGROUND: Hypoxia in solid tumors potentially stimulates angiogenesis by promoting vascular endothelial growth factor (VEGF) production and upregulating VEGF receptor expression. However, it is unknown whether hypoxia can modulate the effect of anti-angiogenic treatment on tumor-derived endothelium. METHODS: Human tumor-derived endothelial cells (HTDEC) were freshly isolated from surgically removed human colorectal tumors by collagenase\\/DNase digestion and Percol gradient sedimentation. Cell proliferation was assessed by measuring BrdU incorporation, and capillary tube formation was measured using Matrigel. Cell apoptosis was assessed by flow cytometry and ELISA, and Bcl-2 expression was detected by Western blot analysis. RESULTS: Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-gamma-induced apoptosis with significant reductions in both cell proliferation and capillary tube formation, when compared with normal human macrovascular and microvascular EC. Following exposure of HTDEC to hypoxia (5% CO2 plus 2% O2), IFN-gamma-induced cell apoptosis, and antiangiogenic activity (i.e. an inhibition in cell proliferation and capillary tube formation) in HTDEC were markedly attenuated. This finding correlated with hypoxia-induced upregulation of Bcl-2 expression in HTDEC. CONCLUSIONS: These results indicate that hypoxia can protect HTDEC against IFN-gamma-mediated cell death and antiangiogenic activity, and suggest that improvement of tumor oxygenation may potentiate the efficacy of anti-cancer therapies specifically targeting the inhibition of tumor angiogenesis.

  9. Role of Immunomodulators in Tumor Regression in Mice Exposed to Fractionated Low Dose of Gamma Radiation

    International Nuclear Information System (INIS)

    Rokaya Elsayed Maaroaf Elsayed

    2015-01-01

    Immunotherapy is one of the most promising approaches of cancer treatment. The present study was designed to examine the role of irradiated tumor cell lysate vaccine, IFNα-2b and low dose of gamma irradiation as immunomodulators either alone or combined in tumor regression. Ehrlich ascite carcinoma (EAC) cells and 9 groups of female mice were used. Mice were immunized intramuscularly by tumor cell lysate vaccine one time/week for 3 weeks in the right thigh of mice. After two weeks from last immunization, all mice were challenged with normal viable EAC cells at count of 2.5 ×10 6 /mouse in the opposite left thigh for Ehrlich carcinoma (EC) production. Mice were subcutaneously injected with 10.000 units of IFNα-2b 3 times/week for 4 weeks and others were exposed to fractionated dose of γ- radiation (0.5 Gy/day x 4, day after day). Tumor size, serum tumor markers (TNF-α and CEA), tumor DNA fragmentation and Caspase-3 were evaluated. Oxidative stress (MDA and NO) markers and antioxidants (GSH, GPX and SOD) were determined in spleen and tumor tissues. Histopathological examinations, apoptosis and necrosis in spleen and tumor tissues were also examined. The results revealed significant inhibition in tumor size throughout the observation period either for treatments with vaccine or IFNα-2b either alone or combined with γ-irradiation. DNA fragmentation and Caspase-3 enzyme activities were significantly elevated in immunized mice as compared with EC group along with diminished tumor size while, tumor markers were significantly decreased. MDA and NO were significantly increased in tumor tissue.while, tumor GSH content, GPX and SOD activities were significantly decreased. Combined treatments of female mice bearing EC with IFN-α-2b, tumor cell lysate vaccine and low dose of γ-radiation cause a highly significant decrease in serum TNF-α and CEA levels, increase in Cas-3 activity, no DNA fragmentation, significant increase in MDA, decrease in SOD activity and decreased

  10. The Role of Fine Needle Aspiration in the Diagnosis of Parotid Gland Tumors: Correlation With Preoperative Computerized Tomography Tumor Size.

    Science.gov (United States)

    Ghantous, Yasmine; Naddaf, Raja; Barak, Michal; Abd-Elraziq, Murad; Abu Eln-Naaj, Imad

    2016-03-01

    The role of fine needle aspiration cytology (FNAC) in the diagnosis of parotid gland masses is still controversial, regarding its sensitivity and specificity that vary between 41% and 100% and between 86% and 100% respectively.The aim of this study was to identify the specificity and sensitivity of FNAC of parotid gland tumors in relation to the tumor size as characterized preoperatively by computer tomography. The medical files of 79 patients whom were referred to the MaxilloFacila Surgery Department, Rambam medical center, over a 10.5-year period (2000-2010) were analyzed retrospectively.The extensity of the operation was determined by the location of the tumor as presented in computed tomography (CT) radiography, and preoperative FNAC examination.The majority of the masses were located in the superficial lobe (88.52%), and only 11.48% of the patients were located in the deep lobe (8:1 ratio). FNAC results were nondiagnostic in 7 patients (8.86%), 62 patients were diagnosed as inflammatory and benign lesion in (78.48%), malignant tumors were diagnosed in 10 patients (12.65%).The sensitivity in our study was 90%, the specificity was 98%, positive predictive value was 90%, negative predictive value was 98%, and diagnostic accuracy was 88%. The positive predictive value was 90%, the negative predictive value was 98%.Analyzing the effect of the preoperative CT size upon the accuracy of the FNAC diagnosis, we found that lesion with preoperative CT size greater than 24 mm has a more accurate FNAC result (P = 0.034).

  11. Functional role for suppression of the insular-striatal circuit in modulating interoceptive effects of alcohol.

    Science.gov (United States)

    Jaramillo, Anel A; Agan, Verda E; Makhijani, Viren H; Pedroza, Stephen; McElligott, Zoe A; Besheer, Joyce

    2017-09-27

    The insular cortex (IC) is a region proposed to modulate, in part, interoceptive states and motivated behavior. Interestingly, IC dysfunction and deficits in interoceptive processing are often found among individuals with substance-use disorders. Furthermore, the IC projects to the nucleus accumbens core (AcbC), a region known to modulate the discriminative stimulus/interoceptive effects of alcohol and other drug-related behaviors. Therefore, the goal of the present work was to investigate the possible role of the IC ➔ AcbC circuit in modulating the interoceptive effects of alcohol. Thus, we utilized a chemogenetic technique (hM4D i designer receptor activation by designer drugs) to silence neuronal activity in the IC of rats trained to discriminate alcohol (1 g/kg, IG) versus water using an operant or Pavlovian alcohol discrimination procedure. Chemogenetic silencing of the IC or IC ➔ AcbC neuronal projections resulted in potentiated sensitivity to the interoceptive effects of alcohol in both the operant and Pavlovian tasks. Together, these data provide critical evidence for the nature of the complex IC circuitry and, specifically, suppression of the insular-striatal circuit in modulating behavior under a drug stimulus control. © 2017 Society for the Study of Addiction.

  12. EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage

    Directory of Open Access Journals (Sweden)

    Kuroda S

    2014-08-01

    G2/M checkpoint by inhibiting BRCA1, Chk1, and phospho-Cdc2/CDK1 protein expression. In vivo therapy studies showed 225-NP treatment reduced EGFR phosphorylation, increased γH2AX foci, and induced tumor cell apoptosis, resulting in suppression of tumor growth. Conclusion: The 225-NP treatment induces DNA damage and abrogates G2/M phase of the cell cycle, leading to cellular apoptosis and suppression of lung tumor growth both in vitro and in vivo. Our findings provide a rationale for combining 225-NP with other DNA-damaging agents for achieving enhanced anticancer activity. Keywords: lung cancer, epidermal growth factor receptor, autophagy

  13. Discovery and validation of the tumor-suppressive function of long noncoding RNA PANDA in human diffuse large B-cell lymphoma through the inactivation of MAPK/ERK signaling pathway.

    Science.gov (United States)

    Wang, Yingjun; Zhang, Mingzhi; Xu, Huanan; Wang, Yifei; Li, Zhaoming; Chang, Yu; Wang, Xinhuan; Fu, Xiaorui; Zhou, Zhiyuan; Yang, Siyuan; Wang, Bei; Shang, Yufeng

    2017-09-22

    Diffuse large B-cell lymphoma (DLBCL) is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel prognostic markers and therapeutic targets of DLBCL. Recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in the development of cancer. By using the next generation HiSeq sequencing assay, we determined lncRNAs exhibiting differential expression between DLBCL patients and healthy controls. Then, RT-qPCR was performed for identification in clinical samples and cell materials, and lncRNA PANDA was verified to be down-regulated in DLBCL patients and have considerable diagnostic potential. In addition, decreased serum PANDA level was correlated to poorer clinical outcome and lower overall survival in DLBCL patients. Subsequently, we determined the experimental role of lncRNA PANDA in DLBCL progression. Luciferase reporter assay and chromatin immunoprecipitation assay suggested that lncRNA PANDA was induced by p53 and p53 interacts with the promoter region of PANDA. Cell functional assay further indicated that PANDA functioned as a tumor suppressor gene through the suppression of cell growth by a G0/G1 cell cycle arrest in DLBCL. More importantly, Cignal Signal Transduction Reporter Array and western blot assay showed that lncRNA PANDA inactivated the MAPK/ERK signaling pathway. In conclusion, our integrated approach demonstrates that PANDA in DLBCL confers a tumor suppressive function through inhibiting cell proliferation and silencing MAPK/ERK signaling pathway. Thus, PANDA may be a promising therapeutic target for patients with DLBCL.

  14. The role of computed tomography in the localization of adrenal cortex tumors

    International Nuclear Information System (INIS)

    Baranowska, B.; Misiorowski, W.; Pacho, R.; Wysocki, M.; Kobuszewska, M.; Zgliczynski, S.; Medical Center of Postgraduate Education, Warsaw

    1982-01-01

    The aim of this study was to evaluate the usefulness of computed tomography in the localisation of adrenal tumors producing aldosterone and cortisol. One case each of Conn's and Cushing's syndrome are described. The diagnosis of Conn's syndrome was established by demonstrating an elevated plasma aldosterone level 'at rest' and its decrease after stimulation, the absence of plasma renin activity and a lowered plasma potassium level. The diagnosis of Cushing's syndrome due to adrenal adenoma was established by demonstrating the typical clinical features, an abnormal diurnal rhythm of cortisol and ACTH secretion and an increased urine excretion of 17-OHCS without suppression by large doses of dexamethasone. The localisation and the size of the tumors as determined by computed tomography were confirmed during surgery. (orig.) [de

  15. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.

    Science.gov (United States)

    Cramer, Shira L; Saha, Achinto; Liu, Jinyun; Tadi, Surendar; Tiziani, Stefano; Yan, Wupeng; Triplett, Kendra; Lamb, Candice; Alters, Susan E; Rowlinson, Scott; Zhang, Yan Jessie; Keating, Michael J; Huang, Peng; DiGiovanni, John; Georgiou, George; Stone, Everett

    2017-01-01

    Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53 -/- mice, which develop disease resembling human chronic lymphocytic leukemia. It was observed that enzyme-mediated depletion of the serum L-Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods, suggesting that cyst(e)inase represents a safe and effective therapeutic modality for inactivating antioxidant cellular responses in a wide range of malignancies.

  16. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    Energy Technology Data Exchange (ETDEWEB)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Cleary, Margot P. [Hormel Institute, University of Minnesota, Austin, MN 55912 (United States); Gonzalez-Perez, Ruben R. [Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30314 (United States); Torroella-Kouri, Marta, E-mail: mtorroella@med.miami.edu [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136 (United States)

    2015-01-15

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

  17. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    International Nuclear Information System (INIS)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P.; Gonzalez-Perez, Ruben R.; Torroella-Kouri, Marta

    2015-01-01

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity

  18. Mothers' responses to children's negative emotions and child emotion regulation: the moderating role of vagal suppression.

    Science.gov (United States)

    Perry, Nicole B; Calkins, Susan D; Nelson, Jackie A; Leerkes, Esther M; Marcovitch, Stuart

    2012-07-01

    The current study examined the moderating effect of children's cardiac vagal suppression on the association between maternal socialization of negative emotions (supportive and nonsupportive responses) and children's emotion regulation behaviors. One hundred and ninety-seven 4-year-olds and their mothers participated. Mothers reported on their reactions to children's negative emotions and children's regulatory behaviors. Observed distraction, an adaptive self-regulatory strategy, and vagal suppression were assessed during a laboratory task designed to elicit frustration. Results indicated that children's vagal suppression moderated the association between mothers' nonsupportive emotion socialization and children's emotion regulation behaviors such that nonsupportive reactions to negative emotions predicted lower observed distraction and lower reported emotion regulation behaviors when children displayed lower levels of vagal suppression. No interaction was found between supportive maternal emotion socialization and vagal suppression for children's emotion regulation behaviors. Results suggest physiological regulation may serve as a buffer against nonsupportive emotion socialization. Copyright © 2011 Wiley Periodicals, Inc.

  19. Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism.

    Science.gov (United States)

    De Rosa, Veronica; Di Rella, Francesca; Di Giacomo, Antonio; Matarese, Giuseppe

    2017-06-01

    Novel concepts in immunometabolism support the hypothesis that glucose consumption is also used to modulate anti-tumor immune responses, favoring growth and expansion of specific cellular subsets defined in the past as suppressor T cells and currently reborn as regulatory T (Treg) cells. During the 1920s, Otto Warburg and colleagues observed that tumors consumed high amounts of glucose compared to normal tissues, even in the presence of oxygen and completely functioning mitochondria. However, the role of the Warburg Effect is still not completely understood, particularly in the context of an ongoing anti-tumor immune response. Current experimental evidence suggests that tumor-derived metabolic restrictions can drive T cell hyporesponsiveness and immune tolerance. For example, several glycolytic enzymes, deregulated in cancer, contribute to tumor progression independently from their canonical metabolic activity. Indeed, they can control apoptosis, gene expression and activation of specific intracellular pathways, thus suggesting a direct link between metabolic switches and pro-tumorigenic transcriptional programs. Focus of this review is to define the specific metabolic pathways controlling Treg cell immunobiology in the context of anti-tumor immunity and tumor progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. The role of imaging for the surgeon in primary malignant bone tumors of the chest wall

    Energy Technology Data Exchange (ETDEWEB)

    Rocca, M., E-mail: michele.rocca@ior.it [General and Thoracic Surgery, The Rizzoli Orthopaedic Institute, Via Pupilli 1, 40136 Bologna (Italy); Salone, M. [General and Thoracic Surgery, The Rizzoli Orthopaedic Institute, Via Pupilli 1, 40136 Bologna (Italy); Galletti, S. [Ultrasound Unit, The Rizzoli Orthopaedic Institute, Bologna (Italy); Balladelli, A. [Laboratory of Experimental Oncology, The Rizzoli Orthopaedic Institute, Bologna (Italy); Vanel, D. [Research in Imaging Musculo Skeletal Tumors, The Rizzoli Orthopaedic Institute, Bologna (Italy); Briccoli, A. [General and Thoracic Surgery, The Rizzoli Orthopaedic Institute, Via Pupilli 1, 40136 Bologna (Italy)

    2013-12-01

    Primary malignant chest wall tumors are rare. The most frequent primary malignant tumor of the chest wall is chondrosarcoma, less common are primary bone tumors belonging to the Ewing Family Bone Tumors (EFBT), or even rarer are osteosarcomas. They represent a challenging clinical entities for surgeons as the treatment of choice for these neoplasms is surgical resection, excluding EFBT which are normally treated by a multidisciplinary approach. Positive margins after surgical procedure are the principal risk factor of local recurrence, therefore to perform adequate surgery a correct preoperative staging is mandatory. Imaging techniques are used for diagnosis, to determine anatomic site and extension, to perform a guided biopsy, for local and general staging, to evaluate chemotherapy response, to detect the presence of a recurrence. This article will focus on the role of imaging in guiding this often difficult surgery and the different technical possibilities adopted in our department to restore the mechanics of the thoracic cage after wide resections.

  1. A tumor suppressor role of the Bub3 spindle checkpoint protein after apoptosis inhibition

    Science.gov (United States)

    Moutinho-Santos, Tatiana

    2013-01-01

    Most solid tumors contain aneuploid cells, indicating that the mitotic checkpoint is permissive to the proliferation of chromosomally aberrant cells. However, mutated or altered expression of mitotic checkpoint genes accounts for a minor proportion of human tumors. We describe a Drosophila melanogaster tumorigenesis model derived from knocking down spindle assembly checkpoint (SAC) genes and preventing apoptosis in wing imaginal discs. Bub3-deficient tumors that were also deficient in apoptosis displayed neoplastic growth, chromosomal aneuploidy, and high proliferative potential after transplantation into adult flies. Inducing aneuploidy by knocking down CENP-E and preventing apoptosis does not induce tumorigenesis, indicating that aneuploidy is not sufficient for hyperplasia. In this system, the aneuploidy caused by a deficient SAC is not driving tumorigenesis because preventing Bub3 from binding to the kinetochore does not cause hyperproliferation. Our data suggest that Bub3 has a nonkinetochore-dependent function that is consistent with its role as a tumor suppressor. PMID:23609535

  2. GF-15, a Novel Inhibitor of Centrosomal Clustering, Suppresses Tumor Cell Growth In Vitro and In Vivo

    DEFF Research Database (Denmark)

    Raab, Marc S.; Breitkreutz, Iris; Anderhub, Simon

    2012-01-01

    In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells......) for proliferation and survival were in the range of 1 to 5 μmol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro...

  3. Role of laminin receptor in tumor cell migration

    DEFF Research Database (Denmark)

    Wewer, U M; Taraboletti, G; Sobel, M E

    1987-01-01

    Polyclonal antisera were made against biochemically purified laminin receptor protein as well as against synthetic peptides deduced from a complementary DNA clone corresponding to the COOH-terminal end of the laminin receptor (U.M. Wewer et al., Proc. Natl. Acad. Sci. USA, 83: 7137-7141, 1986......). These antisera were used to study the potential role of laminin receptor in laminin-mediated attachment and haptotactic migration of human A2058 melanoma cells. The anti-laminin receptor antisera reacted with the surface of suspended, nonpermeabilized melanoma and carcinoma cells. The anti-laminin receptor...... antisera blocked the surface interaction of A2058 cells with endogenous laminin, resulting in the inhibition of laminin-mediated cell attachment. The A2058 melanoma cells migrated toward a gradient of solid phase laminin or fibronectin (haptotaxis). Anti-laminin antiserum abolished haptotaxis on laminin...

  4. Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.

    Directory of Open Access Journals (Sweden)

    Byoungduck Park

    Full Text Available Pancreatic cancer (PaCa is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA, an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation. These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.

  5. Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4

    NARCIS (Netherlands)

    Heideman, Daniëlle A. M.; van Beusechem, Victor W.; Bloemena, Elisabeth; Snijders, Peter J. F.; Craanen, Mikael E.; Offerhaus, G. Johan A.; Derksen, Patrick W. B.; de Bruin, Michiel; Witlox, M. Adhiambo; Molenaar, Bonnie; Meijer, Chris J. L. M.; Gerritsen, Winald R.

    2004-01-01

    Background To improve the prognosis of patients with gastric cancer it is important to develop novel treatment modalities targeting the malignant behavior of tumor cells. Concerning this, NK4, which acts as HGF-antagonist and angiogenesis inhibitor, might be a potential therapeutic agent for gastric

  6. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene

    DEFF Research Database (Denmark)

    Grum-Schwensen, Birgitte; Klingelhofer, Jörg; Berg, Christian Hededam

    2005-01-01

    distribution of host-derived stroma cells. Coinjection of CSML100 cells with immortalized S100A4(+/+) fibroblasts partially restored the dynamics of tumor development and the ability to form metastasis. These fibroblasts were characterized by an enhanced motility and invasiveness in comparison with S100A4...

  7. Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma.

    Science.gov (United States)

    Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene; Hay, Shelley; Ponomarev, Vladimir; Panagopoulos, Vasilios; DeNichilo, Mark; Ingman, Wendy; Atkins, Gerald J; Findlay, David M; Zannettino, Andrew C W; Evdokiou, Andreas

    2015-02-01

    Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumor hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumors. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

  8. Current Research of the Roles of IL-35 in Tumor Progression

    Directory of Open Access Journals (Sweden)

    Chongbiao HUANG

    2016-04-01

    Full Text Available Interleukin(IL-35 is a new member of the interleukin-12 superfamily. Since its first report in 2007, IL-35 rapidly became a research highlight in the field of immunology. Like other IL-12 superfamily members, IL-35 was a heterodimer which was composed of an α chain P35 and a β chain Epstein-Barr virus induced gene 3 (EBI3. Recent research work revealed two distinct roles of IL-35. Firstly, IL-35 is highly expressed in some kinds of inflammatory diseases and autoimmune diseases and plays import roles in the pathogenesis. Secondly, IL-35 is positively expressed in some cancers and plays some roles in the process of tumor progression. Here we demonstrate the structure and the signalling of IL-35. We reviewed the the roles of IL-35 in promoting tumor progression.

  9. The Role of Tumor Protein 53 Mutations in Common Human Cancers and Targeting the Murine Double Minute 2–P53 Interaction for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Tayebeh Hamzehloie

    2012-03-01

    Full Text Available The gene TP53 (also known as protein 53 or tumor protein 53, encoding transcription factor P53, is mutated or deleted in half of human cancers, demonstrating the crucial role of P53 in tumor suppression. There are reports of nearly 250 independent germ line TP53 mutations in over 100 publications. The P53 protein has the structure of a transcription factor and, is made up of several domains. The main function of P53 is to organize cell defense against cancerous transformation. P53 is a potent transcription factor that is activated in response to diverse stresses, leading to the induction of cell cycle arrest, apoptosis or senescence. The P53 tumor suppressor is negatively regulated in cells by the murine double minute 2 (MDM2 protein. Murine double minute 2 favors its nuclear export, and stimulates its degradation. Inhibitors of the P53-MDM2 interaction might be attractive new anticancer agents that could be used to activate wild-type P53 in tumors. Down regulation of MDM2 using an small interfering RNA (siRNA approach has recently provided evidence for a new role of MDM2 in the P53 response, by modulating the inhibition of the cyclin dependent kinase 2 (cdk2 by P21/WAF1 (also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1.

  10. The role of radiotherapy in the treatment of malignant salivary gland tumors

    NARCIS (Netherlands)

    Terhaard, CHJ; Lubsen, H; Rasch, CRN; Levendag, PC; Kaanders, HHAM; Tjho-Heslinga, RE; Van Den Ende, PLA; Burlage, F

    2005-01-01

    Purpose: We analyzed the role of primary and postoperative low linear energy transfer radiotherapy in 538 patients treated for salivary gland cancer in centers of the Dutch Head and Neck Oncology Cooperative Group, in search for prognostic factors and dose response. Methods and Materials: The tumor

  11. Radiosynthesis, biodistribution and imaging of [11C]YM155, a novel survivin suppressant, in a human prostate tumor-xenograft mouse model

    International Nuclear Information System (INIS)

    Murakami, Yoshihiro; Matsuya, Takahiro; Kita, Aya; Yamanaka, Kentaro; Noda, Akihiro; Mitsuoka, Keisuke; Nakahara, Takahito; Miyoshi, Sosuke; Nishimura, Shintaro

    2013-01-01

    Introduction: Sepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [ 11 C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts. Methods: Methods utilizing [ 11 C]acetyl chloride and [ 11 C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [ 11 C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [ 11 C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS). Results: Sufficient quantities of radiopharmaceutical grade [ 11 C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16–22%, within a synthesis time of 47 min. The radiochemical purity was higher than 99%, and the specific activity was 29–60 GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean ± SE) were observed in tumor (0.0613 ± 0.0056), kidneys (0.0513 ± 0.0092), liver (0.0368 ± 0.0043) and cecum (0.0623 ± 0.0070). The highest tumor uptake was observed at an early time point (from 10 min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [ 11 C]YM155, at 40 min after injection, were 26.5 (± 2.9) and 25.6 (± 3.6), respectively. Conclusion: A rapid method for producing a radiopharmaceutical grade [ 11 C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [ 11 C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent

  12. Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway

    International Nuclear Information System (INIS)

    Zhang, Jing-Tao; Sun, Wei; Zhang, Wen-Zhong; Ge, Chun-Yan; Liu, Zhong-Yan; Zhao, Ze-Ming; Lu, Xing-Sui; Fan, Yue-Zu

    2014-01-01

    < 0.01, vs. control group); NCTD down-regulated expression of these VM signaling-related markers in vitro and in vivo. NCTD inhibited tumor growth and VM of human GBCs in vitro and in vivo by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway. It is firstly concluded that NCTD may be a potential anti-VM agent for human GBCs

  13. Role of Oxidative Stress in the Suppression of Immune Responses in Peripheral Blood Mononuclear Cells Exposed to Combustible Tobacco Product Preparation.

    Science.gov (United States)

    Arimilli, Subhashini; Schmidt, Eckhardt; Damratoski, Brad E; Prasad, G L

    2017-10-01

    Cigarette smoking is a major risk factor for several human diseases. Chronic inflammation, resulting from increased oxidative stress, has been suggested as a mechanism that contributes to the increased susceptibility of smokers to cancer and microbial infections. We have previously shown that whole-smoke conditioned medium (WS-CM) and total particulate matter (TPM) prepared from Kentucky 3R4F reference cigarettes [collectively called as combustible tobacco product preparations (TPPs)] potently suppressed agonist-stimulated cytokine secretion and target cell killing in peripheral blood mononuclear cells (PBMCs). Here we have investigated the role of oxidative stress from TPPs, which alters inflammatory responses in vitro. Particularly, we investigated the mechanisms of WS-CM-induced suppression of select cytokine secretions in Toll-like receptor (TLR) agonist-stimulated cells and target cell killing by effector cells in PBMCs. Pretreatment with N-acetyl cysteine (NAC), a precursor of reduced glutathione and an established anti-oxidant, protected against DNA damage and cytotoxicity caused by exposure to WS-CM. Similarly, secretion of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 in response to TLR-4 stimulation was restored by pretreatment with NAC. Target cell killing, a functional measure of cytolytic cells in PBMCs, is suppressed by WS-CM. Pretreatment with NAC restored the target cell killing in WS-CM treated PBMCs. This was accompanied by higher perforin levels in the effector cell populations. Collectively, these data suggest that reducing oxidative stress caused by cigarette smoke components restores select immune responses in this ex vivo model.

  14. Negative regulatory role of PI3-kinase in TNF-induced tumor necrosis.

    Science.gov (United States)

    Matschurat, Susanne; Blum, Sabine; Mitnacht-Kraus, Rita; Dijkman, Henry B P M; Kanal, Levent; De Waal, Robert M W; Clauss, Matthias

    2003-10-20

    Tissue factor is the prime initiator of blood coagulation. Expression of tissue factor in tumor endothelial cells leads to thrombus formation, occlusion of vessels and development of hemorrhagic infarctions in the tumor tissue, often followed by regression of the tumor. Tumor cells produce endogenous vascular endothelial growth factor (VEGF), which sensitizes endothelial cells for systemically administered tumor necrosis factor alpha (TNF alpha) and synergistically enhances the TNF-induced expression of tissue factor. We have analyzed the pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells (HUVECs) after combined stimulation with TNF and VEGF. By using specific low molecular weight inhibitors, we demonstrated that protein kinase C (PKC), p44/42 and p38 mitogen-activated protein (MAP) kinases, and stress-activated protein kinase (JNK) are essentially involved in the induction of tissue factor. In contrast, the application of wortmannin, an inhibitor of phosphatidylinositol 3 (PI3)-kinase, led to strongly enhanced expression of tissue factor in TNF- and VEGF-treated cells, implicating a negative regulatory role for PI3-kinase. In vivo, the application of wortmannin promoted the formation of TNF-induced hemorrhages and intratumoral necroses in murine meth A tumors. The co-injection of wortmannin lowered the effective dose of applied TNF. Therefore, it is conceivable that the treatment of TNF-sensitive tumors with a combination of TNF and wortmannin will ensure the selective damage of the tumor endothelium and minimize the risk of systemic toxicity of TNF. TNF-treatment in combination with specific inhibition of PI3-kinase is a novel concept in anti-cancer therapy. Copyright 2003 Wiley-Liss, Inc.

  15. The Role of Mechanical Variance and Spatial Clustering on the Likelihood of Tumor Incidence and Growth

    Science.gov (United States)

    Mirzakhel, Zibah

    When considering factors that contribute to cancer progression, modifications to both the biological and mechanical pathways play significant roles. However, less attention is placed on how the mechanical pathways can specifically contribute to cancerous behavior. Experimental studies have found that malignant cells are significantly softer than healthy, normal cells. In a tissue environment where healthy or malignant cells exist, a distribution of cell stiffness values is observed, with the mean values used to differentiate between these two populations. Rather than focus on the mean values, emphasis will be placed on the distribution, where instances of soft and stiff cells exist in the healthy tissue environment. Since cell deformability is a trait associated with cancer, the question arises as to whether the mechanical variation observed in healthy tissue cell stiffness distributions can influence any instances of tumor growth. To approach this, a 3D discrete model of cells is used, able to monitor and predict the behavior of individual cells while determining any instances of tumor growth in a healthy tissue. In addition to the mechanical variance, the spatial arrangement of cells will also be modeled, as cell interaction could further implicate any incidences of tumor-like malignant populations within the tissue. Results have shown that the likelihood of tumor incidence is driven by both by the increases in the mechanical variation in the distributions as well as larger clustering of cells that are mechanically similar, quantified primarily through higher proliferation rates of tumor-like soft cells. This can be observed though prominent negative shifts in the mean of the distribution, as it begins to transition and show instances of earlystage tumor growth. The model reveals the impact that both the mechanical variation and spatial arrangement of cells has on tumor progression, suggesting the use of these parameters as potential novel biomarkers. With a

  16. Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

    Directory of Open Access Journals (Sweden)

    Yuanyuan Li

    Full Text Available Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE, a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1 (p21 and p16(INK4a (p16, although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

  17. Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

    Science.gov (United States)

    Li, Yuanyuan; Chen, Huaping; Hardy, Tabitha M; Tollefsbol, Trygve O

    2013-01-01

    Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

  18. Erucin, the major isothiocyanate in arugula (Eruca sativa, inhibits proliferation of MCF7 tumor cells by suppressing microtubule dynamics.

    Directory of Open Access Journals (Sweden)

    Olga Azarenko

    Full Text Available Consumption of cruciferous vegetables is associated with reduced risk of various types of cancer. Isothiocyanates including sulforaphane and erucin are believed to be responsible for this activity. Erucin [1-isothiocyanato-4-(methylthiobutane], which is metabolically and structurally related to sulforaphane, is present in large quantities in arugula (Eruca sativa, Mill., kohlrabi and Chinese cabbage. However, its cancer preventive mechanisms remain poorly understood. We found that erucin inhibits proliferation of MCF7 breast cancer cells (IC50 = 28 µM in parallel with cell cycle arrest at mitosis (IC50 = 13 µM and apoptosis, by a mechanism consistent with impairment of microtubule dynamics. Concentrations of 5-15 µM erucin suppressed the dynamic instability of microtubules during interphase in the cells. Most dynamic instability parameters were inhibited, including the rates and extents of growing and shortening, the switching frequencies between growing and shortening, and the overall dynamicity. Much higher erucin concentrations were required to reduce the microtubule polymer mass. In addition, erucin suppressed dynamic instability of microtubules reassembled from purified tubulin in similar fashion. The effects of erucin on microtubule dynamics, like those of sulforaphane, are similar qualitatively to those of much more powerful clinically-used microtubule-targeting anticancer drugs, including taxanes and the vinca alkaloids. The results suggest that suppression of microtubule dynamics by erucin and the resulting impairment of critically important microtubule-dependent cell functions such as mitosis, cell migration and microtubule-based transport may be important in its cancer preventive activities.

  19. Contemporary Role of Radiotherapy in the Management of Primary Penile Tumors and Metastatic Disease.

    Science.gov (United States)

    Crook, Juanita

    2016-11-01

    Squamous cell cancer of the penis is a radiocurable malignancy all too often managed solely by partial or total penectomy. Effective management of the primary tumor while preserving penile morphology and function is a priority. External radiotherapy and brachytherapy have a role to play in the definitive management of the primary tumor. Surgical nodal staging remains a cornerstone of management because it is the strongest predictor of survival, and inguinal status determines pelvic management. Postoperative radiotherapy of the regional nodes for high-risk pathology is indicated. Chemoradiotherapy should be considered as neoadjuvant treatment for unresectable nodes or as definitive management. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration.

    Science.gov (United States)

    Yu, Ting; Xu, Bei; He, Lili; Xia, Shan; Chen, Yan; Zeng, Jun; Liu, Yongmei; Li, Shuangzhi; Tan, Xiaoyue; Ren, Ke; Yao, Shaohua; Song, Xiangrong

    2016-01-01

    Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely

  1. Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, SB; Andersen, O; Pedersen, Steen Bønløkke

    2006-01-01

    Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients...... with lipodystrophy (LIPO) and those without (controls). LIPOX was estimated by indirect calorimetry during fasting and steady state of a hyperinsulinemic euglycemic clamp in 36 (18 LIPO and 18 controls) normoglycemic HIV-infected men on highly active antiretroviral therapy. In LIPO, TNF-alpha correlated with clamp...... were significant in controls. In all patients, TNF-alpha correlated with clamp FFA (r = 0.61, P

  2. HBV-specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell-mediated antitumor immunity.

    Science.gov (United States)

    Meng, Fanzhi; Zhen, Shoumei; Song, Bin

    2017-08-01

    In East Asia and sub-Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell-based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV-specific CD4 + cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV-specific cytotoxic CD4 + and CD8 + T cells were identified by HBV peptide pool stimulation. We found that in HBV-induced hepatocellular carcinoma patients, the HBV-specific cytotoxic CD4 + T cells and cytotoxic CD8 + T cells were present at similar numbers. But compared to the CD8 + cytotoxic T cells, the CD4 + cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4 + T cells suppressed the cytotoxicity mediated by CD8 + T cells, even when CD4 + CD25 + regulator T cells were absent. Interestingly, we found that interleukin 10 (IL-10)-secreting Tr1 cells were enriched in the cytotoxic CD4 + T cells. Neutralization of IL-10 abrogated the suppression of CD8 + T cells by CD4 + CD25 - T cells. Neither the frequency nor the absolute number of HBV-specific CD4 + cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV-related hepatocellular carcinoma, CD4 + T cell-mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties. © 2017 APMIS. Published by John Wiley & Sons Ltd.

  3. The role of thyrotropin suppression in patients with differentiated thyroid carcinoma.

    LENUS (Irish Health Repository)

    Deasy, J

    2010-07-01

    Thyroid carcinoma is the commonest endocrine malignancy. The majority of these are differentiated thyroid carcinomas, which have a good overall prognosis. Treatment includes surgical excision, radio-iodine ablation and long-term thyrotropin suppression. The degree and length of suppression required, as well as the potential side-effect remain controversial. Therefore, the aim of this study was to establish the degree of thyrotropin suppression achieved in a cohort of patients with differentiated thyroid carcinoma. A retrospective review was performed of a prospectively maintained database. All patients with a diagnosis of differentiated thyroid carcinoma between January 1998 and January 2008 were identified. Demographic data, pathological stage and the treatment that the patient received was documented. TSH and free T4 levels were identified at specific time points post-operatively. Eighty-eight patients with differentiated thyroid carcinoma were identified. Seventy patients (79.5%) were female. The mean age was 55, with a range of 18 to 79 years. The majority of patients underwent a total thyroidectomy (n=79; 89.7%) and of those 29 (32.9%) had an associated modified neck dissection. Accurate follow-up was available on forty-nine patients. TSH and free T4 were measured at 3 and 6 months, as well as at 1 and 2 years post-operatively. Adequate TSH suppression was taken at a level < 0.1 mU\\/L. The majority of patients (69.5%) had achieved adequate TSH suppression at 2 years. However, 65% of these same patients had a high free T4 at 2 years indicating a degree of hyperthyroidism. This study has demonstrated that TSH suppression is being adequately achieved in the majority of patients with differentiated thyroid carcinoma. However, this must be carefully weighed against the potential detrimental side-effects of long-term sub-clinical hyperthyroidism.

  4. Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration

    Directory of Open Access Journals (Sweden)

    Yu T

    2016-02-01

    Full Text Available Ting Yu,1,* Bei Xu,1,* Lili He,2 Shan Xia,3 Yan Chen,1 Jun Zeng,1 Yongmei Liu,1 Shuangzhi Li,1 Xiaoyue Tan,4 Ke Ren,1 Shaohua Yao,1 Xiangrong Song1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 2College of Chemistry and Environment Protection Engineering, Southwest University for Nationalities, 3Central Laboratory, Science Education Department, Chengdu Normal University, Chengdu, Sichuan, 4Department of Pathology/Collaborative Innovation Center of Biotherapy, Medical School of Nankai University, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%, probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on

  5. Role of computed tomography in the integral diagnostic process of paranasal cavities tumors

    International Nuclear Information System (INIS)

    Lazarova, I.

    1990-01-01

    Results are reported of computed tomographic examination of 129 patients from 3 to 74 years of age, on clinical grounds suspected of having, or histologically verified, tumors of the paranasal cavities. Axial and/or coronary scanning (depending on the case) was performed on computed tomograph Tomoscan-310, according to previously selected programs. Computed tomography was evaluated with regard to the possibility for diagnosing tumors of the paranasal sinuses and its role in furnishing additional information in these diseases. The clearcut differentiation on the computed tomograms both of the bone structures and of the soft tissue - muscles, vessels, connective tissue and fatty tissue spaces - is emphasized. The clinical significance of this special X-ray method of examination in the preoperative period by demonstrating the different directions in which the tumors spread and the possibility for adequate planning of the radiotherapeutic field and posttherapeutic follow-up the pathologic process are pointed out. 5 figs., 5 refs

  6. Oxidative stress in tumor microenvironment——Its role in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Armando ROJAS; Raúl SILVA; Héctor FIGUEROA; Miguel A MORALES

    2008-01-01

    The tumor angiogenesis process is believed to be dependent on an "angiogenic switch" formed by a cascade of biologic events as a consequence of the "cross-talk" between tumor cells and several components of local microenvironment including endothelial cells, macrophages, mast cells and stromal components. Oxidative stress represents an important stimulus that widely contributes to this angiogenic switch, which is particularly relevant in lungs,where oxidative stress is originated from different sources including the incomplete reduction of oxygen during respiration,exposure to hypoxia/reoxygenation, stimulated resident or chemoattracted immune ceils to lung tissues, as well as by a variety of chemicals compounds. In the present review we highlight the role of oxidative stress in tumor angiogenesis as a key signal linked to other relevant actors in this complex process.

  7. The Role of Thought Suppression, Meta-Cognitive Factors and Negative Emotions in Prediction of Substance Dependency Disorder

    Directory of Open Access Journals (Sweden)

    Omid Saed

    2011-08-01

    Full Text Available Introduction: This study investigated the role of thought suppression, meta- cognitive factors, and negative emotions in predicting of substance dependency disorder. Method: Subjects were 70 patients with substance dependence disorder and 70 normal individuals (total 140. Substance dependants were selected of outpatient treatment centers and the normal sample was selected of the general population too. Sampling methods in both samples were convenience sampling. All people were assessed by MCQ-30, White Bear Suppression Inventory, and Beck’s Anxiety and Depression Questionnaires. For data analysis, discriminant analysis were used. Results: Negative meta-cognitive beliefs about worry, depression, and thought suppression were the most significant predictors of substance dependence disorder. Conclusion: Through meta-cognitive beliefs, thought suppression and negative emotion (especially depression, substance dependency disorder can be predicted. Based on this model can be used to take a substance dependency disorder prevention approach and psychotherapy approach (based on cognitive and meta-cognitive therapies. In addition, the findings of this research can be applied in clinical and counseling environments to help substance dependant clients.

  8. The Novel miR-9600 Suppresses Tumor Progression and Promotes Paclitaxel Sensitivity in Non–small-cell Lung Cancer Through Altering STAT3 Expression

    Directory of Open Access Journals (Sweden)

    Cheng-Cao Sun

    2016-01-01

    Full Text Available MicroRNAs have been identified to be involved in center stage of cancer biology. They accommodate cell proliferation and migration by negatively regulate gene expression either by hampering the translation of targeted mRNAs or by promoting their degradation. We characterized and identified the novel miR-9600 and its target in human non–small-cell lung cancer (NSCLC. Our results demonstrated that the miR-9600 were downregulated in NSCLC tissues and cells. It is confirmed that signal transducer and activator of transcription 3 (STAT3, a putative target gene, is directly inhibited by miR-9600. The miR-9600 markedly suppressed the protein expression of STAT3, but with no significant influence in corresponding mRNA levels, and the direct combination of miR-9600 and STAT3 was confirmed by a luciferase reporter assay. miR-9600 inhibited cell growth, hampered expression of cell cycle-related proteins and inhibited cell migration and invasion in human NSCLC cell lines. Further, miR-9600 significantly suppressed tumor growth in nude mice. Similarly, miR-9600 impeded tumorigenesis and metastasis through directly targeting STAT3. Furthermore, we identified that miR-9600 augmented paclitaxel and cisplatin sensitivity by downregulating STAT3 and promoting chemotherapy-induced apoptosis. These data demonstrate that miR-9600 might be a useful and novel therapeutic target for NSCLC.

  9. Human recombinant interleukin-1 beta- and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells

    International Nuclear Information System (INIS)

    Kobayashi, M.; Shimada, K.; Ozawa, T.

    1990-01-01

    Cytokines are known to tip the balance of the coagulant-anticoagulant molecules on the endothelial cell surface toward intravascular coagulation. Their effects on endothelial cell surface-associated heparin-like compounds have not been examined yet. Incorporation of [35S]sulfate into heparan sulfate on cultured porcine aortic endothelial cells was suppressed by human recombinant interleukin-1 beta (rIL-1 beta) or tumor necrosis factor alpha (rTNF alpha) in a dose- and time-dependent manner with little effect on cell number, protein content, and [3H]leucine incorporation of cells. Maximal inhibition was achieved by incubation of cells with 100 ng/ml of rIL-1 beta or 5 ng/ml of rTNF alpha for 12-24 hours, resulting in a reduction of the synthesis of heparan sulfate on the cell surface by approximately 50%. The dose dependency was consistent with that seen in the stimulation of endothelial cell procoagulant activity by each cytokine. The suppression of heparan sulfate synthesis was sustained for at least 48 hours after pretreatment of cells with cytokines and was unchanged after the addition of indomethacin or polymyxin B. The rate of degradation of prelabeled 35S-heparan sulfate on the cell surface was not altered by cytokine treatments. Neither the size, the net negative charge, nor the proportion of the molecule with high affinity for antithrombin III of endothelial cell heparan sulfate was changed by cytokines. Furthermore, specific binding of 125I-labeled antithrombin III to the endothelial cell surface was reduced to 40-60% of control by cytokines. In parallel with reduction in binding, antithrombin III cofactor activity was partially diminished in cytokine-treated endothelial cells. Thus, cytokine-mediated suppression of heparin-like substance on endothelial cells appears to be another cytokine-inducible endothelial effects affecting coagulation

  10. Possible Therapeutic Application of Targeting Type II Natural Killer T Cell-Mediated Suppression of Tumor Immunity

    Science.gov (United States)

    Kato, Shingo; Berzofsky, Jay A.; Terabe, Masaki

    2018-01-01

    Natural killer T (NKT) cells are a unique T cell subset that exhibits characteristics from both the innate immune cells and T cells. There are at least two subsets of NKT cells, type I and type II. These two subsets of NKT cells have opposite functions in antitumor immunity. Type I NKT cells usually enhance and type II NKT cells suppress antitumor immunity. In addition, these two subsets of NKT cells cross-regulate each other. In this review, we mainly focus on immunosuppressive NKT cells, type II NKT cells. After summarizing their definition, experimental tools to study them, and subsets of them, we will discuss possible therapeutic applications of type II NKT cell pathway targeted therapies. PMID:29520281

  11. miRNA-218-loaded carboxymethyl chitosan - Tocopherol nanoparticle to suppress the proliferation of gastrointestinal stromal tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Tu, Lin; Wang, Ming; Zhao, Wen-Yi; Zhang, Zi-Zhen; Tang, De-Feng; Zhang, Ye-Qian [Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Cao, Hui, E-mail: caohui10281@163.com [Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Zhang, Zhi-Gang, E-mail: zhangzhiganggz@hotmail.com [State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240 (China)

    2017-03-01

    Gastrointestinal stromal tumors (GIST) are one of the most common forms of mesenchymal cancers of the gastrointestinal tract. Although chemotherapeutic drugs inhibited the proliferation of GIST, however, sizable proportion of people developed resistance and therefore difficult to treat. In the present study, O-carboxymethyl chitosan (OCMC)-tocopherol polymer conjugate was synthesized and formulated into stable polymeric nanoparticles. The main aim of present study was to increase the therapeutic efficacy of miR-218 in GIST. The mean size of nanoparticles was ~ 110 nm with a spherical shape. The miR-218 NP has been shown inhibit the cell proliferation and exhibited a superior cell apoptosis. The miR-218 NP inhibited the cell invasion and promoted the apoptosis of GIST cancer cells. In the present study, we have successfully showed that KIT1 is the target gene of miR-218 as shown by the luciferase reporter assay. These findings collectively suggest the miR-218 loaded nanoparticle by virtue of effective transfection could act as a tumor suppressor miRNA in the treatment of GIST. - Highlights: • O-carboxymethyl chitosan (OCMC)-tocopherol polymer conjugate was synthesized and formulated in nanoparticles. • The miR-218 NP has been shown inhibit the cell proliferation and exhibited a superior cell apoptosis. • We have successfully showed that KIT1 is the target gene of miR-218 as shown by the luciferase reporter assay.

  12. The dual role of tumor necrosis factor (TNF) in cancer biology.

    Science.gov (United States)

    Bertazza, Loris; Mocellin, Simone

    2010-01-01

    Tumor necrosis factor (TNF) is a cytokine with well known anticancer properties and is being utilized as anticancer agent for the treatment of patients with locally advanced solid tumors. However, TNF role in cancer biology is debated. In fact, in spite of the wealth of evidence supporting its antitumor activity, the cascade of molecular events underlying TNF-mediated tumor regression observed in vivo is still incompletely elucidated. Furthermore, some preclinical findings suggest that TNF may even promote cancer development and progression. With this work we intend to summarize the molecular biology of TNF (with particular regard to its tumor-related activities) and review the experimental and clinical evidence currently available describing the complex and sometime apparently conflicting relationship between this cytokine, cancer biology and antitumor therapy. We also propose a model to explain the dual effect of TNF based on the exposure time and cytokine levels reached within the tumor microenvironment. Finally, we overview recent research findings that might lead to new ways for exploiting the anticancer potential of TNF in the clinical setting.

  13. Systematic review on the role of serum tumor markers in the detection of recurrent pancreatic cancer.

    Science.gov (United States)

    Daamen, Lois A; Groot, Vincent P; Heerkens, Hanne D; Intven, Martijn P W; van Santvoort, Hjalmar C; Molenaar, I Quintus

    2018-04-01

    Biomarker testing can be helpful to monitor disease progression after resection of pancreatic cancer. This systematic review aims to give an overview of the literature on the diagnostic value of serum tumor markers for the detection of recurrent pancreatic cancer during follow-up. A systematic search was performed to 2 October 2017. All studies reporting on the diagnostic value of postoperatively measured serum biomarkers for the detection of pancreatic cancer recurrence were included. Data on diagnostic accuracy of tumor markers were extracted. Forest plots and pooled values of sensitivity and specificity were calculated. Four articles described test results of CA 19-9. A pooled sensitivity and specificity of respectively 0.73 (95% CI 0.66-0.80) and 0.83 (95% CI 0.73-0.91) were calculated. One article reported on CEA, showing a sensitivity of 50% and specificity of 65%. No other serum tumor markers were discussed for surveillance purposes in the current literature. Although testing of serum CA 19-9 has considerable limitations, CA 19-9 remains the most used serum tumor marker for surveillance after surgical resection of pancreatic cancer. Further studies are needed to assess the role of serum tumor marker testing in the detection of recurrent pancreatic cancer and to optimize surveillance strategies. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

  14. MR staging of pelvic endometriosis. Role of fat-suppression T{sub 1}-weighted images

    Energy Technology Data Exchange (ETDEWEB)

    Oishi-Tanaka, Yumiko; Itai, Yuji; Anno, Izumi; Matsumoto, Kunihiko; Ebihara, Reiko; Nishida, Masato [Tsukuba Univ., Ibaraki (Japan). Inst. of Clinical Medicine

    1996-05-01

    We examined whether MR can determine the stage of endometriosis according to the scoring system established and revised by the American Fertility Society (r-AFS), a system which is widely used by gynecologists. We also studied the utility of fat suppression T{sub 1}-weighted images in improving accuracy. Seventeen patients with endometriosis examined by conventional MR were included in this study. All the patients had surgically proved stage III or IV disease. We determined the stage by MR using the following criteria according to the r-AFS system: adnexal masses without normal ovarian tissue were considered deep ovarian lesions, while those with normal tissue were considered superficial. A lack of fat between the lesion and surrounding structures was considered a dense adhesion, and hyperintense spots were considered peritoneal implants. The MR scores of patients with and without fat suppression were correlated with the surgical scores. MR staging corresponded to surgical staging in 15 of the 17 patients. In eight patients, peritoneal implants of less than 1.5 cm were depicted only by fat-suppression images. However, these lesions did not change the score significantly. MR imaging could determine the stage in advanced endometriosis. Fat-suppression could highlight smaller implants. These tiny lesions had little clinical meaning in these advanced cases; however, the clinical value of this technique should be evaluated in milder disease. (author)

  15. MR staging of pelvic endometriosis. Role of fat-suppression T1-weighted images

    International Nuclear Information System (INIS)

    Oishi-Tanaka, Yumiko; Itai, Yuji; Anno, Izumi; Matsumoto, Kunihiko; Ebihara, Reiko; Nishida, Masato

    1996-01-01

    We examined whether MR can determine the stage of endometriosis according to the scoring system established and revised by the American Fertility Society (r-AFS), a system which is widely used by gynecologists. We also studied the utility of fat suppression T 1 -weighted images in improving accuracy. Seventeen patients with endometriosis examined by conventional MR were included in this study. All the patients had surgically proved stage III or IV disease. We determined the stage by MR using the following criteria according to the r-AFS system: adnexal masses without normal ovarian tissue were considered deep ovarian lesions, while those with normal tissue were considered superficial. A lack of fat between the lesion and surrounding structures was considered a dense adhesion, and hyperintense spots were considered peritoneal implants. The MR scores of patients with and without fat suppression were correlated with the surgical scores. MR staging corresponded to surgical staging in 15 of the 17 patients. In eight patients, peritoneal implants of less than 1.5 cm were depicted only by fat-suppression images. However, these lesions did not change the score significantly. MR imaging could determine the stage in advanced endometriosis. Fat-suppression could highlight smaller implants. These tiny lesions had little clinical meaning in these advanced cases; however, the clinical value of this technique should be evaluated in milder disease. (author)

  16. The Role of Competition in Support of Socio-Political Stability and Suppression of Corruption

    Directory of Open Access Journals (Sweden)

    Юлий Анатольевич Нисневич

    2009-09-01

    Full Text Available Fair, transparent and professional competition is the basis of functioning and dynamic stabilization of political system. Further broadening of economical, political and informational freedom and competition is a requirement for lowering of corruption and securing of effectiveness of application of special legal and administrative measures for its suppression.

  17. Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA.

    Science.gov (United States)

    Zhang, Haiyang; Wang, Yi; Bai, Ming; Wang, Junyi; Zhu, Kegan; Liu, Rui; Ge, Shaohua; Li, JiaLu; Ning, Tao; Deng, Ting; Fan, Qian; Li, Hongli; Sun, Wu; Ying, Guoguang; Ba, Yi

    2018-03-01

    Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  18. CD155/PVR plays a key role in cell motility during tumor cell invasion and migration

    International Nuclear Information System (INIS)

    Sloan, Kevin E; Ilag, Leodevico L; Jay, Daniel G; Eustace, Brenda K; Stewart, Jean K; Zehetmeier, Carol; Torella, Claudia; Simeone, Marina; Roy, Jennifer E; Unger, Christine; Louis, David N

    2004-01-01

    Invasion is an important early step of cancer metastasis that is not well understood. Developing therapeutics to limit metastasis requires the identification and validation of candidate proteins necessary for invasion and migration. We developed a functional proteomic screen to identify mediators of tumor cell invasion. This screen couples Fluorophore Assisted Light Inactivation (FALI) to a scFv antibody library to systematically inactivate surface proteins expressed by human fibrosarcoma cells followed by a high-throughput assessment of transwell invasion. Using this screen, we have identified CD155 (the poliovirus receptor) as a mediator of tumor cell invasion through its role in migration. Knockdown of CD155 by FALI or by RNAi resulted in a significant decrease in transwell migration of HT1080 fibrosarcoma cells towards a serum chemoattractant. CD155 was found to be highly expressed in multiple cancer cell lines and primary tumors including glioblastoma (GBM). Knockdown of CD155 also decreased migration of U87MG GBM cells. CD155 is recruited to the leading edge of migrating cells where it colocalizes with actin and αv-integrin, known mediators of motility and adhesion. Knockdown of CD155 also altered cellular morphology, resulting in cells that were larger and more elongated than controls when plated on a Matrigel substrate. These results implicate a role for CD155 in mediating tumor cell invasion and migration and suggest that CD155 may contribute to tumorigenesis

  19. Role of adjuvant radiotherapy in granulosa cell tumors of the ovary.

    Science.gov (United States)

    Hauspy, Jan; Beiner, Mario E; Harley, Ian; Rosen, Barry; Murphy, Joan; Chapman, William; Le, Lisa W; Fyles, Anthony; Levin, Wilfred

    2011-03-01

    To review the role of adjuvant radiotherapy (RT) in the outcome and recurrence patterns of granulosa cell tumors (GCTs) of the ovary. The records of all patients with GCTs referred to the Princess Margaret Hospital University Health Network between 1961 and 2006 were retrospectively reviewed. The patient, tumor, and treatment factors were assessed by univariate and multivariate analyses using disease-free survival (DFS) as the endpoint. A total of 103 patients with histologically confirmed GCTs were included in the present study. The mean duration of follow-up was 100 months (range, 1-399). Of the 103 patients, 31 received adjuvant RT. A total of 39 patients developed tumor recurrence. The tumor size, incidence of intraoperative rupture, and presence of concurrent endometrial cancer were not significant risk factors for DFS. The median DFS was 251 months for patients who underwent adjuvant RT compared with 112 months for patients who did not (p=.02). On multivariate analysis, adjuvant RT remained a significant prognostic factor for DFS (p=.004). Of the 103 patients, 12 had died and 44 were lost to follow-up. Ovarian GCTs can be indolent, with patients achieving long-term survival. In our series, adjuvant RT resulted in a significantly longer DFS. Ideally, randomized trials with long-term follow-up are needed to define the role of adjuvant RT for ovarian GCTs. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

  20. Non-odontogenic tumors of the facial bones in children and adolescents: role of multiparametric imaging

    International Nuclear Information System (INIS)

    Becker, Minerva; Stefanelli, Salvatore; Poletti, Pierre Alexandre; Merlini, Laura; Rougemont, Anne-Laure

    2017-01-01

    Tumors of the pediatric facial skeleton represent a major challenge in clinical practice because they can lead to functional impairment, facial deformation, and long-term disfigurement. Their treatment often requires a multidisciplinary approach, and radiologists play a pivotal role in the diagnosis and management of these lesions. Although rare, pediatric tumors arising in the facial bones comprise a wide spectrum of benign and malignant lesions of osteogenic, fibrogenic, hematopoietic, neurogenic, or epithelial origin. The more common lesions include Langerhans cell histiocytosis and osteoma, while rare lesions include inflammatory myofibroblastic and desmoid tumors; juvenile ossifying fibroma; primary intraosseous lymphoma; Ewing sarcoma; and metastases to the facial bones from neuroblastoma, Ewing sarcoma, or retinoblastoma. This article provides a comprehensive approach for the evaluation of children with non-odontogenic tumors of the facial skeleton. Typical findings are discussed with emphasis on the added value of multimodality multiparametric imaging with computed tomography (CT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI), positron emission tomography CT (PET CT), and PET MRI. Key imaging findings and characteristic histologic features of benign and malignant lesions are reviewed and the respective role of each modality for pretherapeutic assessment and post-treatment follow-up. Pitfalls of image interpretation are addressed and how to avoid them. (orig.)

  1. Non-odontogenic tumors of the facial bones in children and adolescents: role of multiparametric imaging

    Energy Technology Data Exchange (ETDEWEB)

    Becker, Minerva; Stefanelli, Salvatore; Poletti, Pierre Alexandre; Merlini, Laura [University of Geneva, Division of Radiology, Department of Imaging and Medical Informatics, Geneva University Hospital, Geneva (Switzerland); Rougemont, Anne-Laure [University of Geneva, Division of Clinical Pathology, Department of Genetic and Laboratory Medicine, Geneva University Hospital, Geneva (Switzerland)

    2017-04-15

    Tumors of the pediatric facial skeleton represent a major challenge in clinical practice because they can lead to functional impairment, facial deformation, and long-term disfigurement. Their treatment often requires a multidisciplinary approach, and radiologists play a pivotal role in the diagnosis and management of these lesions. Although rare, pediatric tumors arising in the facial bones comprise a wide spectrum of benign and malignant lesions of osteogenic, fibrogenic, hematopoietic, neurogenic, or epithelial origin. The more common lesions include Langerhans cell histiocytosis and osteoma, while rare lesions include inflammatory myofibroblastic and desmoid tumors; juvenile ossifying fibroma; primary intraosseous lymphoma; Ewing sarcoma; and metastases to the facial bones from neuroblastoma, Ewing sarcoma, or retinoblastoma. This article provides a comprehensive approach for the evaluation of children with non-odontogenic tumors of the facial skeleton. Typical findings are discussed with emphasis on the added value of multimodality multiparametric imaging with computed tomography (CT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI), positron emission tomography CT (PET CT), and PET MRI. Key imaging findings and characteristic histologic features of benign and malignant lesions are reviewed and the respective role of each modality for pretherapeutic assessment and post-treatment follow-up. Pitfalls of image interpretation are addressed and how to avoid them. (orig.)

  2. Role of stem cells in tumor initiation, metastasis formation and their use in cancer therapy

    International Nuclear Information System (INIS)

    Altaner, C.; Altanerova, V.

    2010-01-01

    This review considers recent advances in the stem cell field focusing on the challenges and opportunities for their use in clinical practice. Various kinds of stem cells and their roles in the human organism are in the review described. Attention is given to the role of mesenchymal stem cells as a potential tool in regenerative medicine. The origin and consequences of existence of tumor-initiating cells known as cancer stem cells is discussed also in context of metastasis formation. It seems that tumor-initiating cells might be responsible for resistance to many conventional cancer therapies, which might explain the limitations of these therapeutic modalities. Furthermore, the review focuses to tumor homing property of adult mesenchymal (stromal) stem cells. The feasibility of mesenchymal stem cells isolation from human adipose tissue, their genetic modifications with suicide genes together with ability to find tumor in the organism make them an attractive vehicle for cancer therapy without systemic toxicity. Published achievements from our laboratory in stem cell-based gene cancer therapy are shortly summarized. Generally, it is believed that the stem cell therapies might be ideal future treatment modality for inherited, degenerative diseases and in curing human malignancies as well. (author)

  3. Trimethoxy-resveratrol and piceatannol administered orally suppress and inhibit tumor formation and growth in prostate cancer xenografts

    Science.gov (United States)

    Resveratrol (Res) is recognized as a promising cancer chemoprevention dietary polyphenol with antioxidative, anti-inflammatory and anticancer properties. However, the role of its analogues in prostate cancer (PCa) chemoprevention is still unknown. METHODS. We synthesized natural and synthetic anal...

  4. A key role of microRNA-29b for the suppression of colon cancer cell migration by American ginseng.

    Directory of Open Access Journals (Sweden)

    Deepak Poudyal

    Full Text Available Metastasis of colon cancer cells increases the risk of colon cancer mortality. We have recently shown that American ginseng prevents colon cancer, and a Hexane extract of American Ginseng (HAG has particularly potent anti-inflammatory and anti-cancer properties. Dysregulated microRNA (miR expression has been observed in several disease conditions including colon cancer. Using global miR expression profiling, we observed increased miR-29b in colon cancer cells following exposure to HAG. Since miR-29b plays a role in regulating the migration of cancer cells, we hypothesized that HAG induces miR-29b expression to target matrix metalloproteinase-2 (MMP-2 thereby suppressing the migration of colon cancer cells. Results are consistent with this hypothesis. Our study supports the understanding that targeting MMP-2 by miR-29b is a mechanism by which HAG suppresses the migration of colon cancer cells.

  5. Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma‑associated epileptic discharge (Review).

    Science.gov (United States)

    Dong, Hui; Zhou, Xing-Wang; Wang, Xiang; Yang, Yuan; Luo, Jie-Wen; Liu, Yan-Hui; Mao, Qing

    2017-12-01

    Connexin (Cx)43 is a multifunction protein which forms gap junction channels and hemi‑channels. It also contains abundant binding domains which possess the ability to interact with certain Cx43‑associated proteins and therefore serve a fundamental role in various physiological and pathological functions. However, the understanding of the association between cancer and Cx43 along with Cx43‑gap junctions (GJ) remains unclear. All available data illustrate that Cx43 and its associated GJ serve important functions in cancers. The expression levels of Cx43 demonstrate a downward trend and an increase in the levels of malignancy, particularly in astrocytomas. The GJ intercellular communication activity in glioma cells can be adjusted via Cx43 phosphorylation and through the combination of Cx43 and its associated protein. Available evidence reveals Cx43 as a tumor‑inhibiting factor that suppresses glioma growth and proliferation. However, its mechanism is also regarded as complicated and ambiguous. Furthermore, it is apparent that Cx43‑GJ and the carboxyl tail may contribute to glioma growth and proliferation too. However, this valuable role could be weakened by its effects on migration and invasiveness. The detailed mechanism remains unclear and full of controversies. Cx43 can enhance the motor ability and invasiveness of astrocytic glioma cells. It is also able to influence glioma cells to detach from the tumor core to the peritumoral neocortex. This peritumoral region has recently been regarded as the basic focus of glioma‑associated seizure. Thus, Cx43 may take part in the onset and development of glioma‑associated epileptic discharge. In addition, change and increase of Cx43 expression in GJs has been observed in seizure perilesional tissue, which is associated with brain tumors. Cx43 or GJ/hemi‑channels exert enduring effects in the promotion of glioma‑associated epileptic release through direct mass effects and change of the tumor microenvironment

  6. The prognostic role of tumor size in early breast cancer in the era of molecular biology.

    Directory of Open Access Journals (Sweden)

    Anaid Anna Kasangian

    Full Text Available The prognosis of early breast cancer (EBC depends on patient and tumor characteristics. The association between tumor size, the largest diameter in TNM staging, and prognosis is well recognized. According to TNM, tumors classified as T2, could have very different volumes; e.g. a tumor of 2.1 cm has a volume of 4500 mm3, while a tumor of 4.9 cm has a volume of 60.000 mm3 even belonging to the same class. The aim of the study is to establish if the prognostic role of tumor size, expressed as diameter and volume, has been overshadowed by other factors.The primary objective is to evaluate the association between tumor dimensions and overall survival (OS / disease free survival (DFS, in our institution from January 1st 2005 to September 30th 2013 in a surgical T1-T2 population. Volume was evaluated with the measurement of three half-diameters of the tumor (a, b and c, and calculated using the following formula: 4/3π x a x b x c.341 patients with T1-T2 EBC were included. 86.5% were treated with conservative surgery. 85.1% had a Luminal subtype, 9.1% were Triple negative and 7.4% were HER2 positive. Median volume was 942 mm3 (range 0.52-31.651.2. 44 patients (12.9% relapsed and 23 patients died. With a median follow-up of 6.5 years, the univariate analysis for DFS showed an association between age, tumor size, volume, histological grading and molecular subtype. The multivariate analysis confirmed the statistically significant association only for molecular subtype (p 0.005, with a worse prognosis for Triple negative and HER2 positive subtypes compared with Luminal (HR: 2.65; 95%CI: 1.34-5.22. Likewise for OS, an association was shown by the multivariate analysis solely for molecular subtype (HER2 and Triple negative vs. Luminal. HR: 2.83; 95% CI:1.46-5.49; p 0.002.In our study, the only parameter that strongly influences survival is molecular subtype. These findings encourage clinicians to choose adjuvant treatment not based on dimensional criteria

  7. The prognostic role of tumor size in early breast cancer in the era of molecular biology.

    Science.gov (United States)

    Kasangian, Anaid Anna; Gherardi, Giorgio; Biagioli, Elena; Torri, Valter; Moretti, Anna; Bernardin, Elena; Cordovana, Andrea; Farina, Gabriella; Bramati, Annalisa; Piva, Sheila; Dazzani, Maria Chiara; Paternò, Emanuela; La Verde, Nicla Maria

    2017-01-01

    The prognosis of early breast cancer (EBC) depends on patient and tumor characteristics. The association between tumor size, the largest diameter in TNM staging, and prognosis is well recognized. According to TNM, tumors classified as T2, could have very different volumes; e.g. a tumor of 2.1 cm has a volume of 4500 mm3, while a tumor of 4.9 cm has a volume of 60.000 mm3 even belonging to the same class. The aim of the study is to establish if the prognostic role of tumor size, expressed as diameter and volume, has been overshadowed by other factors. The primary objective is to evaluate the association between tumor dimensions and overall survival (OS) / disease free survival (DFS), in our institution from January 1st 2005 to September 30th 2013 in a surgical T1-T2 population. Volume was evaluated with the measurement of three half-diameters of the tumor (a, b and c), and calculated using the following formula: 4/3π x a x b x c. 341 patients with T1-T2 EBC were included. 86.5% were treated with conservative surgery. 85.1% had a Luminal subtype, 9.1% were Triple negative and 7.4% were HER2 positive. Median volume was 942 mm3 (range 0.52-31.651.2). 44 patients (12.9%) relapsed and 23 patients died. With a median follow-up of 6.5 years, the univariate analysis for DFS showed an association between age, tumor size, volume, histological grading and molecular subtype. The multivariate analysis confirmed the statistically significant association only for molecular subtype (p 0.005), with a worse prognosis for Triple negative and HER2 positive subtypes compared with Luminal (HR: 2.65; 95%CI: 1.34-5.22). Likewise for OS, an association was shown by the multivariate analysis solely for molecular subtype (HER2 and Triple negative vs. Luminal. HR: 2.83; 95% CI:1.46-5.49; p 0.002). In our study, the only parameter that strongly influences survival is molecular subtype. These findings encourage clinicians to choose adjuvant treatment not based on dimensional criteria but on

  8. Emerging Roles of Tumor Necrosis Factor-Stimulated Gene-6 in the Pathophysiology and Treatment of Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Rena Watanabe

    2018-02-01

    Full Text Available Tumor necrosis factor-stimulated gene-6 (TSG-6 is a 35-kDa glycoprotein that has been shown to exert anti-inflammatory effects in experimental models of arthritis, acute myocardial infarction, and acute cerebral infarction. Several lines of evidence have shed light on the pathophysiological roles of TSG-6 in atherosclerosis. TSG-6 suppresses inflammatory responses of endothelial cells, neutrophils, and macrophages as well as macrophage foam cell formation and vascular smooth muscle cell (VSMC migration and proliferation. Exogenous TSG-6 infusion and endogenous TSG-6 attenuation with a neutralizing antibody for four weeks retards and accelerates, respectively, the development of aortic atherosclerotic lesions in ApoE-deficient mice. TSG-6 also decreases the macrophage/VSMC ratio (a marker of plaque instability and promotes collagen fibers in atheromatous plaques. In patients with coronary artery disease (CAD, plasma TSG-6 levels are increased and TSG-6 is abundantly expressed in the fibrous cap within coronary atheromatous plaques, indicating that TSG-6 increases to counteract the progression of atherosclerosis and stabilize the plaque. These findings indicate that endogenous TSG-6 enhancement and exogenous TSG-6 replacement treatments are expected to emerge as new lines of therapy against atherosclerosis and related CAD. Therefore, this review provides support for the clinical utility of TSG-6 in the diagnosis and treatment of atherosclerotic cardiovascular diseases.

  9. Prognostic role of tumor volume for radiotherapy outcome in patient with T2 laryngeal cancer

    International Nuclear Information System (INIS)

    Rutkowski, T.; Wygoda, A.; Skladowski, K.; Rutkowski, R.; Maciejewski, B.; Hejduk, B.; Kolosza, Z.

    2013-01-01

    Background and purpose: Tumor volume (TV) is recognized as a prognostic factor of treatment outcome for head and neck tumors but is not routinely included in the treatment decision-making process. The purpose of the study was to define its prognostic role for patients with T2 laryngeal cancer. Material and methods: TV of 160 patients who underwent RT between 2002 and 2006 for T2 laryngeal squamous cell carcinoma were reviewed. The tumor was located in the glottis and epiglottis in 82 (51 %) and 78 (49 %) patients, respectively. TV was manually contoured on pretreatment, planning, contrast-enhanced CT scans and the volumetric measurement (cm 3 ) was calculated by the volume algorithm. Results: The median TV value was 2.01 cm 3 (range 0.15-21.68 cm 3 ). The median TV was significantly lower in patients with glottic tumors (p < 0.0001), N0 (p < 0.001), or well histopatologically differentiated tumors (p = 0.01). A significant correlation between TV, hemoglobin concentration (p < 0.01), and total dose (TD; p < 0.001) was observed. On univariate analyses, TV influenced local control (LC; p = 0.02) and overall survival (OS, p < 0.001). On multivariate analysis, both age (HR 1.038, p = 0.03) and TV (HR = 1.075, p = 0.01) remained significantly related to LC and OS (age: HR 1.038, p = 0.005; TV: HR 1.097, p = 0.0001). Conclusion: Large TV worsen prognosis of patients with T2 laryngeal cancer. A large TV is more common for supraglottic, poorly differentiated tumors and may suggest higher risk of nodal spread. The routine estimation of TV prior to therapy may be essential in order to select the best treatment option for patients with T2 laryngeal cancer. (orig.)

  10. Role of 18F FDG PET scan to localize tumor in patients of oncogenic osteomalacia

    International Nuclear Information System (INIS)

    Malhotra, Gaurav; Mukta, K.; Asopa, V.; Varsha, J.; Vijaya, S.; Shah, Nalini S.; Padmavathy, M.

    2010-01-01

    Full text: Oncogenic osteomalacia is a rare paraneoplastic syndrome of renal phosphate wasting which is usually caused by phosphaturic mesenchymal tumors. Conventional radiologic techniques usually fail to detect these small, slow growing neoplasms located at unusual sites. The objective of this study was to evaluate the role of 18 F FDG PET imaging in patients of oncogenic osteomalacia. Materials and Methods: Fifteen patients (8 males and 7 females) (mean age: 38.5 ± 12.2 years) with clinical and biochemical evidence of oncogenic osteomalacia were subjected to 'total' whole body 18 F FDG PET scan including both limbs and skull views. The images were reconstructed and the final output was displayed as per the standard institution protocol. Results: 18 F FDG PET imaging localized suspicious hypermetabolic foci of SUVmax ranging from 1.4 to 3.8 (Mean ± S.D.: 2.39 ± 0.63) suggesting presence of occult tumor in 11 of 15 patients. The suspected foci were localized in lower limbs in ten patients and in the petrous temporal region of skull in 1 patient. FDG localized tumors were histopathologically correlated in 6 patients who underwent surgical biopsy/excision after correlative radiological investigations. Four of these patients were cured after surgical excision while partial surgical excision/biopsy was performed in two patients. Conclusions: 18 F FDG PET imaging is a promising technique for detection of occult tumors in patients of oncogenic osteomalacia. It is mandatory to include limbs in the field as these tumors are common in limbs and may be easily missed. Preoperative localization increases odds for cure after surgical removal of tumor

  11. Role of Active Listening and Listening Effort on Contralateral Suppression of Transient Evoked Otoacousic Emissions

    OpenAIRE

    Kalaiah, Mohan Kumar; Theruvan, Nikhitha B; Kumar, Kaushlendra; Bhat, Jayashree S

    2017-01-01

    Background and Objectives The present study aimed to investigate the effect of active listening and listening effort on the contralateral suppression of transient evoked otoacoustic emissions (CSTEOAEs). Subjects and Methods Twenty eight young adults participated in the study. Transient evoked otoacoustic emissions (TEOAEs) were recorded using ?linear? clicks at 60 dB peSPL, in three contralateral noise conditions. In condition 1, TEOAEs were obtained in the presence of white noise in the con...

  12. When passion makes the heart grow colder: the role of passion in alternative goal suppression.

    Science.gov (United States)

    Bélanger, Jocelyn J; Lafrenière, Marc-André K; Vallerand, Robert J; Kruglanski, Arie W

    2013-01-01

    Quality of goal engagement and alternative goal suppression were investigated in this research. Integrating the dualistic model of passion (Vallerand et al., 2003) with goal-systems theory (Kruglanski et al., 2002), we hypothesized that obsessive passion--associated with recurrent goal-conflicts--would predict greater alternative goal suppression (i.e., goal-shielding) than would harmonious passion--characterized by effective synthesis of the passionate activity with other life domains. Results from 5 laboratory studies supported these hypotheses. In Study 1, participants' dispositional measures of harmonious and obsessive passion were correlated with an implicit measure of goal-shielding. Obsessive (but not harmonious) passion predicted the suppression of alternative goals and the progressive inhibition of unfamiliar goals. In Study 2, we extended these findings by demonstrating the interrelation between quality of goal engagement and goal-commitment such that goal-shielding effects were enhanced, but only for goals in conflict with other life domains (vs. well-integrated goals). In Study 3, the causal influence of passion on goal-shielding was supported via an experimental manipulation of passion. In Study 4, we replicated and extended Studies 1 and 3 by experimentally demonstrating that obsessive (but not harmonious) passion is a mindset conducive to the development of inhibitory links with alternative goals. Study 5 explored the psychological costs associated with repeated unconscious goal suppression by examining its effects on the depletion of self-regulatory resources. Collectively, the present results suggest that the qualitative distinction between obsessive and harmonious passion has implications for the goal-shielding effect and for subsequent self-regulatory behavior.

  13. MicroRNA regulation of cancer metabolism: role in tumour suppression

    Czech Academy of Sciences Publication Activity Database

    Tomasetti, M.; Santarelli, L.; Neužil, Jiří; Dong, L.

    2014-01-01

    Roč. 19, part a SI (2014), s. 29-38 ISSN 1567-7249 R&D Projects: GA ČR(CZ) GAP301/10/1937; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : MicroRNA * Mitochondria * Tumour suppression Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.249, year: 2014

  14. Off and back-on again: a tumor suppressor's tale.

    Science.gov (United States)

    Acosta, Jonuelle; Wang, Walter; Feldser, David M

    2018-06-01

    Tumor suppressor genes play critical roles orchestrating anti-cancer programs that are both context dependent and mechanistically diverse. Beyond canonical tumor suppressive programs that control cell division, cell death, and genome stability, unexpected tumor suppressor gene activities that regulate metabolism, immune surveillance, the epigenetic landscape, and others have recently emerged. This diversity underscores the important roles these genes play in maintaining cellular homeostasis to suppress cancer initiation and progression, but also highlights a tremendous challenge in discerning precise context-specific programs of tumor suppression controlled by a given tumor suppressor. Fortunately, the rapid sophistication of genetically engineered mouse models of cancer has begun to shed light on these context-dependent tumor suppressor activities. By using techniques that not only toggle "off" tumor suppressor genes in nascent tumors, but also facilitate the timely restoration of gene function "back-on again" in disease specific contexts, precise mechanisms of tumor suppression can be revealed in an unbiased manner. This review discusses the development and implementation of genetic systems designed to toggle tumor suppressor genes off and back-on again and their potential to uncover the tumor suppressor's tale.

  15. Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression

    International Nuclear Information System (INIS)

    Choi, Byung-Min; Pae, Hyun-Ock; Jeong, Young-Ran; Kim, Young-Myeong; Chung, Hun-Taeg

    2005-01-01

    Foxp3, which encodes the transcription factor scurfin, is indispensable for the development and function of CD4 + CD25 + regulatory T cells (Treg). Recent data suggest conversion of peripheral CD4 + CD25 - naive T cells to CD4 + CD25 + Treg by acquisition of Foxp3 through costimulation with TCR and TGF-β or forced expression of the gene. One critical question is how Foxp3 causes T cells to become regulatory. In the present work, we demonstrate that Foxp3 can induce heme oxygenase-1 (HO-1) expression and subsequently such regulatory phenotypes as the suppression of nontransfected cells in a cell-cell contact-dependent manner as well as impaired proliferation and production of cytokines upon stimulation in Jurkat T cells. Moreover, we confirm the expression of both Foxp3 and HO-1 in peripheral CD4 + CD25 + Treg and suppressive function of the cells are relieved by the inhibition of HO-1 activity. In summary, we demonstrate that Foxp3 induces HO-1 expression and HO-1 engages in Foxp3-mediated immune suppression

  16. Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

    Institute of Scientific and Technical Information of China (English)

    Tianjian Yu; Genhong Di

    2017-01-01

    Breast cancer has been shown to live in the tumor microenvironment,which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells.Diverse components of the breast cancer microenvironment,such as suppressive immune cells,re-programmed fibroblast cells,altered extracellular matrix (ECM) and certain soluble factors,synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis.Among these components,stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways,whereas the ECM features biochemical and biomechanical changes.However,triple-negative breast cancer (TNBC),the most aggressive subtype of this disease that lacks effective therapies available for other subtypes,is considered to feature a unique microenvironment distinct from that of other subtypes,especially compared to Luminal A subtype.Because these changes are now considered to significantly impact breast cancer development and progression,these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC.In this review,we focus on the composition of the TNBC microenvironment,concomitant distinct biological alteration,specific interplay between various cell types and TNBC cells,and the prognostic implications of these findings.

  17. Paris polyphylla Suppresses Proliferation and Vasculogenic Mimicry of Human Osteosarcoma Cells and Inhibits Tumor Growth In Vivo.

    Science.gov (United States)

    Yao, Nan; Ren, Ke; Wang, Yimin; Jin, Qiaomei; Lu, Xiao; Lu, Yan; Jiang, Cuihua; Zhang, Dongjian; Lu, Jun; Wang, Chen; Huo, Jiege; Chen, Yong; Zhang, Jian

    2017-01-01

    Paris polyphylla, a traditional antipyretic-detoxicate chinese medicinal herb, has been applied extensively in cancer treatments for nearly 2000 years. The purpose of the present study is to evaluate the potential anti-osteosarcoma effects of Paris polyphylla ethanol extract (PPEE) and to investigate its underlying mechanisms. The antiproliferation activity of PPEE was tested on 143B, MG-63, U-2 OS and hFOB1.19 cells using MTT assay. The pro-apoptotic and cell cycle arrest effects of PPEE were confirmed by Hoechst 33342 staining and flow cytometry. The antimigratory, anti-invasive and antivasculogenic mimicry (VM) effects of PPEE were investigated by wound healing, Transwell and 3D culture assays. Mouse xenograft model was used to examine its anti-osteosarcoma efficacy in vivo. Hematologic profiles and hepatorenal functions were evaluated to assess the toxicity of PPEE. PPEE evidently suppressed cell proliferation of 143B, MG-63 and U-2 OS with IC50 values of 10-60[Formula: see text][Formula: see text]g/mL, but showed little cytotoxicity against normal osteoblastic cell. PPEE promoted apoptosis in 143B cell via caspase activation, increased Bax/Bcl-2 ratio and PARP cleavage. It also induced G2/M phase arrest associated with elevated phosphorylation of CDK1, Cdc25C, Chk2 and down-regulation of cyclin B1, CDK1, Cdc25C expression. Additionally, PPEE inhibited 143B cell migration, invasion and VM formation at noncytotoxic concentrations through decreasing the expression of FAK, Mig-7, MMP2 and MMP9. Finally, daily oral administration of PPEE for four weeks exhibits potent antitumor and anti-VM activity in 143B xenograft model with low toxicity. Taken together, these findings demonstrated PPEE possesses anti-osteosarcoma and anti-VM activity in vitro and in vivo, and therefore is a potential candidate for osteosarcoma treatment.

  18. Role of pathogen-derived cell wall carbohydrates and prostaglandin E2 in immune response and suppression of fish immunity by the oomycete Saprolegnia parasitica.

    Science.gov (United States)

    Belmonte, Rodrigo; Wang, Tiehui; Duncan, Gary J; Skaar, Ida; Mélida, Hugo; Bulone, Vincent; van West, Pieter; Secombes, Christopher J

    2014-11-01

    Saprolegnia parasitica is a freshwater oomycete that is capable of infecting several species of fin fish. Saprolegniosis, the disease caused by this microbe, has a substantial impact on Atlantic salmon aquaculture. No sustainable treatment against saprolegniosis is available, and little is known regarding the host response. In this study, we examined the immune response of Atlantic salmon to S. parasitica infection and to its cell wall carbohydrates. Saprolegnia triggers a strong inflammatory response in its host (i.e., induction of interleukin-1β1 [IL-1β1], IL-6, and tumor necrosis factor alpha), while severely suppressing the expression of genes associated with adaptive immunity in fish, through downregulation of T-helper cell cytokines, antigen presentation machinery, and immunoglobulins. Oomycete cell wall carbohydrates were recognized by fish leukocytes, triggering upregulation of genes involved in the inflammatory response, similar to what is observed during infection. Our data suggest that S. parasitica is capable of producing prostaglandin [corrected] E2 (PGE2) in vitro, a metabolite not previously shown to be produced by oomycetes, and two proteins with homology to vertebrate enzymes known to play a role in prostaglandin biosynthesis have been identified in the oomycete genome. Exogenous PGE2 was shown to increase the inflammatory response in fish leukocytes incubated with cell wall carbohydrates while suppressing genes involved in cellular immunity (gamma interferon [IFN-γ] and the IFN-γ-inducible protein [γ-IP]). Inhibition of S. parasitica zoospore germination and mycelial growth by two cyclooxygenase inhibitors (aspirin and indomethacin) also suggests that prostaglandins may be involved in oomycete development. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  19. IL-15 deficient tax mice reveal a role for IL-1α in tumor immunity.

    Directory of Open Access Journals (Sweden)

    Daniel A Rauch

    Full Text Available IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia/lymphoma (ATL and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15(-/- TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma.

  20. Targeting Angiogenesis and Tumor Microenvironment in Metastatic Colorectal Cancer: Role of Aflibercept

    Directory of Open Access Journals (Sweden)

    Guido Giordano

    2014-01-01

    Full Text Available In the last decades, we have progressively observed an improvement in therapeutic options for metastatic colorectal cancer (mCRC treatment with a progressive prolongation of survival. mCRC prognosis still remains poor with low percentage of 5-year survival. Targeted agents have improved results obtained with standard chemotherapy. Angiogenesis plays a crucial role in colorectal cancer growth, proliferation, and metastasization and it has been investigated as a potential target for mCRC treatment. Accordingly, novel antiangiogenic targeted agents bevacizumab, regorafenib, and aflibercept have been approved for mCRC treatment as the result of several phase III randomized trials. The development of a tumor permissive microenvironment via the aberrant expression by tumor cells of paracrine factors alters the tumor-stroma interactions inducing an expansion of proangiogenic signals. Recently, the VELOUR study showed that addition of aflibercept to FOLFIRI regimen as a second-line therapy for mCRC improved significantly OS, PFS, and RR. This molecule represents a valid second-line therapeutic option and its peculiar ability to interfere with placental growth factor (PlGF/vascular endothelial growth factor receptor 1 (VEGFR1 axis makes it effective in targeting angiogenesis, inflammatory cells and in overcoming resistances to anti-angiogenic first-line treatment. Here, we discuss about Aflibercept peculiar ability to interfere with tumor microenvironment and angiogenic pathway.

  1. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Pimenta, Erica M. [Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States); Barnes, Betsy J., E-mail: barnesbe@njms.rutgers.edu [Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States)

    2014-04-23

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin{sup ®}) and rituximab (Rituxan{sup ®})) and the first approved cancer vaccine, Provenge{sup ®} (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

  2. Role of Tertiary Lymphoid Structures (TLS in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Directory of Open Access Journals (Sweden)

    Erica M. Pimenta

    2014-04-01

    Full Text Available Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin® and rituximab (Rituxan® and the first approved cancer vaccine, Provenge® (sipuleucel-T, investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS within the tumor microenvironment may be used to enhance immunotherapy response.

  3. Blocking the chaperone kinome pathway: Mechanistic insights into a novel dual inhibition approach for supra-additive suppression of malignant tumors

    Energy Technology Data Exchange (ETDEWEB)

    Grover, Abhinav [Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016 (India); Shandilya, Ashutosh [Supercomputing Facility for Bioinformatics and Computational Biology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016 (India); Agrawal, Vibhuti; Pratik, Piyush; Bhasme, Divya; Bisaria, Virendra S. [Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016 (India); Sundar, Durai, E-mail: sundar@dbeb.iitd.ac.in [Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016 (India)

    2011-01-07

    Research highlights: {yields} Withaferin A and 17-DMAG synergistically inhibit the Hsp90-Cdc37 chaperone pair. {yields} Binding of WA to Cdc37 cleft suppresses its kinase binding activity. {yields} 17-DMAG binding to the association complex results in H-bonds with 60% clustering. {yields} The ligands' bound complex was found structurally and thermodynamically stable. -- Abstract: The chaperone Hsp90 is involved in regulating the stability and activation state of more than 200 'client' proteins and takes part in the cancer diseased states. The major clientele-protein kinases depend on Hsp90 for their proper folding and functioning. Cdc37, a kinase targeting co-chaperone of Hsp90, mediates the interactions between Hsp90 and protein kinases. Targeting of Cdc37 has the prospect of delivering predominantly kinase-selective molecular responses as compared to the current pharmacologic Hsp90 inhibitors. The present work reports a bio-computational study carried out with the aim of exploring the dual inhibition of Hsp90/Cdc37 chaperone/co-chaperone association complex by the naturally occurring drug candidates withaferin A and 17-DMAG along with their possible modes of action. Our molecular docking studies reveal that withaferin A in combination with 17-DMAG can act as potent chaperone system inhibitors. The structural and thermodynamic stability of the ligands' bound complex was also observed from molecular dynamics simulations in water. Our results suggest a novel tumor suppressive action mechanism of herbal ligands which can be looked forward for further clinical investigations for possible anticancer drug formulations.

  4. Therapeutic effects of a novel tylophorine analog, NK-007, on collagen-induced arthritis through suppressing tumor necrosis factor α production and Th17 cell differentiation.

    Science.gov (United States)

    Wen, Ti; Li, Yangguang; Wu, Meng; Sun, Xiaolin; Bao, Xiucong; Lin, Yuquan; Hao, Jianlei; Han, Lin; Cao, Guangchao; Wang, Ziwen; Liu, Yuxiu; Wu, Zhenzhou; Hong, Zhangyong; Wang, Puyue; Zhao, Liqing; Li, Zhanguo; Wang, Qingmin; Yin, Zhinan

    2012-09-01

    To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms. We determined the effect of NK-007 on lipopolysaccharide (LPS)-triggered tumor necrosis factor α (TNFα) production by murine splenocytes and a macrophage cell line (RAW 264.7) by enzyme-linked immunosorbent assay, intracellular cytokine staining, and Western blotting. The LPS-boosted CIA model was adopted, and NK-007 or vehicle was administered at different time points after immunization. Mice were monitored for clinical severity of arthritis, and joint tissues were used for histologic examination, cytokine detection, and immunohistochemical staining. Finally, stability of TNFα production and Th17 cell differentiation were studied using quantitative polymerase chain reaction and flow cytometry. NK-007 significantly suppressed LPS-induced TNFα production in vitro. Administration of NK-007 completely blocked CIA development and delayed its progression. Furthermore, treatment with NK-007 at the onset of arthritis significantly inhibited the progress of joint inflammation. Administration of NK-007 also suppressed production of TNFα, interleukin-6 (IL-6), and IL-17A in the joint and reduced percentages of IL-17+ cells among CD4+ and γ/δ T cells in draining lymph nodes. We further demonstrated that NK-007 acted on the stability of TNFα messenger RNA and reduced Th17 cell differentiation. In addition, it significantly inhibited levels of IL-6 and IL-17A in human coculture assay. For its effects on the development and progression of CIA and for its therapeutic effect on CIA, NK-007 has great potential to be a therapeutic agent for human rheumatoid arthritis. Copyright © 2012 by the American College of Rheumatology.

  5. Role of Active Listening and Listening Effort on Contralateral Suppression of Transient Evoked Otoacousic Emissions.

    Science.gov (United States)

    Kalaiah, Mohan Kumar; Theruvan, Nikhitha B; Kumar, Kaushlendra; Bhat, Jayashree S

    2017-04-01

    The present study aimed to investigate the effect of active listening and listening effort on the contralateral suppression of transient evoked otoacoustic emissions (CSTEOAEs). Twenty eight young adults participated in the study. Transient evoked otoacoustic emissions (TEOAEs) were recorded using 'linear' clicks at 60 dB peSPL, in three contralateral noise conditions. In condition 1, TEOAEs were obtained in the presence of white noise in the contralateral ear. While, in condition 2, speech was embedded into white noise at +3, -3, and -9 dB signal-to-noise ratio (SNR) and delivered to the contralateral ear. The SNR was varied to investigate the effect of listening effort on the CSTEOAE. In condition 3, speech was played backwards and embedded into white noise at -3 dB SNR. The conditions 1 and 3 served as passive listening condition and the condition 2 served as active listening condition. In active listening condition, the participants categorized the words in to two groups (e.g., animal and vehicle). CSTEOAE was found to be largest in the presence of white noise, and the amount of CSTEOAE was not significantly different between active and passive listening conditions (condition 2 and 3). Listening effort had an effect on the CSTEOAE, the amount of suppression increased with listening effort, when SNR was decreased from +3 dB to -3 dB. However, when the SNR was further reduced to -9 dB, there was no further increase in the amount of CSTEOAE, instead there was a reduction in the amount of suppression. The findings of the present study show that listening effort might affect CSTEOAE.

  6. The role of stereotactic radiation therapy in the management of children with brain tumors.

    Science.gov (United States)

    Lew, C M; LaVally, B

    1995-10-01

    Conventional radiation therapy plays an important role in the management of intracranial tumors in children. For certain tumors radiation therapy serves as the primary mode of treatment, and for others it plays an adjuvant role with surgery and/or chemotherapy. Improvements in long-term survival rates have focused attention on the long-term sequelae of brain tumors and their treatment, and the sequelae, in turn, have become important targets for clinical investigation. Long-term side effects of particular concern in children include cranial nerve damage, memory and intellectual deficits, pituitary-hypothalamic dysfunction, demyelinization of brain tissue, and secondary malignancies. A new form of radiation therapy, stereotactic radiotherapy (SRT), merges the technologies of stereotactic surgery and conventional fractionated radiotherapy. The intent is to deliver maximum tumoricidal doses to the target while limiting the dose to normal surrounding brain tissue. The key feature of SRT is a noninvasive, relocatable immobilization system to assure accurate and reproducible positioning during planning and treatment. The headframes used for children have been modified to address their specific needs. The complexities of this process require careful preparation of patients and their families and the participation of many disciplines. Long-term follow-up will be essential to evaluate the effectiveness of this innovative treatment.

  7. Coordination of BRCA1/BARD1- and MRE11/RAD50/NBS1-Dependent DNA Transactions in Breast Tumor Suppression

    Science.gov (United States)

    2011-07-01

    human DNA repair proteins at a unique double-strand break in vivo, EMBO J 25, 222-231. 19. Berkovich, E., Monnat, R. J., Jr., and Kastan, M. B...structures around DNA as SMC complexes do. Rad50 exhibits ATPase activity in vitro, which is required for DNA repair and meiosis (3, 57). The rad50S...151). Exo1 expression is induced dur- ing meiosis , suggesting a role in meiotic DSB resection (149). Studies in the dmc1 mutant, which exhibits hyper

  8. COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro

    Directory of Open Access Journals (Sweden)

    Petasis Nicos A

    2008-05-01

    Full Text Available Abstract Background An increasing number of reports is challenging the notion that the antitumor potential of the selective COX-2 inhibitor celecoxib (Celebrex® is mediated primarily via the inhibition of COX-2. We have investigated this issue by applying two different analogs of celecoxib that differentially display COX-2-inhibitory activity: the first analog, called unmethylated celecoxib (UMC, inhibits COX-2 slightly more potently than its parental compound, whereas the second analog, 2,5-dimethyl-celecoxib (DMC, has lost the ability to inhibit COX-2. Results With the use of glioblastoma and pancreatic carcinoma cell lines, we comparatively analyzed the effects of celecoxib, UMC, and DMC in various short-term (≤48 hours cellular and molecular studies, as well as in long-term (≤3 months focus formation assays. We found that DMC exhibited the most potent antitumor activity; celecoxib was somewhat less effective, and UMC clearly displayed the overall weakest antitumor potential in all aspects. The differential growth-inhibitory and apoptosis-stimulatory potency of these compounds in short-term assays did not at all correlate with their capacity to inhibit COX-2, but was closely aligned with their ability to trigger endoplasmic reticulum stress (ERS, as indicated by the induction of the ERS marker CHOP/GADD153 and activation of the ERS-associated caspase 7. In addition, we found that these compounds were able to restore contact inhibition and block focus formation during long-term, chronic drug exposure of tumor cells, and this was achieved at sub-toxic concentrations in the absence of ERS or inhibition of COX-2. Conclusion The antitumor activity of celecoxib in vitro did not involve the inhibition of COX-2. Rather, the drug's ability to trigger ERS, a known effector of cell death, might provide an alternative explanation for its acute cytotoxicity. In addition, the newly discovered ability of this drug to restore contact inhibition and

  9. Profile of patients with brain tumors and the role of nursing care

    Directory of Open Access Journals (Sweden)

    Kênia Cristina Soares Fonseca de Magalhães

    2016-02-01

    Full Text Available ABSTRACT Objective: to describe the profile of 200 patients with central nervous system tumors (CNST, and the role of the nursing care. Method: prospective, quantitative and descriptive analysis of medical records of 200 patients with TSNC. Results: a total of 61% of our patients had benign CNST and 39% had malignant tumors. The extent of patient dependence, according to the Karnofsky Performance Status scale, was significantly greater for patients with malignant CNST (p < .05, indicating that these patients needed more support with their activities of daily living. Conclusion: patients with CNST need specialized care, with specific guidance regarding their disease and aspects of daily living after treatment. Thus, the nurse can function as a key element for the effectiveness of care provided to patients and family members with the aim of enhancing the quality of life of all those affected, directly or indirectly, by the disease.

  10. Role of respiratory-gated PET/CT for pancreatic tumors: A preliminary result

    International Nuclear Information System (INIS)

    Kasuya, Takeo; Tateishi, Ukihide; Suzuki, Kazufumi; Daisaki, Hiromitsu; Nishiyama, Yuji; Hata, Masaharu; Inoue, Tomio

    2013-01-01

    Purpose: The aim of this study is to ascertain role of respiratory-gated PET/CT for accurate diagnosis of pancreatic tumors. Materials and methods: Prior to clinical study, the phantom study was performed to evaluate the impact of respiratory motion on lesion quantification. Twenty-two patients (mean age 65 years) with pancreatic tumors were enrolled. Pathological diagnoses by surgical specimens consisted of pancreatic cancer (n = 15) and benign intraductal papillary mucinous neoplasm (IPMN, n = 7). Whole-body scan of non-respiratory-gated PET/CT was performed at first, and subsequent respiratory-gated PET/CT for one bed position was performed. All PET/CT studies were performed prior to surgery. The SUV max obtained by non-respiratory-gated PET/CT and respiratory-gated PET/CT, and percent difference in SUVmax (%SUVmax) were compared. Results: The profile curve of 5 respiratory bin image was most similar to that of static image. The third bin of 5 respiratory bin image showed highest FWHM (24.0 mm) and FWTM (32.7 mm). The mean SUVmax of pancreatic cancer was similar to that of benign IPMN on non-respiratory-gated PET/CT (p = 0.05), whereas significant difference was found between two groups on respiratory-gated PET/CT (p = 0.016). The mean %SUV of pancreatic cancer was greater than that of benign IPMN (p < 0.0001). Identification of the primary tumor in pancreatic head (n = 13, 59%) was improved by using respiratory-gated PET/CT because of minimal affection of physiological accumulation in duodenum. Conclusion: Respiratory-gated PET/CT is a feasible technique for evaluation of pancreatic tumors and allows more accurate identification of pancreatic tumors compared with non-respiratory-gated PET/CT

  11. TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

    Science.gov (United States)

    Lai, De-Wei; Lin, Keng-Hung; Sheu, Wayne Huey-Herng; Lee, Maw-Rong; Chen, Chung-Yu; Lee, Wen-Jane; Hung, Yi-Wen; Shen, Chin-Chang; Chung, Tsung-Ju; Liu, Shing-Hwa; Sheu, Meei-Ling

    2017-09-01

    Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N ε -(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Serum N ε -(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N ε -(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). This study demonstrates that inhibiting the N ε -(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. © 2017

  12. Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth.

    Science.gov (United States)

    Liu, Yanling; Zhang, Yujuan; Zheng, Xiufen; Zhang, Xusheng; Wang, Hongmei; Li, Qin; Yuan, Keng; Zhou, Nanjing; Yu, Yanrong; Song, Na; Fu, Jiamin; Min, Weiping

    2016-05-31

    Indoleamine 2,3-dioxygenase 2 (IDO2) is a newly discovered enzyme that catalyzes the initial and rate-limiting step in the degradation of tryptophan. As a homologous protein of IDO1, IDO2 plays an inhibitory role in T cell proliferation, and it is essential for regulatory T cell (Treg) generation in healthy conditions. Little is known about the immune-independent functions of IDO2 relevant to its specific contributions to physiology and pathophysiology in cancer cells. The purpose of this study was to assess the impact of IDO2 gene silencing as a way to inhibit B16-BL6 cancer cells in a murine model. Here, for the first time, we show that knockdown of IDO2 using small interfering RNA (siRNA) inhibits cancer cell proliferation, arrests cell cycle in G1, induces greater cell apoptosis, and reduces cell migration in vitro. Knockdown of IDO2 decreased the generation of nicotinamide adenine dinucleotide (NAD+) while increasing the generation of reactive oxygen species (ROS). We further demonstrate that cell apoptosis, induced by IDO2 downregulation, can be weakened by addition of exogenous NAD+, suggesting a novel mechanism by which IDO2 promotes tumor growth through its metabolite product NAD+. In addition to in vitro findings, we also demonstrate that IDO2 silencing in tumor cells using short hairpin RNA (shRNA) delayed tumor formation and arrested tumor growth in vivo. In conclusion, this study demonstrates a new non-immune-associated mechanism of IDO2 in vitro and IDO2 expression in B16-BL6 cells contributes to cancer development and progression. Our research provides evidence of a novel target for gene silencing that has the potential to enhance cancer therapy.

  13. The role of type III effectors from Xanthomonas axonopodis pv. manihotis in virulence and suppression of plant immunity.

    Science.gov (United States)

    Medina, Cesar Augusto; Reyes, Paola Andrea; Trujillo, Cesar Augusto; Gonzalez, Juan Luis; Bejarano, David Alejandro; Montenegro, Nathaly Andrea; Jacobs, Jonathan M; Joe, Anna; Restrepo, Silvia; Alfano, James R; Bernal, Adriana

    2018-03-01

    Xanthomonas axonopodis pv. manihotis (Xam) causes cassava bacterial blight, the most important bacterial disease of cassava. Xam, like other Xanthomonas species, requires type III effectors (T3Es) for maximal virulence. Xam strain CIO151 possesses 17 predicted T3Es belonging to the Xanthomonas outer protein (Xop) class. This work aimed to characterize nine Xop effectors present in Xam CIO151 for their role in virulence and modulation of plant immunity. Our findings demonstrate the importance of XopZ, XopX, XopAO1 and AvrBs2 for full virulence, as well as a redundant function in virulence between XopN and XopQ in susceptible cassava plants. We tested their role in pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) using heterologous systems. AvrBs2, XopR and XopAO1 are capable of suppressing PTI. ETI suppression activity was only detected for XopE4 and XopAO1. These results demonstrate the overall importance and diversity in functions of major virulence effectors AvrBs2 and XopAO1 in Xam during cassava infection. © 2017 BSPP AND JOHN WILEY & SONS LTD.

  14. MicroRNA-200a-3p suppresses tumor proliferation and induces apoptosis by targeting SPAG9 in renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xinsheng; Jiang, Fuquan; Song, Haitao; Li, Xu; Xian, Jiantao; Gu, Xinquan, E-mail: guxqprofessor@163.com

    2016-02-12

    Sperm-associated antigen 9(SPAG9), as a well-recognized oncogene protein, has a critical effect on renal cell carcinoma (RCC) progression. Our study tried to explore the mediator of miR-200a-3p, a tumor suppressing miRNA on SPAG9 expression and renal cell proliferation and apoptosis. We found the expression of miR-200a-3p was significantly lower in RCC specimens. Based on in vitro assays, we found miR-200a-3p significantly inhibit cancer cell proliferation by inducing apoptosis. In addition, our study uncovered that miR-200a-3p directly regulates oncogenic SPAG9 in 786-O and ACHN cells. Silencing of SPAG9 resulted in significantly decreased in the growth and the cell cycle of the renal cancer cell lines. Understanding of oncogenic SPAG9 regulated by miR-200a-3p might be beneficial to reveal new therapeutic targets for RCC. - Highlights: • MiR-200a-3p is downregulated in renal cell carcinoma. • MiR-200a-3p regulates cell proliferation through inducing apoptosis. • MiR-200a-3p is involved in cell cycle regulation. • SPAG9 is a potential target of miR-200a-3p.

  15. Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation.

    Science.gov (United States)

    Le, Catherine T K; Laidlaw, Grace; Morehouse, Christopher A; Naiman, Brian; Brohawn, Philip; Mustelin, Tomas; Connor, Jane R; McDonald, Donald M

    2015-11-01

    Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  16. miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma.

    Science.gov (United States)

    Khella, H W Z; Bakhet, M; Allo, G; Jewett, M A S; Girgis, A H; Latif, A; Girgis, H; Von Both, I; Bjarnason, G A; Yousef, G M

    2013-10-01

    MicroRNAs (miRNAs) play a crucial role in tumor progression and metastasis. We, and others, recently identified a number of miRNAs that are dysregulated in metastatic renal cell carcinoma compared with primary renal cell carcinoma. Here, we investigated three miRNAs that are significantly downregulated in metastatic tumors: miR-192, miR-194 and miR-215. Gain-of-function analyses showed that restoration of their expression decreases cell migration and invasion in renal cell carcinoma cell line models, whereas knockdown of these miRNAs resulted in enhancing cellular migration and invasion abilities. We identified three targets of these miRNAs with potential role in tumor aggressiveness: murine double minute 2, thymidylate synthase, and Smad Interacting protein 1/zinc finger E-box binding homeobox 2. We observed a convergent effect (the same molecule can be targeted by all three miRNAs) and a divergent effect (the same miRNA can control multiple targets) for these miRNAs. We experimentally validated these miRNA-target interactions using three independent approaches. First, we observed that miRNA overexpression significantly reduces the mRNA and protein levels of their targets. In the second, we observed significant reduction of the luciferase signal of a vector containing the 3'UTR of the target upon miRNA overexpression. Finally, we show the presence of inverse correlation between miRNA changes and the expression levels of their targets in patient specimens. We also examined the prognostic significance of miR-215 in renal cell carcinoma. Lower expression of miR-215 is associated with significantly reduced disease-free survival time. These findings were validated on an independent data set from The Cancer Genome Atlas. These results can pave the way to the clinical use of miRNAs as prognostic markers and therapeutic targets.

  17. Role of suppressed hepatocellular regeneration and Ca2+ in chlordecone-potentiated CCl4 hepatotoxicity

    International Nuclear Information System (INIS)

    Bell, A.N.

    1987-01-01

    The mechanism by which the chlorinated pesticide chlordecone (CD; Kepone) potentiates CCl 4 -induced hepatotoxicity and lethality was investigated. It was hypothesized that perturbations in Ca 2+ homeostasis, greater than those observed with a low dose of CCl 4 alone, in concert with a suppression of hepatocellular regeneration induced by CD alone or by CD + CCl 4 are responsible, at least in part, for CD-potentiated CCl 4 hepatotoxicity. Ca 2+ homeostasis was evaluated by measuring total cell Ca 2+ and 45 Ca 2+ uptake in viable isolated hepatocyte suspension obtained from normal and CD-pretreated rats receiving CCl 4 in vivo. In the normal rats in vivo CCL challenge did not affect 45 Ca 2+ uptake by viable isolated hepatocytes. In contrast, 45 Ca 2+ uptake was inhibited in viable isolated hepatocytes obtained from rats exposed to CD + CCl 4

  18. Role of isothiocyanate conjugate of pterostilbene on the inhibition of MCF-7 cell proliferation and tumor growth in Ehrlich ascitic cell induced tumor bearing mice

    Energy Technology Data Exchange (ETDEWEB)

    Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta [Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India); Bodipati, Naganjaneyulu; Krishna Peddinti, Rama [Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India); Roy, Partha, E-mail: paroyfbs@iitr.ernet.in [Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand (India)

    2014-01-15

    Naturally occurring pterostilbene (PTER) and isothiocyanate (ITC) attract great attention due to their wide range of biological properties, including anti-cancer, anti-leukemic, anti-bacterial and anti-inflammatory activities. A novel class of hybrid compound synthesized by introducing an ITC moiety on PTER backbone was evaluated for its anti-cancer efficacy in hormone-dependent breast cancer cell line (MCF-7) in vitro and Ehrlich ascitic tumor bearing mice model in vivo. The novel hybrid molecule showed significant in vitro anti-cancer activity (IC{sub 50}=25±0.38) when compared to reference compound PTER (IC{sub 50}=65±0.42). The conjugate molecule induced both S and G2/M phase cell cycle arrest as indicated by flow cytometry analysis. In addition, the conjugate induced cell death was characterized by changes in cell morphology, DNA fragmentation, activation of caspase-9, release of cytochrome-c into cytosol and increased Bax: Bcl-2 ratio. The conjugate also suppressed the phosphorylation of Akt and ERK. The conjugate induced cell death was significantly increased in presence of A6730 (a potent Akt1/2 kinase inhibitor) and PD98059 (a specific ERK inhibitor). Moreover, the conjugated PTER inhibited tumor growth in Ehrlich ascitic cell induced tumor bearing mice as observed by reduction in tumor volume compared to untreated animals. Collectively, the pro-apoptotic effect of conjugate is mediated through the activation of caspases, and is correlated with the blockade of the Akt and ERK signaling pathways in MCF-7 cells. - Highlights: • Conjugate was prepared by appending isothiocyanate moiety on pterostilbene backbone. • Conjugate showed anticancer effects at comparatively lower dose than pterostilbene. • Conjugate caused blockage of the Akt and ERK signaling pathways in MCF-7 cells. • Conjugate significantly reduced solid tumor volume as compared to pterostilbene.

  19. Role of isothiocyanate conjugate of pterostilbene on the inhibition of MCF-7 cell proliferation and tumor growth in Ehrlich ascitic cell induced tumor bearing mice

    International Nuclear Information System (INIS)

    Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta; Bodipati, Naganjaneyulu; Krishna Peddinti, Rama; Roy, Partha

    2014-01-01

    Naturally occurring pterostilbene (PTER) and isothiocyanate (ITC) attract great attention due to their wide range of biological properties, including anti-cancer, anti-leukemic, anti-bacterial and anti-inflammatory activities. A novel class of hybrid compound synthesized by introducing an ITC moiety on PTER backbone was evaluated for its anti-cancer efficacy in hormone-dependent breast cancer cell line (MCF-7) in vitro and Ehrlich ascitic tumor bearing mice model in vivo. The novel hybrid molecule showed significant in vitro anti-cancer activity (IC 50 =25±0.38) when compared to reference compound PTER (IC 50 =65±0.42). The conjugate molecule induced both S and G2/M phase cell cycle arrest as indicated by flow cytometry analysis. In addition, the conjugate induced cell death was characterized by changes in cell morphology, DNA fragmentation, activation of caspase-9, release of cytochrome-c into cytosol and increased Bax: Bcl-2 ratio. The conjugate also suppressed the phosphorylation of Akt and ERK. The conjugate induced cell death was significantly increased in presence of A6730 (a potent Akt1/2 kinase inhibitor) and PD98059 (a specific ERK inhibitor). Moreover, the conjugated PTER inhibited tumor growth in Ehrlich ascitic cell induced tumor bearing mice as observed by reduction in tumor volume compared to untreated animals. Collectively, the pro-apoptotic effect of conjugate is mediated through the activation of caspases, and is correlated with the blockade of the Akt and ERK signaling pathways in MCF-7 cells. - Highlights: • Conjugate was prepared by appending isothiocyanate moiety on pterostilbene backbone. • Conjugate showed anticancer effects at comparatively lower dose than pterostilbene. • Conjugate caused blockage of the Akt and ERK signaling pathways in MCF-7 cells. • Conjugate significantly reduced solid tumor volume as compared to pterostilbene

  20. Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications

    Science.gov (United States)

    Yoon, Sarah; Jo, Yuna; Kwon, So Mee; Kim, Kyoung Min; Kwon, Keun Sang; Kim, Chan Young; Woo, Hyun Goo

    2015-01-01

    Poly (ADP-ribose) polymerase1 (PARP1) has been reported as a possible target for chemotherapy in many cancer types. However, its action mechanisms and clinical implications for gastric cancer survival are not yet fully understood. Here, we investigated the effect of PARP1 inhibition in the growth of gastric cancer cells. PARP1 inhibition by Olaparib or PARP1 siRNA could significantly attenuate growth and colony formation of gastric cancer cells, and which were mediated through induction of G2/M cell cycle arrest but not apoptosis. FOXO3A expression was induced by PARP1 inhibition, suggesting that FOXO3A might be one of downstream target of the PARP1 effect on gastric cancer cell growth. In addition, by performing tissue microarrays on the 166 cases of gastric cancer patients, we could observe that the expression status of PARP1 and FOXO3A were significantly associated with overall survival (OS) and relapse-free survival (RFS). Strikingly, combined expression status of PARP1 and FOXO3A showed better prediction for patient's clinical outcomes. The patient group with PARP1+/FOXO3A− expression had the worst prognosis while the patient group with PARP1−/FOXO3A+ had the most favorable prognosis (OS: P = 6.0 × 10−9, RFS: P = 2.2 × 10−8). In conclusion, we suggest that PARP1 and FOXO3A play critical roles in gastric cancer progression, and might have therapeutic and/or diagnostic potential in clinic. PMID:26540566

  1. Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

    Science.gov (United States)

    Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

    1993-01-01

    Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

  2. Natural Killer Cell Response to Chemotherapy-Stressed Cancer Cells: Role in Tumor Immunosurveillance

    Directory of Open Access Journals (Sweden)

    Alessandra Zingoni

    2017-09-01

    Full Text Available Natural killer (NK cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. An equilibrium between immune control and tumor growth is maintained as long as cancer cells evade immunosurveillance. Therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. Several chemotherapeutic agents, depending on which drugs and doses are used, give rise to DNA damage and cancer cell death by means of apoptosis, immunogenic cell death, or other forms of non-apoptotic death (i.e., mitotic catastrophe, senescence, and autophagy. However, it is becoming increasingly clear that they can trigger additional stress responses. Indeed, relevant immunostimulating effects of different therapeutic programs include also the activation of pathways able to promote their recognition by immune effector cells. Among stress-inducible immunostimulating proteins, changes in the expression levels of NK cell-activating and inhibitory ligands, as well as of death receptors on tumor cells, play a critical role in their detection and elimination by innate immune effectors, including NK cells. Here, we will review recent advances in chemotherapy-mediated cellular stress pathways able to stimulate NK cell effector functions. In particular, we will address how these cytotoxic lymphocytes sense and respond to different types of drug-induced stresses contributing to anticancer activity.

  3. Role of collagen triple helix repeat containing-1 in tumor and inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Qian Wu

    2017-01-01

    Full Text Available Initially, collagen triple helix repeat containing-1 (CTHRC1 is expressed mainly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels, and increases cell migration, promotes tissue repair in response to injury. A variety of studies demonstrated that over-expression of CTHRC1 in solid tumors results in enhancement of migration and invasion of tumor cells, and is associated with decreased overall survival and disease-free survival. CTHRC1 expression is elevated in hepatitis B virus-infected patients and highly correlated with hepatocellular carcinoma progression as well. Furthermore, CTHRC1 plays a pivotal role in a great many fields, including increases bone mass, prevents myelination, reverses collagen synthesis in keloid fibroblasts, and increases fibroblast-like synoviocytes migration speed and abundant production of arthritic pannus in rheumatoid arthritis. Therefore, it will provide new insight into the pathogenesis of tumor and autoimmune diseases, and will shed new light on the therapy of related clinical diseases.

  4. The Role of Color Doppler Ultrasonography in Characterization of Thyroid Tumors

    International Nuclear Information System (INIS)

    Kim, Hee Soo; Jeon, Pyong; Won, Jong Yoon; Na, Jae Beom; Lee, Hyang Mee; Yoo, Hyung Sik; Lee, Jong Tae; Park, Jeong Soo; Cho, Nam Hoon

    1995-01-01

    To assess the usefulness of color Doppler ultrasonography in the characterization of thyroid tumors, surgically proven 88 nodules in 85 patients were evaluated. Using 10 MHz linear array transducer, gray scale images were initially evaluated. Then, distribution pattern of color signals (marginal, intra-tumoral, mixed) and graded internal vascularity according to morphology of color signal (0:absence of internal signal, 1: spotty, 2: linear,3: branching) were observed on color doppler imaging. Pulsed doppler waves were analyzed with parameters including peak systolic velocity(PSV), resistive index(RI), and pulsatile index(PI). Significantly larger numbers of intra-tumoral type, 20 cases(62.5%), were observed in malignant nodules, whereas mixed forms were predominant in benign group, 37 cases (66%) In graded internal vascularity, malignant nodules tended to have grade 2 or 3 signals, whereas benign nodules tended to have grade 0 or 1 signals. Spectral wave analysis show no significant difference in the value of PSV, RI, and PI between malignancy and benignity group. In conclusion, color Doppler imaging has a potential role in the characterization of thyroid nodules as a supportive method for gray scale diagnosis

  5. Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Carine Bossard

    Full Text Available Ovarian cancer is the gynecological cancer exhibiting the highest morbidity and improvement of treatments is still required. Previous studies have shown that Estrogen-receptor beta (ERβ levels decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ERβ in BG-1 epithelial ovarian cancer cells, which express ERα, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ERβ reduced the frequency of cells in S phase and increased the one of cells in G2/M phase. At the molecular level, we found that ERβ downregulated total retinoblastoma (Rb, phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ERβ had a direct effect on ERα, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ERβ. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ERβ expression reduces tumor growth and the presence of tumor cells in sites of metastasis, hence resulting in improved survival of mice. Altogether, these findings unveil a potential tumor-suppressor role of ERβ in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients.

  6. Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

    Science.gov (United States)

    Gaudin, Françoise; Machelon, Véronique; Brigitte, Madly; Jacquard, Carine; Pillon, Arnaud; Balaguer, Patrick; Balabanian, Karl; Lazennec, Gwendal

    2012-01-01

    Ovarian cancer is the gynecological cancer exhibiting the highest morbidity and improvement of treatments is still required. Previous studies have shown that Estrogen-receptor beta (ERβ) levels decreased along with ovarian carcinogenesis. Here, we present evidence that reintroduction of ERβ in BG-1 epithelial ovarian cancer cells, which express ERα, leads in vitro to a decrease of basal and estradiol-promoted cell proliferation. ERβ reduced the frequency of cells in S phase and increased the one of cells in G2/M phase. At the molecular level, we found that ERβ downregulated total retinoblastoma (Rb), phosphorylated Rb and phospho-AKT cellular content as well as cyclins D1 and A2. In addition, ERβ had a direct effect on ERα, by strongly inhibiting its expression and activity, which could explain part of the anti-proliferative action of ERβ. By developing a novel preclinical model of ovarian cancer based on a luminescent orthotopic xenograft in athymic Nude mice, we further revealed that ERβ expression reduces tumor growth and the presence of tumor cells in sites of metastasis, hence resulting in improved survival of mice. Altogether, these findings unveil a potential tumor-suppressor role of ERβ in ovarian carcinogenesis, which could be of potential clinical relevance for the selection of the most appropriate treatment for patients. PMID:22970307

  7. Tumor immunology

    International Nuclear Information System (INIS)

    Otter, W. den

    1987-01-01

    Tumor immunology, the use of immunological techniques for tumor diagnosis and approaches to immunotherapy of cancer are topics covered in this multi-author volume. Part A, 'Tumor Immunology', deals with present views on tumor-associated antigens, the initiation of immune reactions of tumor cells, effector cell killing, tumor cells and suppression of antitumor immunity, and one chapter dealing with the application of mathematical models in tumor immunology. Part B, 'Tumor Diagnosis and Imaging', concerns the use of markers to locate the tumor in vivo, for the histological diagnosis, and for the monitoring of tumor growth. In Part C, 'Immunotherapy', various experimental approaches to immunotherapy are described, such as the use of monoclonal antibodies to target drugs, the use of interleukin-2 and the use of drugs inhibiting suppression. In the final section, the evaluation, a pathologist and a clinician evaluate the possibilities and limitations of tumor immunology and the extent to which it is useful for diagnosis and therapy. refs.; figs.; tabs

  8. Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer.

    Science.gov (United States)

    Hori, Shunta; Miyake, Makito; Tatsumi, Yoshihiro; Morizawa, Yosuke; Nakai, Yasushi; Onishi, Sayuri; Onishi, Kenta; Iida, Kota; Gotoh, Daisuke; Tanaka, Nobumichi; Fujimoto, Kiyohide

    2018-04-13

    Alpha-Klotho (KLα) and beta-Klotho (KLβ) have recently been reported to correlate with cancer prognosis in some malignancies and we previously reported the association between KLα, KLβ, and urothelial carcinoma of the bladder (UCB), indicating that KLβ acts as a tumor promoter. However, the association between gamma-Klotho (KLγ) and cancer prognosis remains unclear. In the present study, we evaluated the association between KLγ and UCB. To evaluate the effect of KLγ on human bladder cancer cell lines in vitro assays were performed. Exogenous KLγ increased the ability of human bladder cancer cells to proliferate, migrate, invade, form colonies, and provide anchorage-independent growth potential. In in vivo assays, eighteen mice bearing xenografts inoculated using UM-UC-3, were randomly divided into three groups and treated with a small interfering RNA (siRNA) by intratumoral administration once a week for four weeks. Knockdown of KLγ with siRNA led to a dramatic change in tumor growth and suggested that KLγ had effects on tumor growth, including promotion of cell proliferation, inhibition of apoptosis, and enhancement of the epithelial-mesenchymal transition. To confirm the study, human tissue samples were used and patients were divided into two groups according to KLγ expression level. High expression of KLγ was significantly associated with higher stage and grade cancer and the presence of lymphovascular invasion compared to patients with lower expression of KLγ. Our results suggest that KLγ plays an important role in tumor invasion and progression and these results may lead to the development of new therapies and diagnostic methods for UCB.

  9. Pivotal Roles of Ginsenoside Rg3 in Tumor Apoptosis Through Regulation of Reactive Oxygen Species.

    Science.gov (United States)

    Sun, Hwa Yeon; Lee, Jun Hee; Han, Yong-Seok; Yoon, Yeo Min; Yun, Chul Won; Kim, Jae Heon; Song, Yun Seob; Lee, Sang Hun

    2016-09-01

    Elevated production of reactive oxygen species (ROS) is observed in various cancer types and pathophysiological conditions. In cancer cells, ROS induce cell proliferation, genetic instability, and a malignant phenotype. Ginsenoside Rg3 is the main pharmacologically active component in ginseng and has been reported to have an antioxidant effect. To overcome lung cancer by regulating the ROS level, we investigated the antitumor effect and mechanism of Rg3 and its antioxidative property on Lewis lung carcinoma (LLC) cells. Inhibition of ROS was suppressed in LLC cells by Rg3 treatment, and these cells were used to investigate the antioxidant, antiproliferative, and antitumor effects in LLC cells. ROS production was increased in cells grown in serum-containing media (conditioned media) compared to those grown in serum-free media. The high level of ROS induced LLC cell proliferation, but treatment with Rg3 (200 ng/ml) resulted in reduction of ROS, leading to inhibition of cell proliferation. Treatment with Rg3 significantly reduced cyclin and cyclin-dependent kinase expression in LLC cells. Additionally, Rg3 treatment significantly suppressed activation of mitogen-activated protein kinases and induced LLC cell apoptosis through activation of pro-apoptotic proteins and suppression of anti-apoptotic proteins. Taken together, these findings demonstrate the role of Rg3 in reduction of the intracellular ROS level, attenuation of proliferation via augmentation of cell cycle- and cell proliferation-associated proteins, and activation of apoptosis through regulation of apoptosis-associated proteins in LLC. These findings suggest that Rg3 could be used as a therapeutic agent in lung cancer. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. Follistatin during pregnancy and its potential role as an ovarian suppressing agent.

    Science.gov (United States)

    Köninger, Angela; Schmidt, Börge; Damaske, Daniela; Birdir, Cahit; Enekwe, Antje; Kimmig, Rainer; Strowitzki, Thomas; Gellhaus, Alexandra

    2017-05-01

    Ovarian quiescence is a common condition during pregnancy. In vitro, follistatin, an antagonist of follicle-stimulating hormone, blocks follicular development at early stages, and its serum levels increase during pregnancy. A possible surrogate biomarker of ovarian arrest during pregnancy is a decrease in anti-mullerian hormone (AMH) levels followed by an increase in these levels on the second day after labor. The purpose of this study was to determine whether follistatin could act as an ovarian-suppressing agent during pregnancy. Follistatin levels and AMH levels were determined at various stages of pregnancy and postpartum. The follistatin and AMH levels of 69 patients were retrospectively determined with the AMH Gen II ELISA and with the Human Follistatin Quantikine ELISA Kit. For 49 patients, samples were available from various trimesters for cross-sectional analysis; for the other 20, samples were available longitudinally from day one before labor and then daily on days 1 through 4 after labor. Statistical significance was determined with linear regression, the Friedman rank sum test and the Wilcoxon-Nemenyi-McDonald-Thompson post hoc test. The behavior of follistatin levels was exactly opposite that of AMH levels: Follistatin levels increased significantly during pregnancy and on the first day after parturition but declined afterwards, whereas AMH levels decreased significantly during pregnancy and increased after labor. Follistatin can induce ovarian arrest during pregnancy. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. The role of radial particle pinches in ELM suppression by resonant magnetic perturbations

    International Nuclear Information System (INIS)

    Stacey, W.M.; Evans, T.E.

    2011-01-01

    The force balance in the plasma edge in a matched pair of DIII-D (Luxon 2002 Nucl. Fusion 42 6149) tokamak discharges with and without resonant magnetic perturbations (RMPs) is evaluated in order to investigate the effects on particle transport of RMP applied for the purpose of suppressing edge-localized modes (ELMs). Experimental data are used to evaluate the radial and toroidal force balances, which may be written as a pinch-diffusion relation for the radial ion flux to facilitate investigation of transport effects. The radial electric field in the H-mode plasma had a sharp negative dip in the steep gradient region of the edge pedestal, associated with which was a large inward pinch velocity. The main effect of RMP was to make the edge electric field less negative or more positive, reducing this strong negative dip in the radial electric field (even reversing it from negative to positive over some regions), thereby reducing the strong inward particle pinch in the edge of an H-mode discharge, thus causing a reduction in edge density below the ELM threshold.

  12. The role of rare earth oxide nanoparticles in suppressing the photobleaching of fluorescent organic dyes

    Science.gov (United States)

    Guha, Anubhav; Basu, Anindita

    2013-03-01

    Organic dyes are widely used for both industrial as well as in scientific applications such as the fluorescent tagging of materials. However the process of photobleaching can rapidly degrade dye fluorescence rendering the material non-functional. Thus exploring novel methods for preventing photobleaching can have widespread benefits. In this work we show that the addition of minute quantities of rare earth (RE) oxide nanoparticles can significantly suppress the photobleaching of dyes. The fluorescence of Rhodamine and AlexaFluor dyes was measured as a function of time with and without the addition of CeO2 and La2O3 nanoparticle additives (two RE oxides that contain an oxygen vacancy based defect structure), as well as with FeO nanoparticles (which has an oxygen excess stoichiometry). We find that the rare earth oxides significantly prolonged the lifetimes of the dyes. The results allow us to develop a model based upon the presence of oxygen vacancies defects that allow the RE oxides to act as oxygen scavengers. This enables the RE oxide particles to effectively remove reactive oxygen free radicals generated in the dye solutions during the photoabsorption process. Current affiliation: Harvard University

  13. Inducing death in tumor cells: roles of the inhibitor of apoptosis proteins.

    Science.gov (United States)

    Finlay, Darren; Teriete, Peter; Vamos, Mitchell; Cosford, Nicholas D P; Vuori, Kristiina

    2017-01-01

    The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation but also from a lack of accompanying homeostatic cell death. Indeed, cancer cells regularly acquire resistance to programmed cell death, or apoptosis, which not only supports cancer progression but also leads to resistance to therapeutic agents. Thus, various approaches have been undertaken in order to induce apoptosis in tumor cells for therapeutic purposes. Here, we will focus our discussion on agents that directly affect the apoptotic machinery itself rather than on drugs that induce apoptosis in tumor cells indirectly, such as by DNA damage or kinase dependency inhibition. As the roles of the Bcl-2 family have been extensively studied and reviewed recently, we will focus in this review specifically on the inhibitor of apoptosis protein (IAP) family. IAPs are a disparate group of proteins that all contain a baculovirus IAP repeat domain, which is important for the inhibition of apoptosis in some, but not all, family members. We describe each of the family members with respect to their structural and functional similarities and differences and their respective roles in cancer. Finally, we also review the current state of IAPs as targets for anti-cancer therapeutics and discuss the current clinical state of IAP antagonists.

  14. Suppressing Structural Colors of Photocatalytic Optical Coatings on Glass: The Critical Role of SiO2.

    Science.gov (United States)

    Li, Ronghua; Boudot, Mickael; Boissière, Cédric; Grosso, David; Faustini, Marco

    2017-04-26

    The appearance of structural colors on coated-glass is a critical esthetical drawback toward industrialization of photocatalytic coatings on windows for architecture or automobile. Herein we describe a rational approach to suppress the structural color of mesoporous TiO 2 -based coatings preserving photoactivity and mechanical stiffness. Addition of SiO 2 as third component is discussed. Ti x Si (1-x) O 2 mesoporous coatings were fabricated by one-step liquid deposition process through the evaporation induced self-assembling and characterized by GI-SAXS, GI-WAXS, electron microscopies, and in situ Environmental Ellipsometry Porosimetry. Guided by optical simulation, we investigated the critical role of SiO 2 on the optical responses of the films but also on the structural, mechanical, and photocatalytic properties, important requirements to go toward real applications. We demonstrate that adding SiO 2 to porous TiO 2 allows tuning and suppression of structural colors through refractive index matching and up to 160% increase in mechanical stiffening of the films. This study leads us to demonstrate an example of "invisible" coating, in which the light reflection is angle- and thickness-independent, and exhibiting high porosity, mechanical stiffness, and photoactivity.

  15. ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR.

    Science.gov (United States)

    Li, Yan; Wang, Kai; Zou, Qing-Yun; Jiang, Yi-Zhou; Zhou, Chi; Zheng, Jing

    2017-12-01

    Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor is involved in regulation of many essential biological processes including vascular development and angiogenesis. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an AhR ligand, which regulates immune responses and cancer cell growth. However, the roles of the ITE/AhR pathway in mediating placental angiogenesis remains elusive. Here, we determined if ITE affected placental angiogenic responses via AhR in human umbilical vein (HUVECs) and artery endothelial (HUAECs) cells in vitro. We observed that ITE dose- and time-dependently inhibited proliferation and viability of HUAECs and HUVECs, whereas it inhibited migration of HUAECs, but not HUVECs. While AhR siRNA significantly suppressed AhR protein expression in HUVECs and HUAECs, it attenuated the ITE-inhibited angiogenic responses of HUAECs, but not HUVECs. Collectively, ITE suppressed angiogenic responses of HUAECs and HUVECs, dependent and independent of AhR, respectively. These data suggest that ITE may regulate placental angiogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Role of CD44 in Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis

    National Research Council Canada - National Science Library

    Sherman, Larry

    2003-01-01

    Malignant peripheral nerve sheath tumors (MPNST) are aggressive, difficult to treat tumors that occur in type I neurofibromatosis patients with an increased incidence compared to the general population...

  17. Role of CD44 in Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis

    National Research Council Canada - National Science Library

    Sherman, Larry

    2001-01-01

    Malignant peripheral nerve sheath tumors (MPNST) are aggressive, difficult to treat tumors that occur in type I neurofibromatosis patients with an increased incidence compared to the general population...

  18. RNAi-mediated knockdown of pituitary tumor-transforming gene-1 (PTTG1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells

    International Nuclear Information System (INIS)

    Huang, S.Q.; Liao, Q.J.; Wang, X.W.; Xin, D.Q.; Chen, S.X.; Wu, Q.J.; Ye, G.

    2012-01-01

    Pituitary tumor-transforming gene-1 (PTTG1) is a proto-oncogene that promotes tumorigenesis and metastasis in numerous cell types and is overexpressed in a variety of human tumors. We have demonstrated that PTTG1 expression was up-regulated in both human prostate cancer specimens and prostate cancer cell lines. For a more direct assessment of the function of PTTG1 in prostate tumorigenesis, RNAi-mediated knockdown was used to selectively decrease PTTG1 expression in PC3 human prostate tumor cells. After three weeks of selection, colonies stably transfected with PTTG1-targeted RNAi (the knockdown PC3 cell line) or empty vector (the control PC3 cell line) were selected and expanded to investigate the role of PTTG1 expression in PC3 cell growth and invasion. Cell proliferation rate was significantly slower (28%) in the PTTG1 knockdown line after 6 days of growth as indicated by an MTT cell viability assay (P < 0.05). Similarly, a soft agar colony formation assay revealed significantly fewer (66.7%) PTTG1 knockdown PC3 cell colonies than control colonies after three weeks of growth. In addition, PTTG1 knockdown resulted in cell cycle arrest at G1 as indicated by fluorescence-activated cell sorting. The PTTG1 knockdown PC3 cell line also exhibited significantly reduced migration through Matrigel in a transwell assay of invasive potential, and down-regulation of PTTG1 could lead to increased sensitivity of these prostate cancer cells to a commonly used anticancer drug, taxol. Thus, PTTG1 expression is crucial for PC3 cell proliferation and invasion, and could be a promising new target for prostate cancer therapy

  19. The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Markus Schosserer

    2017-11-01

    situations and signals, which induce senescence. Among them, oncogene-induced senescence and stress-induced premature senescence are prominent. New findings about the role of senescence in tumor biology are critically reviewed with respect to new suggestions for cancer therapy leveraging genetic and pharmacological methods to prevent senescence or to selectively kill senescent cells in tumors.

  20. The Role of Chemotherapy in Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors.

    Science.gov (United States)

    Strosberg, Jonathan; Goldman, Jamie; Costa, Frederico; Pavel, Marianne

    2015-01-01

    Even though the neuroendocrine tumor (NET) field has entered the era of 'targeted therapy', the role of cytotoxic chemotherapy continues to be debated. High response rates, ranging from 30 to 70% depending on the line of therapy, are consistently observed in the treatment of pancreatic NETs, with lesser evidence of activity in other foregut tumors. Activity in midgut carcinoid tumors appears to be negligible. Unfortunately, placebo-controlled randomized controlled trials using modern response criteria are lacking: the bulk of the literature consists of small phase II trials and retrospective series. There are also no completed trials comparing modern chemotherapy regimens, and therefore little data exist to favor the use of streptozocin- versus temozolomide- versus oxaliplatin-based therapies. Due to the absence of high-level evidence, it is difficult to generate data-based guidelines on the appropriate sequencing of cytotoxic drugs versus targeted agents. Although conventional wisdom holds that targeted agents such as everolimus or sunitinib are more tolerable than cytotoxic drugs, there is no evidence to support this perception. As a general principle, chemotherapy may be more appropriate as early-line therapy in patients with bulky and/or symptomatic and/or rapidly progressive tumors, particularly of pancreatic origin. In patients with low-volume disease or slow-growing tumors, noncytotoxic drugs may be preferable in early lines of therapy, reserving chemotherapy for the salvage setting. Validation of predictive factors is imperative in order to appropriately match patients with optimal treatment. Methyl-guanine-methyl-transferase (MGMT) deficiency is likely to be a positive predictive factor for alkylating agents, but needs to be evaluated prospectively. It is also unclear whether immunostaining for MGMT expression, which can be somewhat subjective, is superior to PCR-based techniques, which assess MGMT methylation status. Other basic predictive factors, such

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

    Science.gov (United States)

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

    2017-01-01

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

  2. Video-rate resonant scanning multiphoton microscopy: An emerging technique for intravital imaging of the tumor microenvironment

    OpenAIRE

    Kirkpatrick, Nathaniel D.; Chung, Euiheon; Cook, Daniel C.; Han, Xiaoxing; Gruionu, Gabriel; Liao, Shan; Munn, Lance L.; Padera, Timothy P.; Fukumura, Dai; Jain, Rakesh K.

    2012-01-01

    The abnormal tumor microenvironment fuels tumor progression, metastasis, immune suppression, and treatment resistance. Over last several decades, developments in and applications of intravital microscopy have provided unprecedented insights into the dynamics of the tumor microenvironment. In particular, intravital multiphoton microscopy has revealed the abnormal structure and function of tumor-associated blood and lymphatic vessels, the role of aberrant tumor matrix in drug delivery, invasion...

  3. Critical role of tumor necrosis factor receptor 1 in the pathogenesis of pulmonary emphysema in mice.

    Science.gov (United States)

    Fujita, Masaki; Ouchi, Hiroshi; Ikegame, Satoshi; Harada, Eiji; Matsumoto, Takemasa; Uchino, Junji; Nakanishi, Yoichi; Watanabe, Kentaro

    2016-01-01

    COPD is a major cause of chronic morbidity and mortality throughout the world. Although tumor necrosis factor-α (TNF-α) has a critical role in the development of COPD, the role of different TNF receptors (TNFRs) in pulmonary emphysema has not been resolved. We aimed to clarify the role of TNFRs in the development of pulmonary emphysema. TNF-α transgenic mice, a murine model of COPD in which the mice spontaneously develop emphysema with a large increase in lung volume and pulmonary hypertension, were crossed with either TNFR1-deficient mice or TNFR2-deficient mice. After 6 months, the gross appearance of the lung, lung histology, and pulmonary and cardiac physiology were determined. In addition, the relationship between apoptosis and emphysema was investigated. Pulmonary emphysema-like changes disappeared with deletion of TNFR1. However, slight improvements were attained with deletion of TNFR2. Apoptotic cells in the interstitium of the lung were observed in TNF-α transgenic mice. The apoptotic signals through TNFR1 appear critical for the pathogenesis of pulmonary emphysema. In contrast, the inflammatory process has a less important role for the development of emphysema.

  4. The role of adjuvant radiotherapy in the treatment of resectable desmoid tumors

    International Nuclear Information System (INIS)

    Goy, Barry W.; Lee, Steve P.; Eilber, Frederick; Dorey, Fred; Eckardt, Jeffrey; Fu, Yao-Shi; Juillard, Guy J. F.; Selch, Michael T.

    1997-01-01

    control with adjuvant radiotherapy, but this was not statistically significant. None of the patients treated with radiotherapy developed serious complications or a secondary malignancy. Conclusions: Margin status is the most important predictor of local recurrence for patients with resectable, unifocal desmoid tumor. Adjuvant radiotherapy is indicated in the treatment of patients with positive margins following wide excision of recurrent disease. The role of adjuvant radiotherapy in patients with positive margins following resection of primary disease is controversial, and should be based on a balanced discussion of the potential morbidity from radiotherapy compared to the potential morbidity of another local recurrence. Adjuvant radiotherapy is less likely to benefit those with clear margins due to the excellent results for these patients treated with surgery alone. The local control of desmoid tumor in the adjuvant setting is excellent with total doses ranging from 50-60 Gy, with acceptable morbidity. Field sizes should be generous to prevent marginal recurrences, and large volume MRIs of patients with extremity lesions should be used to identify those patients with multifocal disease

  5. The role of preoperative serum cancer antigen 125 in malignant ovarian germ cell tumors

    Directory of Open Access Journals (Sweden)

    Ju-Hyun Kim

    2018-04-01

    Full Text Available Objective: To determine the role of preoperative serum cancer antigen 125 (CA 125 in malignant ovarian germ cell tumors (MOGCTs. Materials and methods: Using information from medical databases of Asan Medical Center (Seoul, Korea, we investigated 161 patients with histologically diagnosed MOGCTs and whose preoperative serum CA 125 had been checked. We determined the optimal cutoff value of CA 125 as > 249.5 U/mL in MOGCTs using a receiver operating characteristic curve. Results: The median patient age was 24 years (range, 6–52 years. The most common histologic type was immature teratoma. Most patients had stage I disease. Thirty-two patients (19.9% had elevated preoperative serum CA 125 levels over 249.5 U/mL. On univariate analysis, tumor size, advanced stage, the presence of ascites, ovarian surface involvement, and tumor rupture were significantly associated with elevated preoperative CA 125 levels (>249.5 U/mL. In the median follow-up time of 87 months (range, 9–271 months, 14 patients had a recurrence, and 5 died of the disease. Patients with an elevated serum preoperative CA 125 level (>249.5 U/mL had poorer disease-free survival, but this was not statistically significant. However, elevated preoperative CA 125 (>249.5 U/mL was significantly associated with poorer overall survival. Conclusions: Elevated preoperative serum CA 125 may have prognostic value in patients with MOGCTs. Keywords: CA-125 antigen, Ovarian germ cell cancer, Prognosis

  6. [Angiotensin converting enzyme: the antigenic properties of the domain, role in Alzheimer's disease and tumor progression].

    Science.gov (United States)

    Kugaevskaya, E V; Timoshenko, O S; Solovyeva, N I

    2015-01-01

    Angiotensin converting enzyme (ACE, EC 3.4.15.1) was discovered and characterized in the Laboratory of biochemistry and chemical pathology of proteins under the direction of academician V.N. Orekhovich, where its physiological function, associated with a key role in the regulation of the renin-angiotensin (RAS) and the kallikrein-kinin systems that control blood flow in the body and homeostasis was first deciphered. We carried out a search for structural differences between the two highly homologous domains (N- and C-domains) of somatic ACE (sACE); it was based on a comparative analysis of antigenic determinants (or B-epitopes) of both domains. The revealed epitopes were classified with variable and conserved regions and functionally important sites of the molecule ACE. Essential difference was demonstrated between locations of the epitopes in the N- and C-domains. These data indicate the existence of structural differences between the domains of sACE. We studied the role of the domains of ACE in the metabolism of human amyloid beta peptide (Ab) - the main component of senile plaques, found in the brains of patients with Alzheimer's disease (AD). Our results demonstrated that only N-domain ACE cleaved the Ab between residues R5-H6, while, the C-domain of ACE failed to hydrolyze this region. In addition, the effect of post-translational modifications of Ab on its hydrolysis by the ACE was investigated. We show that isomerization of residue D7, a common non-enzymatic age-related modification found in AD-associated species, does not reduce the affinity of the peptide to the N-domain of ACE, and conversely, it increases. According to our data, the role of ACE in the metabolism of Ab becomes more significant in the development of AD. RAS is involved in malignant transformation and tumor progression. RAS components, including ACE and angiotensin II receptors type 1 (AT1R) are expressed in various human tumors. We found a significant increase in the level of ACE activity

  7. Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

    DEFF Research Database (Denmark)

    Quintana, Albert; Giralt, Mercedes; Rojas, Santiago

    2005-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracell......Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via...... intracellular signaling. This cytokine exerts its functions via interaction with two receptors: type-1 receptor (TNFR1) and type-2 receptor (TNFR2). In this work, the inflammatory response after a freeze injury (cryolesion) in the cortex was studied in wild-type (WT) animals and in mice lacking TNFR1 (TNFR1 KO...... signaling also affected the expression of apoptosis/cell death-related genes (Fas, Rip, p53), matrix metalloproteinases (MMP3, MMP9, MMP12), and their inhibitors (TIMP1), suggesting a role of TNFR1 in extracellular matrix remodeling after injury. However, GDNF, NGF, and BDNF expression were not affected...

  8. The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors

    International Nuclear Information System (INIS)

    Daya-Grosjean, Leela; Sarasin, Alain

    2005-01-01

    Xeroderma pigmentosum (XP), a rare hereditary syndrome, is characterized by a hypersensitivity to solar irradiation due to a defect in nucleotide excision repair resulting in a predisposition to squamous and basal cell carcinomas as well as malignant melanomas appearing at a very early age. The mutator phenotype of XP cells is evident by the higher levels of UV specific modifications found in key regulatory genes in XP skin tumors compared to those in the same tumor types from the normal population. Thus, XP provides a unique model for the study of unrepaired DNA lesions, mutations and skin carcinogenesis. The high level of ras oncogene activation, Ink4a-Arf and p53 tumor suppressor gene modifications as well as alterations of the different partners of the mitogenic sonic hedgehog signaling pathway (patched, smoothened and sonic hedgehog), characterized in XP skin tumors have clearly demonstrated the major role of the UV component of sunlight in the development of skin tumors. The majority of the mutations are C to T or tandem CC to TT UV signature transitions, occurring at bipyrimidine sequences, the specific targets of UV induced lesions. These characteristics are also found in the same genes modified in sporadic skin cancers but with lower frequencies confirming the validity of studying the XP model. The knowledge gained by studying XP tumors has given us a greater perception of the contribution of genetic predisposition to cancer as well as the consequences of the many alterations which modulate the activities of different genes affecting crucial pathways vital for maintaining cell homeostasis

  9. The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors

    Energy Technology Data Exchange (ETDEWEB)

    Daya-Grosjean, Leela [Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, IFR 54, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex (France)]. E-mail: daya@igr.fr; Sarasin, Alain [Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, IFR 54, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex (France)

    2005-04-01

    Xeroderma pigmentosum (XP), a rare hereditary syndrome, is characterized by a hypersensitivity to solar irradiation due to a defect in nucleotide excision repair resulting in a predisposition to squamous and basal cell carcinomas as well as malignant melanomas appearing at a very early age. The mutator phenotype of XP cells is evident by the higher levels of UV specific modifications found in key regulatory genes in XP skin tumors compared to those in the same tumor types from the normal population. Thus, XP provides a unique model for the study of unrepaired DNA lesions, mutations and skin carcinogenesis. The high level of ras oncogene activation, Ink4a-Arf and p53 tumor suppressor gene modifications as well as alterations of the different partners of the mitogenic sonic hedgehog signaling pathway (patched, smoothened and sonic hedgehog), characterized in XP skin tumors have clearly demonstrated the major role of the UV component of sunlight in the development of skin tumors. The majority of the mutations are C to T or tandem CC to TT UV signature transitions, occurring at bipyrimidine sequences, the specific targets of UV induced lesions. These characteristics are also found in the same genes modified in sporadic skin cancers but with lower frequencies confirming the validity of studying the XP model. The knowledge gained by studying XP tumors has given us a greater perception of the contribution of genetic predisposition to cancer as well as the consequences of the many alterations which modulate the activities of different genes affecting crucial pathways vital for maintaining cell homeostasis.

  10. Pancreatic Neuroendocrine Tumors With Involved Surgical Margins: Prognostic Factors and the Role of Adjuvant Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Arvold, Nils D. [Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA (United States); Willett, Christopher G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Fernandez-del Castillo, Carlos [Department of Surgery, Massachusetts General Hospital, Boston, MA (United States); Ryan, David P. [Department of Medicine, Massachusetts General Hospital, Boston, MA (United States); Ferrone, Cristina R. [Department of Surgery, Massachusetts General Hospital, Boston, MA (United States); Clark, Jeffrey W.; Blaszkowsky, Lawrence S. [Department of Medicine, Massachusetts General Hospital, Boston, MA (United States); Deshpande, Vikram [Department of Pathology, Massachusetts General Hospital, Boston, MA (United States); Niemierko, Andrzej [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); Allen, Jill N.; Kwak, Eunice L.; Wadlow, Raymond C.; Zhu, Andrew X. [Department of Medicine, Massachusetts General Hospital, Boston, MA (United States); Warshaw, Andrew L. [Department of Surgery, Massachusetts General Hospital, Boston, MA (United States); Hong, Theodore S., E-mail: Tshong1@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States)

    2012-07-01

    Purpose: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. Methods and Materials: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). Results: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. Conclusions: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further

  11. Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition.

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    Serena Battaglia

    Full Text Available BACKGROUND: Chronic hepatitis C virus (HCV infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. PRINCIPAL FINDINGS: We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT, a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. CONCLUSION/SIGNIFICANCE: Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.

  12. Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: comparison between RU486 and a new 21-substituted-19-nor-progestin.

    Science.gov (United States)

    Wiehle, Ronald D; Christov, Konstantin; Mehta, Rajendra

    2007-07-01

    In this report, we evaluate the effects of a 21-substituted-19-nor-progestin, CDB-4124, on 7,12,-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats in comparison with RU486. Sprague-Dawley female rats were treated with DMBA at 50 days of age in order to induce mammary tumors. When the tumors reached the size of 10-12 mm, the animals were treated for 28 days with the vehicle, RU486, progesterone, CDB-4124 at various doses, or CDB-4124 plus progesterone. Anti-progestins resulted in the regression in the size of the existing tumors, and in the suppressed development of new tumors and tumor multiplicity. Progesterone treatment, however, increased the size and multiplicity. Progesterone rendered an increased number of growing tumors as compared to the regression in the anti-progesterone treatment groups. The combination of CDB-4124 and high doses of progesterone opposed the efficacy of CDB-4124. The growth inhibitory effects of the anti-progestins were correlated with increased apoptosis and reduced cell proliferation. These results indicate that anti-progestins should be developed for the chemoprevention and treatment of hormone-responsive breast cancer.

  13. The Emerging Role of Polo-Like Kinase 1 in Epithelial-Mesenchymal Transition and Tumor Metastasis

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    Zheng Fu

    2017-09-01

    Full Text Available Polo-like kinase 1 (PLK1 is a serine/threonine kinase that plays a key role in the regulation of the cell cycle. PLK1 is overexpressed in a variety of human tumors, and its expression level often correlates with increased cellular proliferation and poor prognosis in cancer patients. It has been suggested that PLK1 controls cancer development through multiple mechanisms that include canonical regulation of mitosis and cytokinesis, modulation of DNA replication, and cell survival. However, emerging evidence suggests novel and previously unanticipated roles for PLK1 during tumor development. In this review, we will summarize the recent advancements in our understanding of the oncogenic functions of PLK1, with a focus on its role in epithelial-mesenchymal transition and tumor invasion. We will further discuss the therapeutic potential of these functions.

  14. EG-03EXPRESSION OF PRMT5 CORRELATES WITH MALIGNANT GRADE IN GLIOMAS AND PLAYS A PIVOTAL ROLE IN TUMOR GROWTH

    Science.gov (United States)

    Han, Xiaosi; Li, Rong; Zhang, Wenbin; Yang, Xiuhua; Fathallah-Shaykh, Hassan; Gillespie, Yancey; Nabors, Burt

    2014-01-01

    Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. The modification play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

  15. A role for suppressed skeletal muscle thermogenesis in pathways from weight fluctuations to the insulin resistance syndrome.

    Science.gov (United States)

    Dulloo, A G

    2005-08-01

    An impressive body of epidemiological evidence suggests that a history of large perturbations in body weight earlier in life, independently of excess weight, is a risk factor for later development of insulin-related complications, namely central obesity, type 2 diabetes and cardiovascular disease. Such an increased risk has been reported in men and women who in young adulthood experienced weight fluctuations that involved weight recovery after weight loss caused by disease, famine or voluntary 'yoyo' dieting, and is particularly strong when the weight fluctuations occurred much earlier in life and are characterized by catch-up growth after foetal and/or neonatal growth retardation. As the phase of weight recovery/catch-up growth is associated with both hyperinsulinaemia and an accelerated rate for recovering fat mass (i.e. catch-up fat), the questions arise as to whether, why and how processes that regulate catch-up fat might predispose to hyperinsulinaemia and to insulin-related diseases. In addressing these issues, this paper first reviews evidence for the existence of an adipose-specific control of thermogenesis, whose suppression contributes to the phenomenon of catch-up fat during weight recovery/catch-up growth. It subsequently concentrates upon recent findings suggesting that: (i) such suppression of thermogenesis directed at catch-up fat is accompanied by a redistribution of glucose from skeletal muscle to white adipose tissue, and (ii) substrate cycling between de novo lipogenesis and lipid oxidation can operate as a thermogenic effector in skeletal muscle in response to signalling interactions between leptin and insulin - two key 'adiposity' hormones implicated in the peripheral control of substrate metabolism. These new findings are integrated into the proposal that, in its 'evolutionary adaptive' role to spare glucose for rapid rebuilding of the fat stores, suppressed thermogenesis in skeletal muscle - via inhibition of substrate cycling between de novo

  16. Respective roles and interactions of T-lymphocyte and PGE2-mediated monocyte suppressive activities in human newborns and mothers at the time of delivery

    International Nuclear Information System (INIS)

    Durandy, A.; Fischer, A.; Mamas, S.; Dray, F.; Griscelli, C.

    1982-01-01

    Recently the concept of a poorly functional humoral immune response in the newborn was proposed. Data have been presented indicating that the impaired newborn B cell maturation, as shown in vitro in a pokeweed mitogen-induced B cell maturation system, is due both to an immaturity of lymphocyte subsets and to an increased suppressive T activity. In the present work, we present evidence that there exists a predominance of a naturally occurring T lymphocyte suppressive activity in the cord blood in that the removal of the suppressive activity by irradiation allows a normal maturation of newborn B cells. Such normal maturation of newborn B cells can also be obtained using mixed cultures of adult T cells and newborn B cells. Newborn suppressor T cells belong to both EA gamma (+) and EA gamma (-) fractions, and it is not known whether these two groups do or do not belong to different subsets. The PGE2-dependent monocyte suppressive activity does not play any role in the suppression observed in newborns since newborn monocytes are poorly suppressive and since they produce a smaller amount of PGE2 than adult monocytes. Some observations suggest, on the contrary, that the suppressive T lymphocytes can regulate the level of the PGE2-dependent monocyte suppressive activity. It should be noticed that similar observations about T lymphocyte and PGE2-dependent monocyte suppressive activities have been made at the same time using mothers' cells. These observations suggest the possibility that such changes in B cell immune regulation may result from an interaction between maternal and fetal lymphoid cells

  17. Multifunctional roles of leader protein of foot-and-mouth disease viruses in suppressing host antiviral responses.

    Science.gov (United States)

    Liu, Yingqi; Zhu, Zixiang; Zhang, Miaotao; Zheng, Haixue

    2015-10-28

    Foot-and-mouth disease virus (FMDV) leader protein (L(pro)) is a papain-like proteinase, which plays an important role in FMDV pathogenesis. L(pro) exists as two forms, Lab and Lb, due to translation being initiated from two different start codons separated by 84 nucleotides. L(pro) self-cleaves from the nascent viral polyprotein precursor as the first mature viral protein. In addition to its role as a viral proteinase, L(pro) also has the ability to antagonize host antiviral effects. To promote FMDV replication, L(pro) can suppress host antiviral responses by three different mechanisms: (1) cleavage of eukaryotic translation initiation factor 4 γ (eIF4G) to shut off host protein synthesis; (2) inhibition of host innate immune responses through restriction of interferon-α/β production; and (3) L(pro) can also act as a deubiquitinase and catalyze deubiquitination of innate immune signaling molecules. In the light of recent functional and biochemical findings regarding L(pro), this review introduces the basic properties of L(pro) and the mechanisms by which it antagonizes host antiviral responses.

  18. Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory.

    Directory of Open Access Journals (Sweden)

    Fraser T Sparks

    Full Text Available Damage to the hippocampus (HPC using the excitotoxin N-methyl-D-aspartate (NMDA can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX, a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours or remote (5 weeks time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.

  19. Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: Involvement of the RB-microRNA axis

    International Nuclear Information System (INIS)

    Liu, Xianpeng; Gu, Xin; Sun, Limin; Flowers, Ashley B; Rademaker, Alfred W; Zhou, Yiran; Kiyokawa, Hiroaki

    2014-01-01

    The HECT family ubiquitin ligase Smurf2 regulates cell polarity, migration, division, differentiation and death, by targeting diverse substrates that are critical for receptor signaling, cytoskeleton, chromatin remodeling and transcription. Recent studies suggest that Smurf2 functions as a tumor suppressor in mice. However, no inactivating mutation of SMURF2 has been reported in human, and information about Smurf2 expression in human cancer remains limited or complicated. Here we demonstrate that Smurf2 expression is downregulated in human breast cancer tissues, especially of the triple-negative subtype, and address the mechanism of Smurf2 downregulation in triple-negative breast cancer cells. Human breast cancer tissues (47 samples expressing estrogen receptor (ER) and 43 samples with triple-negative status) were examined by immunohistochemistry for the expression of Smurf2. Ten widely-studied human breast cancer cell lines were examined for the expression of Smurf2. Furthermore, microRNA-mediated regulation of Smurf2 was investigated in triple-negative cancer cell lines. Immunohistochemical analysis showed that benign mammary epithelial cells expressed high levels of Smurf2, so did cells in ductal carcinomas in situ. In contrast, invasive ductal carcinomas showed focal or diffuse decrease in Smurf2 expression, which was observed more frequently in triple-negative tumors than in ER-positive tumors. Consistently, human triple-negative breast cancer cell lines such as BT549, MDA-MB-436, DU-4475 and MDA-MB-468 cells showed significantly lower expression of Smurf2 protein, compared to ER + or HER2+ cell lines. Studies using quantitative PCR and specific microRNA inhibitors indicated that increased expression of miR-15a, miR-15b, miR-16 and miR-128 was involved in Smurf2 downregulation in those triple-negative cancer cell lines, which have mutations in the retinoblastoma (RB) gene. Forced expression of RB increased levels of Smurf2 protein with concomitant decreases in

  20. The role of chronic acanthosis and subacute inflammation in tumor promotion in CD-1 mice by petroleum middle distillates.

    Science.gov (United States)

    Skisak, C

    1991-07-01

    An initiation-promotion bioassay using CD-1 mice was conducted to examine the role of chronic acanthosis and inflammation in tumor promotion by petroleum middle distillates (MD). Test groups were initiated with 7,12-dimethylbenz[a]anthracene (DMBA). Promotion with MD consisted of twice weekly treatments for 25 weeks with either 25 or 50 microliters, 50 microliters + daily treatment with 15 micrograms dexamethasone, 50 microliters + postapplication washings, or 100 microliters. Three mice from each group were euthanized at 21-day intervals (24 total per group). The skin from interim euthanized mice was examined histopathologically for tumors, acanthosis, and subacute inflammation. Tumor incidence at study termination was as follows: 25 microliters (45%), 50 microliters (43%), 50 microliters + dexamethasone (0%), 50 microliters + washing (70%), and 100 microliters (81%). A correlation of greater than 0.93 was observed at all intervals between tumor incidence and cumulative group mean degrees of acanthosis in interim euthanized mice. The correlation between subacute inflammation at early through midstudy interval weeks and tumor incidence at study termination was poor. These results support the hypothesis that induction of a lasting, albeit mild, hyperplasia is an essential, but not sufficient requirement for tumor promotion. Furthermore, subacute inflammation does not appear to be a significant factor in tumor promotion by petroleum MD.

  1. A hypothesis about the potential role of statin administration as adjuvant treatment in the management of Merlin-deficient tumors

    Directory of Open Access Journals (Sweden)

    Alexandros G. Brotis, MD, PhD

    2014-03-01

    Full Text Available Merlin, a tumor suppressor protein, controls essential steps of cell cycle, and its deficiency results in cellular overgrowth, proliferation, angiogenesis, invasion and metastasis. Lack of Merlin is responsible for neurofibromatosis-2, most schwannomas, and many meningiomas and ependymomas. We hypothesize that there is a role for statins to ameliorate Merlin's deficiency in this set of tumors by inhibiting a number of Merlin's downstream effectors, the small Rho-GTP-ases, and we present the relevant data. The ultimate goal is to offer a medical therapy promising to halt or reduce the tumor growth-rate in patients harboring Merlin-deficient neoplasms and to provide an adjuvant systemic therapy for patients undergoing stereotactic radio-surgery and partial tumor resection.

  2. Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma

    NARCIS (Netherlands)

    Pardali, E.; Schaft, van der D.W.J.; Wiercinska, E.; Gorter, A.; Hogendoorn, P.C.W.; Griffioen, A.W.; Dijke, ten P.

    2011-01-01

    Tumor cell plasticity enables certain types of highly malignant tumor cells to dedifferentiate and engage a plastic multipotent embryonic-like phenotype, which enables them to ‘adapt’ during tumor progression and escape conventional therapeutic strategies. This plastic phenotype of aggressive cancer

  3. Role of cyclic nucleotide-dependent actin cytoskeletal dynamics:Ca(2+](i and force suppression in forskolin-pretreated porcine coronary arteries.

    Directory of Open Access Journals (Sweden)

    Kyle M Hocking

    Full Text Available Initiation of force generation during vascular smooth muscle contraction involves a rise in intracellular calcium ([Ca(2+]i and phosphorylation of myosin light chains (MLC. However, reversal of these two processes alone does not account for the force inhibition that occurs during relaxation or inhibition of contraction, implicating that other mechanisms, such as actin cytoskeletal rearrangement, play a role in the suppression of force. In this study, we hypothesize that forskolin-induced force suppression is dependent upon changes in actin cytoskeletal dynamics. To focus on the actin cytoskeletal changes, a physiological model was developed in which forskolin treatment of intact porcine coronary arteries (PCA prior to treatment with a contractile agonist resulted in complete suppression of force. Pretreatment of PCA with forskolin suppressed histamine-induced force generation but did not abolish [Ca(2+]i rise or MLC phosphorylation. Additionally, forskolin pretreatment reduced filamentous actin in histamine-treated tissues, and prevented histamine-induced changes in the phosphorylation of the actin-regulatory proteins HSP20, VASP, cofilin, and paxillin. Taken together, these results suggest that forskolin-induced complete force suppression is dependent upon the actin cytoskeletal regulation initiated by the phosphorylation changes of the actin regulatory proteins and not on the MLC dephosphorylation. This model of complete force suppression can be employed to further elucidate the mechanisms responsible for smooth muscle tone, and may offer cues to pathological situations, such as hypertension and vasospasm.

  4. The Role of Tumor Necrosis Factor- alpha and Resistin in Nonalcoholic Fatty Liver Disease

    International Nuclear Information System (INIS)

    Alkady, M.M.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver diseases. It is strongly associated with obesity and insulin resistance and is thought to be a part of the metabolic syndrome. It can progress from simple fatty liver to steatohepatitis, cirrhosis and liver failure. Adipocytokines, synthesized in adipose tissue, are involved in the pathophysiology of many acute and chronic liver diseases. The aim of this study was to investigate the role of Tumor Necrosis Factor-alpha (TNF-alpha) and resistin in the pathogenesis of NAFLD and their correlation to the severity of the disease. Serum concentration of TNF-alpha and resistin were measured in 20 patients with NAFLD and 20 healthy controls with ELISA method. The results of this study revealed that serum levels of both adipokines were significantly elevated in NAFLD patients than controls (P<0.01). Moreover, they were significantly higher in patients with nonalcoholic steatohepatitis than in patients with simple fatty liver. There was a significant positive correlation between TNF-alpha, resistin and each of AST, ALT and HOMA. Similarly, the results showed a significant positive correlation between the two studied adipokines, TNF-alpha and resistin (P<0.001). We conclude that TNF-alpha and resistin have a role in the pathogenesis of NAFLD and they may be promising markers for the progressin to steatohepatitis and inhibition of their activities by drugs may be a new approach for the treatment of NAFLD

  5. Exploring the role of CHI3L1 in pre-metastatic lungs of mammary tumor-bearing mice

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    Stephania eLibreros

    2013-12-01

    Full Text Available Elevated levels of chitinase-3-like-1 (CHI3L1 are associated with poor prognosis, shorter recurrence-free intervals and low survival in breast cancer patients. Breast cancer often metastasizes to the lung. We hypothesized that molecules expressed in the pre-metastatic lung microenvironment could support the newly immigrant tumor cells by providing growth and angiogenic factors. Macrophages are known to play an important role in tumor growth by releasing pro-angiogenic molecules. Using mouse mammary tumor models, we have previously shown that during neoplastic progression both the mammary tumor cells and splenic macrophages from tumor-bearing mice express higher levels of CHI3L1 compared to normal control mice. However, the role of CHI3L1 in inducing angiogenesis by macrophages at the pulmonary microenvironment to support newly arriving breast cancer cells is not yet known. In this study, we determined the expression of CHI3L1 in bronchoalveolar lavage macrophages and interstitial macrophages in regulating angiogenesis that could support the growth of newly immigrant mammary tumor cells into the lung. Here we show that in vitro treatment of pulmonary macrophages with recombinant murine CHI3L1 resulted in enhanced expression of pro-angiogenic molecules including CCL2, CXCL2 and MMP-9. We and others have previously shown that inhibition of CHI3L1 decreases the production of angiogenic molecules. In this study, we explored if in vivo administration of chitin microparticles has an effect on the expression of CHI3L1 and pro-angiogenic molecules in the lungs of mammary tumor-bearing mice. We show that treatment with chitin microparticles decreases the expression of CHI3L1 and pro-angiogenic molecules in the metastatic lung. These studies suggest that targeting CHI3L1 may serve as a potential therapeutic agent to inhibit angiogenesis and thus possibly tumor growth and metastasis.

  6. The role of chemotherapy in the treatment of patients with brain metastases from solid tumors

    International Nuclear Information System (INIS)

    Walbert, T.; Gilbert, M.R.

    2009-01-01

    Brain metastases are the most frequent cancer in the central nervous system, being ten times more common than primary brain tumors. Patients generally have a poor outcome with a median survival of 4 months after diagnosis of the metastases. Therapeutic options include surgery, stereotactic, radiosurgery, whole-brain radiotherapy (WBRT), and chemotherapy. Patients with a limited number of brain metastases and well-controlled systemic cancer benefit from brain metastases-specific therapies, including surgery, radiosurgery, and conventional radiation. The role of chemotherapy for brain metastases remains limited. There is concern about drug delivery because of the blood-brain barrier. However, higher response rates are noted with initial therapies, suggesting that part of the poor response rate may be related to the late onset of brain metastases and the use of second- and third-line regimens. Recent studies have demonstrated objective responses with systemic therapy in a variety of cancer types, especially when combined with WBRT. Individual therapeutic strategies for central nervous system metastases must be chosen based on performance status, the extent of intracranial disease, and the chemosensitivity of the underlying tumor, as well as the control of the systemic cancer. In this article we review important prognostic factors and challenges in using chemotherapy. We specifically review recent advances in the treatment of brain metastases from breast and lung cancer as well as melanoma. Future treatment advances will require a multidisciplinary approach integrating surgical, radiation, and chemotherapeutic options to improve neurological function and quality of life, rather than just focusing on survival endpoints. (author)

  7. Tumor Hypoxia: Causative Mechanisms, Microregional Heterogeneities, and the Role of Tissue-Based Hypoxia Markers.

    Science.gov (United States)

    Vaupel, Peter; Mayer, Arnulf

    Tumor hypoxia is a hallmark of solid malignant tumor growth, profoundly influences malignant progression and contributes to the development of therapeutic resistance. Pathogenesis of tumor hypoxia is multifactorial, with contributions from both acute and chronic factors. Spatial distribution of hypoxia within tumors is markedly heterogeneous and often changes over time, e.g., during a course of radiotherapy. Substantial changes in the oxygenation status can occur within the distance of a few cell layers, explaining the inability of currently used molecular imaging techniques to adequately assess this crucial trait. Due to the possible importance of tumor hypoxia for clinical decision-making, there is a great demand for molecular tools which may provide the necessary resolution down to the single cell level. Exogenous and endogenous markers of tumor hypoxia have been investigated for this purpose. Their potential use may be greatly enhanced by multiparametric in situ methods in experimental and human tumor tissue.

  8. An active role for endogenous beta-1,3-glucanase genes in transgene-mediated co-suppression in tobacco.

    Science.gov (United States)

    Sanders, Matthew; Maddelein, Wendy; Depicker, Anna; Van Montagu, Marc; Cornelissen, Marc; Jacobs, John

    2002-11-01

    Post-transcriptional gene silencing (PTGS) is characterized by the accumulation of short interfering RNAs that are proposed to mediate sequence-specific degradation of cognate and secondary target mRNAs. In plants, it is unclear to what extent endogenous genes contribute to this process. Here, we address the role of the endogenous target genes in transgene-mediated PTGS of beta-1,3-glucanases in tobacco. We found that mRNA sequences of the endogenous glucanase glb gene with varying degrees of homology to the Nicotiana plumbaginifolia gn1 transgene are targeted by the silencing machinery, although less efficiently than corresponding transgene regions. Importantly, we show that endogene-specific nucleotides in the glb sequence provide specificity to the silencing process. Consistent with this finding, small sense and antisense 21- to 23-nucleotide RNAs homologous to the endogenous glb gene were detected. Combined, these data demonstrate that a co-suppressed endogenous glucan ase gene is involved in signal amplification and selection of homologous targets, and show that endogenous genes can actively participate in PTGS in plants. The findings are introduced as a further sophistication of the post-transciptional silencing model.

  9. The effect of intense intermittent training with and without taking vitamin E on mRNA expression of p53/PTEN tumor suppressing genes in prostate glands of male rats

    Directory of Open Access Journals (Sweden)

    Mohammad Esmaeil Afzalpour

    2016-11-01

    Full Text Available Physical activity and diet are the most important modifiable determinants of cancer risk. The objective of this study was to examine the effect of intense intermittent training with and without taking vitamin E on expression of p53 and PTEN tumor suppressing genes in the prostate gland of male rats. For this purpose, 50 Sprague-Dawley male rats were randomly assigned into 5 groups: [1] control (CON, n = 10, [2] sham (S, n = 10, [3] intense intermittent training (IIT, n = 10, [4] intense intermittent training + vitamin E (IIT + VE, n = 10, [5] vitamin E (VE, n = 10. Protocol of this study was implemented for 6 days per week for 6 weeks, with observing the overload principle on the motorized treadmill. After implementing training protocol, expression rate of p53 and PTEN genes reduced significantly (p<0.000, p<0.031, respectively. Taking vitamin E with intermittent training caused significant reduction in p53 expression (p<0.013, while it caused significant increase in expression of PTEN (p<0.035. These results showed that intense intermittent training reduces expression of p53 and PTEN tumor suppressing genes and taking supplementation vitamin E along with this type of training could cause different effects in expression of these tumor suppressor genes.

  10. A role for HVEM, but not lymphotoxin-beta receptor, in LIGHT-induced tumor cell death and chemokine production

    NARCIS (Netherlands)

    Pasero, Christine; Barbarat, Bernadette; Just-Landi, Sylvaine; Bernard, Alain; Aurran-Schleinitz, Thérèse; Rey, Jérome; Eldering, Eric; Truneh, Alemsedeg; Costello, Régis T.; Olive, Daniel

    2009-01-01

    The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-P receptor (LT-beta R) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of

  11. Distinct roles for soil fungal and bacterial communities associated with the suppression of vanilla Fusarium wilt disease

    NARCIS (Netherlands)

    Xiong, Wu; Li, Rong; Ren, Yi; Liu, Chen; Zhao, Qingyun; Wu, Huasong; Jousset, Alexandre; Shen, Qirong

    2017-01-01

    Characterizing microbial communities associated with disease-suppressive soil is an important first step toward understanding the potential of microbiota to protect crops against plant pathogens. In the present study, we compared microbial communities in suppressive- and conducive-soils associated

  12. Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy.

    LENUS (Irish Health Repository)

    Coffey, J Calvin

    2012-02-03

    Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.

  13. Characterizing the Role of Nanoparticle Design on Tumor Transport and Stability in the Extracellular Environment

    Science.gov (United States)

    Albanese, Alexandre

    Nanotechnology has emerged as an exciting strategy for the delivery of diagnostic and therapeutic agents into established tumors. Advancements in nanomaterial synthesis have generated an extensive number of nanoparticle designs made from different materials. Unfortunately, it remains impossible to predict a design's effectiveness for in vivo tumor accumulation. Little is known about how a nanoparticle's morphology and surface chemistry affect its interactions with cells and proteins inside the tumor tissue. This thesis focuses on the development of in vitro experimental tools to evaluate how nanoparticle design affects transport in a three-dimensional tumor tissue and stability in the tumor microenvironment. Nanoparticle transport was evaluated using a novel 'tumor-on-a-chip' system where multicellular tumor spheroids were immobilized in a microfluidic channel. This setup created a three-dimensional tumor environment displaying physiological cell density, extracellular matrix organization, and interstitial flow rates. The tumor-on-a-chip demonstrated that accumulation of nanoparticles was limited to diameters below 110 nm and was improved by receptor targeting. Nanoparticle stability in the tumor microenvironment was evaluated using media isolated from different tumor cell lines. Nanoparticle diameter and surface chemistry were important determinants of stability in cancer cell-conditioned media. Small nanoparticles with unstable surface chemistries adsorbed cellular proteins on their surface and were prone to aggregation. Nanoparticle aggregation altered cellular interactions leading to changes in cell uptake. Using a novel technique to generate different aggregate sizes possessing a uniform surface composition, it was determined that aggregation can change receptor affinity, cell internalization mechanisms and sub-cellular sequestration patterns. Data from this thesis characterize the behavior of nanoparticles within modeled tumor environments and provide some

  14. Role of hormonal factor in development of primary and secondary tumorous process in the brain

    Directory of Open Access Journals (Sweden)

    O. I. Kit

    2016-01-01

    Full Text Available Introduction. Causes of the development onset of primary malignant cerebral neoplasms have not yet been determined. Not excluded is a possibility of unfavorable effect of the environment, genetic abnormalities, changes alterations in the hormonal background as well as metabolism, ionizing radiation: possible is also the role of viral infections and injuries. One of the main most severest complications of malignant tumors remain are metastatic lesions of the central nervous system whose proportion increases as with the patients’ longlivity. Cerebral metastases of malignant tumors are encountered more often than primary neoplasms of the central nervous system. The brain is not only a hormone-dependent organ the effect of sex hormones as early the embryonic state conditions normal development of the body as a whole and controls the sex related differentiation. It is known that neurons and glyocites like gonads and adrenal glands are able to produce steroid hormones. The enzymes responsible for the synthesis of neurosteroids were detected in the brain tissue in the embryonic period of the development. The human brain is not only a hormone-dependent organ effect influence of sex hormones as early as in the embrional state conditiones normal development of the body as a whole and controls sexual gender differentiation. It is known that neurons and glyocytes like gonads and adrenal glands are able to produce steroid hormones. Enzymes responsible for synthesis of neurosteroids were revealed in cerebral tissue both in during the embryonic period of the development and in adult condition. Besides there are have been obtained large amount of data on the presence in the cerebral cells of receptors to steroidal hormones. In various periods of life the influence effect exerted by steroids on nervous cells can change the morphofunctional state of the brain and manifests as altering myelinization, neuronal growth, and differentiation of nerve cells

  15. S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance

    DEFF Research Database (Denmark)

    Grum-Schwensen, Birgitte; Klingelhöfer, Jörg; Beck, Mette

    2015-01-01

    , decreased vessel density and inhibition of metastases. CONCLUSION: The S100A4 blocking antibody (6B12) reduces tumor growth and metastasis in a model of spontaneous breast cancer. The 6B12 antibody treatment inhibits T cell accumulation at the primary and pre-metastatic tumor sites. The 6B12 antibody acts...

  16. MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ping; Guo, Xueyan; Zong, Wei [Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); Song, Bin [Department of General Surgery, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); Liu, Guisheng [Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710068 (China); He, Shuixiang, E-mail: fisrstsxianghe@163.com [Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Xi' an Jiaotong University, Xi' an 710061 (China)

    2015-11-27

    MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer (GC). The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of GC. In this study, we aimed to investigate the role and mechanism of miR-128b in the development and progression of GC. Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of miR-128b in GC tissues and cell lines. We found that miR-128b was significantly down-regulated in GC tissues and cell lines. In addition, over-expression of miR-128b inhibited GC cell proliferation, migration and invasion of GC cells in vitro. Gain-of-function in vitro experiments further showed that the miR-128b mimic significantly promoted GC cell apoptosis. Subsequent dual-luciferase reporter assay identified one of the proto-oncogene A2bR as direct target of miR-128b. Therefore, our results indicate that miR-128b is a proto-oncogene miRNA that can suppresses GC proliferation and migration through down-regulation of the oncogene gene A2bR. Taken together, our results indicate that miR-128b could serve as a potential diagnostic biomarker and therapeutic option for human GC in the near future. - Highlights: • The expression of MiR-128b is significantly down-regulated in GC tissues and cell lines. • Ectopic expression of miR-128b directly affects cell proliferation, migration and invasion in vitro. • Overexpression of miR-128b increases apoptosis in GC cells. • A2bR is a candidate target gene of miR-128b. • MiR-128b represses cell proliferation, migration and invasion and promotes apoptosis by targeting A2bR in GC.

  17. Endolymphatic Sac Tumors and Papillary Adenocarcinoma of the Temporal Bone:Role of MRI and CT

    OpenAIRE

    Mahmood F. Mafee; Hemant Shah

    2003-01-01

    Adenomatous Tumors of the temporal bone are rare. Benign adenomatous neoplasms (adenoma) of the middle ear are a distinctive benign tumor based on histological and clinical observations. Papillary adenocarcinomas of the temporal bone are invasive tumors. Although, the exact site of origin of these neoplasms is not identified, owing to the local bone destruction (usually centered at posterior petromastoid plate), the general consensus favors the endolymphatic sac as being the origin of these t...

  18. Cytokine expression in mice exposed to diesel exhaust particles by inhalation. Role of tumor necrosis factor

    Directory of Open Access Journals (Sweden)

    Loft Steffen

    2006-02-01

    Full Text Available Abstract Background Particulate air pollution has been associated with lung and cardiovascular disease, for which lung inflammation may be a driving mechanism. The pro-inflammatory cytokine, tumor necrosis factor (TNF has been suggested to have a key-role in particle-induced inflammation. We studied the time course of gene expression of inflammatory markers in the lungs of wild type mice and Tnf-/- mice after exposure to diesel exhaust particles (DEPs. Mice were exposed to either a single or multiple doses of DEP by inhalation. We measured the mRNA level of the cytokines Tnf and interleukin-6 (Il-6 and the chemokines, monocyte chemoattractant protein (Mcp-1, macrophage inflammatory protein-2 (Mip-2 and keratinocyte derived chemokine (Kc in the lung tissue at different time points after exposure. Results Tnf mRNA expression levels increased late after DEP-inhalation, whereas the expression levels of Il-6, Mcp-1 and Kc increased early. The expression of Mip-2 was independent of TNF if the dose was above a certain level. The expression levels of the cytokines Kc, Mcp-1 and Il-6, were increased in the absence of TNF. Conclusion Our data demonstrate that Tnf is not important in early DEP induced inflammation and rather exerts negative influence on Mcp-1 and Kc mRNA levels. This suggests that other signalling pathways are important, a candidate being one involving Mcp-1.

  19. Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation.

    Directory of Open Access Journals (Sweden)

    Tomas Garzon-Muvdi

    Full Text Available Glioblastoma (GB is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na(+-K(+-Cl(- cotransporter 1 (NKCC1 can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF, which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1 through the regulation of focal adhesion dynamics and cell contractility and (2 through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.

  20. Glioma-secreted soluble factors stimulate microglial activation: The role of interleukin-1β and tumor necrosis factor-α.

    Science.gov (United States)

    Hwang, Ji-Sun; Jung, Eun-Hye; Kwon, Mi-Youn; Han, Inn-Oc

    2016-09-15

    We aimed to elucidate the effect of soluble factors secreted by glioma on microglial activation. Conditioned medium (CM) from glioma cells, CRT-MG and C6, significantly induced nitric oxide (NO) production and stimulated the mRNA expression of inducible NO synthase (iNOS), interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-α) and cyclooxygenase 2 (COX-2) in BV2 cells. Glioma CM stimulated p38 mitogen-activated protein kinase (MAPK) phosphorylation, and a p38 MAPK inhibitor, SB203580, suppressed CM-induced NO production in BV2 cells. In addition, CM stimulated nuclear factor-kappaB (NF-κB) DNA binding and transcriptional activity, which was repressed by SB203580. Gliomas displayed higher mRNA expression and release of TNF-α and IL-1β than primary astrocyte cells. Neutralization of TNF-α and IL-1β in C6-CM using a neutralizing antibody inhibited NO/iNOS expression in BV-2 cells. These results indicate potential contribution of diffusible tumor-derived factors to regulate microglial activation and subsequent tumor microenvironment. Copyright © 2016. Published by Elsevier B.V.

  1. Macrophages support splenic erythropoiesis in 4T1 tumor-bearing mice.

    Directory of Open Access Journals (Sweden)

    Min Liu

    Full Text Available Anemia is a common complication of cancer; a role of spleen in tumor-stress erythropoiesis has been suggested. However, the molecular mechanisms involved in the splenic erythropoiesis following tumor maintenance remain poorly understood. Here we show that tumor development blocks medullar erythropoiesis by granulocyte colony-stimulating factor (G-CSF and then causes anemia in murine 4T1 breast tumor-bearing mice. Meanwhile, tumor-stress promotes splenic erythropoiesis. Splenectomy worsened tumor-induced anemia, and reduced tumor volume and tumor weight, indicating the essential role of spleen in tumor-stress erythropoiesis and tumor growth. Tumor progression of these mice led to increased amounts of bone morphogenetic protein 4 (BMP4 in spleen. The in vivo role of macrophages in splenic erythropoiesis under tumor-stress conditions was investigated. Macrophage depletion by injecting liposomal clodronate decreased the expression of BMP4, inhibited splenic erythropoiesis, aggravated the tumor-induced anemia and suppressed tumor growth. Our results provide insight that macrophages and BMP4 are positive regulators of splenic erythropoiesis in tumor pathological situations. These findings reveal that during the tumor-stress period, the microenvironment of the spleen is undergoing changes, which contributes to adopt a stress erythropoietic fate and supports the expansion and differentiation of stress erythroid progenitors, thereby replenishing red blood cells and promoting tumor growth.

  2. Reduced miR-433 expression is associated with advanced stages and early relapse of colorectal cancer and restored miR-433 expression suppresses the migration, invasion and proliferation of tumor cells in vitro and in nude mice.

    Science.gov (United States)

    Zhang, Jian; Zhang, Lei; Zhang, Tong; Dong, Xin-Min; Zhu, Yu; Chen, Long-Hua

    2018-05-01

    The expression of microRNA (miR-433) is altered in various types of human cancer. The present study analyzed the prognostic and biological value of miR-433 expression in colorectal cancer using reverse transcription-quantitative polymerase chain reaction in 125 colorectal tissue specimens (including a test cohort of 40 cases of paired colorectal cancer and adjacent normal mucosae and a confirmation cohort of 85 cases of stage I-III colorectal cancer). In vitro and nude mouse xenograft experiments were subsequently used to assess the effects of miR-433 expression on the regulation of colorectal cancer cell proliferation, adhesion, migration, and invasion. The data indicated that miR-433 expression was significantly downregulated in colorectal cancer tissues in the test and confirmation patient cohorts and that low miR-433 expression was associated with advanced tumor stage and early relapse. Furthermore, the restoration of miR-433 expression was able to significantly inhibit the proliferation of tumor cells by inducing G1-S cell cycle arrest, suppressing cyclinD1 and CDK4 expression, and markedly inhibited the migratory and invasive capacities of tumor cells in vitro . The restoration of miR-433 expression or liposome-based delivery of miR-433 mimics suppressed the growth of colorectal cancer cell xenografts in nude mice. In conclusion, miR-433 may be a putative tumor suppressor in colorectal cancer, and the detection of low miR-433 expression will be investigated in further studies as a putative biomarker for the detection of early relapse in patients with colorectal cancer.

  3. Critical role of CCDC6 in the neoplastic growth of testicular germ cell tumors

    International Nuclear Information System (INIS)

    Staibano, Stefania; Fusco, Alfredo; Chieffi, Paolo; Celetti, Angela; Ilardi, Gennaro; Leone, Vincenza; Luise, Chiara; Merolla, Francesco; Esposito, Francesco; Morra, Francesco; Siano, Maria; Franco, Renato

    2013-01-01

    DNA damage response has been clearly described as an anti-cancer barrier in early human tumorigenesis. Moreover, interestingly, testicular germ cell tumors (TGCTs) have been reported to lack the DNA Damage Response (DDR) pathway activation. CCDC6 is a pro-apoptotic phosphoprotein substrate of the kinase ataxia telangectasia mutated (ATM) able to sustain DNA damage checkpoint in response to genotoxic stress and is commonly rearranged in malignancies upon fusion with different partners. In our study we sought to determine whether CCDC6 could have a role in the patho-genesis of testicular germ cell tumors. To achieve this aim, analysis for CCDC6 expression has been evaluated on serial sections of the mouse testis by immunohistochemistry and on separate populations of murine testicular cells by western blot. Next, the resistance to DNA damage-induced apoptosis and the production of reactive oxygen species has been investigated in GC1 cells, derived from immortalized type B murine germ cells, following CCDC6 silencing. Finally, the CCDC6 expression in normal human testicular cells, in Intratubular Germ Cell Neoplasia Unclassified (IGCNU), in a large series of male germ cell tumours and in the unique human seminoma TCam2 cell line has been evaluated by immunohistochemistry and by Western Blot analyses. The analysis of the CCDC6 expression revealed its presence in Sertoli cells and in spermatogonial cells. CCDC6 loss was the most consistent feature among the primary tumours and TCam2 cells. Interestingly, following treatment with low doses of H 2 O 2 , the silencing of CCDC6 in GC1 cells caused a decrease in the oxidized form of cytochrome c and low detection of Bad, PARP-1 and Caspase 3 proteins. Moreover, in the silenced cells, upon oxidative damage, the cell viability was protected, the γH2AX activation was impaired and the Reactive Oxygen Species (ROS) release was decreased. Therefore, our results suggest that the loss of CCDC6 could aid the spermatogonial cells to

  4. Apoptosis induced by chlormethine and ionizing radiations in normal and tumoral lymphocytes: role of caspase-3

    International Nuclear Information System (INIS)

    Holl, V.P.

    2000-01-01

    Apoptosis can be induced by various stimuli like ionizing radiations or alkylating agents. Recent works have shown that apoptosis due to ionizing radiations can be initiated by DNA and cell membrane alterations, via radical species generation, implying the in fine activation of effector caspases, and in particular caspase-3. The main goal of this work is to clarify the role of caspase-3 in the radio-induced apoptosis mechanisms and to study the effects of apoptosis inhibition on the behaviour of the damaged cells. The effects of activation and caspase-3 activity inhibition on the progress of spontaneous, radio-induced or chlormethine-induced apoptosis have been evaluated for normal and tumoral lymphocytes. A chemical molecule, the ebselen, which can mime the action of the endogenous glutathione peroxidase, and a tetra-peptide inhibitor, AC-DEVD-CHO, selective of effector caspases, have been selected. The results indicate an inhibition by ebselen of all morphological and biochemical characteristics of chlormethine-induced apoptosis and a restoring of the cells viability. This seleno-organic compound also reduces the drop of the intra-cellular glutathione level and the loss of the trans-membrane potential (M) of the mitochondrion in the MOLT-4 tumoral cells treated with chlormethine. In parallel, the AC-DEVD-CHO effect on apoptosis induction has been tested. This inhibitor stops some chlormethine-induced criteria of apoptosis without affecting the final loss of the mitochondrial M and the cells proliferation. AC-DEVD-CHO has been also incubated just before the irradiation of the culture cells. The inhibition of the specific DEVD caspases prevents the inter-nucleosomal fragmentation of DNA and partially delays the externalization of phosphatidylserine without changing the viability of the irradiated cells. Moreover, the analysis of the AC-DEVD-CHO pre-treated irradiated cells floating on the surface shows a strong mitochondrial lactate dehydrogenase activity, which

  5. The role of CT in diagnosing small hepatic tumors; Usefulness of table incremental dynamic CT (ICT)

    Energy Technology Data Exchange (ETDEWEB)

    Usuki, Noriaki; Daikokuya, Hideo; Fukuda, Haruyuki; Saiwai, Shigeo; Nakajima, Hideyuki; Miyamoto, Takeshi; Kudo, Masatoshi (Kobe General Hospital, Hyogo (Japan))

    1992-11-01

    Twenty-seven cases of small hepatic tumors were examined by MRI and CT (ICT). MRI was more sensitive than plain and contrast CT. But ICT could detect more small lesions than MRI. CT is not more superior modality than MRI untill ICT is performed. It is concluded ICT should be done when diagnosing small hepatic tumors by CT. (author).

  6. Omega-3 Fatty Acids and a Novel Mammary Derived Growth Inhibitor Fatty Acid Binding Protein MRG in Suppression of Mammary Tumor

    National Research Council Canada - National Science Library

    Liu, Yiliang

    2001-01-01

    We have previously identified and characterized a novel tumor growth inhibitor and a fatty acid binding protein in human mammary gland and named it as Mammary derived growth inhibitor Related Gene MRG...

  7. Experimental assessment of the role of the blood flow inhibition in hyperglycemia-enhanced radiation injury to tumor

    International Nuclear Information System (INIS)

    Kozin, S.V.;