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1.
Immune checkpoint blockade combined with IL‐6 and TGF‐β inhibition improves the therapeutic outcome of mRNA‐based immunotherapy
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Lukasz Bialkowski Kevin Van der Jeught Sanne Bevers Patrick Tjok Joe Dries Renmans Carlo Heirman Kris Thielemans 《International journal of cancer. Journal international du cancer》2018,143(3):686-698
Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self‐renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T‐cell exhaustion or disrupt the cross‐talk between cancer stem cells and the tumor‐promoting microenvironment. Here, we demonstrate that a three‐arm combination therapy—consisting of an mRNA‐based vaccine to induce antigen‐specific T‐cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD‐1, TIM‐3, LAG‐3), and antibodies targeting IL‐6 and TGF‐β—improves the therapeutic outcome in subcutaneous TC‐1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor‐specific immunity and simultaneously targeting multiple resistance mechanisms. 相似文献
2.
Antitumor effects of interleukin‐6 (IL‐6)/interleukin‐6 receptor (IL‐6R) signaling pathway inhibition in clear cell carcinoma of the ovary
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Nozomu Yanaihara Yukihiro Hirata Noriko Yamaguchi Yukiko Noguchi Misato Saito Chie Nagata Satoshi Takakura Kyosuke Yamada Aikou Okamoto 《Molecular carcinogenesis》2016,55(5):832-841
3.
Sabine Schnur Eva Obermueller Nicola Catone Alexandra Just Norbert E. Fusenig Margareta M. Mueller 《International journal of cancer. Journal international du cancer》2011,128(12):2803-2814
Cytokines play a crucial role in tumor initiation and progression. Here, we demonstrate that interleukin (IL)‐6 is a key factor by driving tumor progression from benign to malignant, invasive tumors in the HaCaT‐model of human skin carcinoma. IL‐6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT‐ras A‐5 cells in vitro. Furthermore, IL‐6 induces a complex, reciprocally regulated cytokine network in the tumor cells that includes inflammatory and angiogenic factors such as IL‐8, GM‐CSF, VEGF and MCP‐1. These IL‐6 effects lead to tumor cell invasion in organotypic cultures in vitro and to the formation of malignant and invasive s.c. tumors in vivo. Tumor invasion is supported by the IL‐6 induced overexpression of MMP‐1 in vitro and in vivo. These data demonstrate a key function of IL‐6 in the progression of skin SCCs by regulating a complex cytokine and protease network and suggest new therapeutic approaches to target this central player in skin carcinogenesis. 相似文献
4.
C/EBPβ promotes angiogenesis through secretion of IL‐6, which is inhibited by genistein,in EGFRvIII‐positive glioblastoma
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Jiazhen Qin Limin Hao Xiaoxia Li Yinan Liu Xiaoyan Zhang Xiuxiu Liu Peng Li Shuo Han Zebin Mao Li Shen 《International journal of cancer. Journal international du cancer》2015,136(11):2524-2534
To study the mechanisms underlying the IL‐6‐promoted angiogenic microenvironment in EGFRvIII‐positive glioblastoma, VEGF expression in EGFRvIII‐positive/negative tumors was determined by optical molecular imaging. Next, the HUVEC tube formation assay, Western blot, qPCR, RNA silencing, chromatin immunoprecipitation, luciferase reporter and ELISA assays were performed to examine the role of IL‐6 and C/EBPβ in the formation of the angiogenic microenvironment in EGFRvIII‐positive tumors. Finally, in vitro and in vivo genistein treatment experiments were conducted to challenge the interaction between the IL‐6 promoter and C/EBPβ. Optical imaging revealed greater VEGF expression in EGFRvIII‐positive tumor‐bearing mice, suggesting an angiogenic microenvironment. In vitro experiments demonstrated that C/EBPβ‐mediated regulation of IL‐6 was indispensable for maintenance of this angiogenic microenvironment. In contrast, genistein‐mediated upregulation of CHOP impeded C/EBPβ interaction with the IL‐6 promoter, thus disturbing the angiogenic microenvironment. This more malignant microenvironment in EGFRvIII glioblastoma is generated, at least in part, by greater VEGF, IL‐6 and C/EBPβ expression. Interaction of C/EBPβ with the IL‐6 promoter maintains this angiogenic microenvironment, while disturbance of this dynamically balanced interaction inhibits EGFRvIII tumor proliferation by reducing both VEGF and IL‐6 expression. 相似文献
5.
Transforming growth factor‐β signaling enhancement by long‐term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells
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Chiaki Furuta Tatsuki Miyamoto Takahiro Takagi Yuri Noguchi Jyunya Kaneko Susumu Itoh Takuya Watanabe Fumiko Itoh 《Cancer science》2015,106(11):1524-1533
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Yoshiaki Norimatsu CT CMIAC Motoyuki Miyamoto PhD Tadao K. Kobayashi PhD Takuya Moriya MD PhD Keiko Shimizu CT CMIAC Kenji Yanoh MD PhD Choutatsu Tsukayama MD Yasuyuki Miyake CT CMIAC Eiji Ohno PhD 《Cancer cytopathology》2008,114(3):155-164
BACKGROUND.
For the current report, the authors examined the characteristic features of morphology and molecular biology of phosphatase and tensin homolog (PTEN), β‐catenin, and p53 immunocytochemistry in endometrial carcinoma by using thin‐layer cytologic preparations.METHODS.
During a 6‐month period, 120 endometrial samples were collected directly by using the Uterobrush, and thin‐layer specimens were prepared. Immunocytochemical expression levels of PTEN, β‐catenin, and p53 were investigated by using 40 specimens of endometrial carcinoma (EC), and 30 specimens each of proliferative endometrium, secretory endometrium, and atrophic endometrium.RESULTS.
For PTEN immunoreactivity, the a cutoff value of 50% PTEN expression appeared to be useful for the correct diagnosis of EC in endometrial cytology. For β‐catenin immunoreactivity, an increase in cytoplasmic and nuclear β‐catenin expression and a loss of β‐catenin expression appeared to be useful for the correct diagnosis of EC in endometrial cytology and may aid in the stratification of EC into low grade and high grade EC. For p53 immunoreactivity, the application of a cutoff score ≥4 for nuclear p53 expression appeared to be useful for the diagnosis of high‐grade EC in endometrial cytology.CONCLUSIONS.
Immunocytochemical findings from a combination of PTEN, β‐catenin, and p53, in addition to cytomorphologic features, appeared to be useful for the more accurate diagnosis of EC in endometrial cytology. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society. 相似文献7.
Guillaume Sarrabayrouse Laure‐Hélène Ouisse Céline Bossard Bernard Le Mével Lucien Potiron Guillaume Meurette Nadine Gervois Francine Jotereau 《International journal of cancer. Journal international du cancer》2011,128(12):2923-2932
High level of T‐cell infiltration in colorectal carcinomas (CRCs) is a good prognostic indicator, but the tumor reactivity of this infiltrate (tumor infiltrating lymphocytes [TIL]) is poorly documented. This study examined the presence, phenotype and functional features of tumor‐reactive lymphocytes in human CRC. Freshly dissociated TIL and T cell lines were isolated from CRC samples and from some paired normal colonic mucosa. Four tumor cell lines were obtained. Autologous tumor reactivity of CRC TIL and tumor‐reactive cell features were analyzed. We demonstrate the presence among CRC TIL of variable fractions (up to 18%) of double positive CD4+CD8αβ+ (DP) αβ T cells. Interestingly, a high proportion (16–20%) of this TIL subset displayed tumor reactivity, whilst this was the case for no or few single positive TIL. Low levels of DP TIL were found in most CRC samples and in normal colonic mucosa, but these cells were higher in metastatic CRC. Furthermore, we showed that DP TIL were polyclonal, restricted by HLA class‐I, proliferated poorly and secreted higher amounts of IL‐4 and IL‐13 than single positive T cells, on cognate or CD3 stimulation. DP CRC TIL also expressed CD103, confirming their mucosal origin. Increased frequencies of tumor‐reactive DP TIL in metastatic CRC suggest that these cells play a role in the metastatic process of this cancer. Based on their high secretion of IL‐4 and IL‐13 and on previously described roles of these cytokines in cancers, we postulate that DP TIL could favor CRC growth or metastasis and/or downmodulate immune responses to these tumors. 相似文献
8.
Neha Minhas Carol Perez‐Iratxeta Barbara C. Vanderhyden 《International journal of cancer. Journal international du cancer》2014,135(5):1072-1084
Exogenous 17β‐estradiol (E2) accelerates the progression of ovarian cancer in the transgenic tgCAG‐LS‐TAg mouse model of the disease. We hypothesized that E2 has direct effects on ovarian cancer cells and this study was designed to determine the molecular mechanisms by which E2 accelerates ovarian tumor progression. Mouse ovarian cancer ascites (MAS) cell lines were derived from tgCAG‐LS‐TAg mice. Following intraperitoneal engraftment of two MAS cell lines, MASC1 and MASE2, into SCID mice, exogenous E2 significantly decreased the survival time and increased the tumor burden. Microarray analysis performed on MASE2‐derived tumors treated with E2 or placebo showed that E2 treatment caused the upregulation of 197 genes and the downregulation of 55 genes. The expression of gene regulated by estrogen in breast cancer 1 (Greb1) was upregulated in mouse tumors treated with E2 and was overexpressed in human ovarian cancers relative to human ovarian surface epithelium, suggesting a role for GREB1 in human ovarian tumor progression. RNA interference‐mediated knockdown of GREB1 in MASE2 cells decreased their proliferation rate in vitro and increased survival time in mice engrafted with the cells. These results emphasize the importance of E2 in ovarian tumor progression and identify Greb1 as a novel gene target for therapeutic intervention. 相似文献
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Sirtuin 6 promotes transforming growth factor‐β1/H2O2/HOCl‐mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence
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Xin‐Xia Feng Jing Luo Mei Liu Wei Yan Zhen‐Zhen Zhou Yu‐Jia Xia Wei Tu Pei‐Yuan Li Zuo‐Hua Feng De‐An Tian 《Cancer science》2015,106(5):559-566
Sirtuin 6 (SIRT6) can function as a tumor suppressor by suppressing aerobic glycolysis and apoptosis resistance. However, the negative effect of SIRT6 on cellular senescence implies that it may also have the potential to promote tumor development. Here we report that the upregulation of SIRT6 expression was required for transforming growth factor (TGF)‐β1 and H2O2/HOCl reactive oxygen species (ROS) to promote the tumorigenicity of hepatocellular carcinoma (HCC) cells. Transforming growth factor‐β1/H2O2/HOCl could upregulate SIRT6 expression in HCC cells by inducing the sustained activation of ERK and Smad pathways. Sirtuin 6 in turn abrogated the inducing effect of TGF‐β1/H2O2/HOCl on cellular senescence of HCC cells, and was required for the ERK pathway to efficiently suppress the expression of p16 and p21. Sirtuin 6 altered the effect of Smad and p38 MAPK pathways on cellular senescence, and contributed to the inhibitory effect of the ERK pathway on cellular senescence. However, SIRT6 was inefficient in antagonizing the promoting effect of TGF‐β1/H2O2/HOCl on aerobic glycolysis and anoikis resistance. Intriguingly, if SIRT6 expression was inhibited, the promoting effect of TGF‐β1/H2O2/HOCl on aerobic glycolysis and anoikis resistance was not sufficient to enhance the tumorigenicity of HCC cells. Suppressing the upregulation of SIRT6 enabled TGF‐β1/H2O2/HOCl to induce cellular senescence, thereby abrogating the enhancement of HCC cell tumorigenicity by TGF‐β1/H2O2/HOCl. These results suggest that SIRT6 is required for TGF‐β1/H2O2/HOCl to enhance the tumorigenicity of HCC cells, and that targeting the ERK pathway to suppress the upregulation of SIRT6 might be a potential approach in comprehensive strategies for the therapy of HCC. 相似文献
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Toshio Fujisawa Hideyuki Nakashima Atsushi Nakajima Bharat H. Joshi Raj K. Puri 《International journal of cancer. Journal international du cancer》2011,128(5):1221-1231
Pancreatic cancer is an aggressive disease with only limited therapeutic options available. We have identified that 71% pancreatic ductal adenocarcinoma (PDA) express high levels of IL‐13Rα2, a high‐affinity receptor for IL‐13. To target IL‐13Rα2, we have developed a recombinant immunotoxin, which is a fusion of IL‐13 and Pseudomonas exotoxin (IL‐13‐PE). Since IL‐13‐PE and a commonly used cytotoxic drug gemcitabine act by a different mechanism, we hypothesized that they synergize in mediating antitumor response. Both IL‐13‐PE and gemcitabine‐mediated cytotoxicity to two pancreatic cancer cell lines and when combined synergistic cytotoxicity was observed. This synergism was also demonstrated in vivo in an orthotopic mouse model of human PDA. IL‐13‐PE and gemcitabine showed complete eradiation of tumors as assessed by whole body imaging of GFP‐transfected tumors in 57% of mice in an early cancer model resulting into prolongation of survival. In contrast, monotherapy with either agent did not produce complete eradiation, but tumor volumes were significantly decreased. In advanced PDA model, combination therapy also produced dramatic reduction in tumor growth and enhanced survival compared to animals treated with either agent alone. When IL‐13Rα2 was knocked‐down by RNAi prior to tumor implantation, IL‐13‐PE and gemcitabine did not synergize indicating that IL‐13Rα2 is essential. Mechanistically, gemcitabine increased IL‐13Rα2 expression in vitro and in vivo, which resulted in a synergism of combination therapy. Interestingly, PDA cancer stem cells were resistant to gemcitabine, but not to IL‐13‐PE. These results suggest that combination therapy with IL‐13‐PE and gemcitabine may be a useful strategy for PDA therapy. 相似文献
15.
Recruited monocytic myeloid‐derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL‐1β‐mediated increase in E‐selectin expression
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Huifang Shi Juechao Zhang Xiaoqing Han Huihan Li Mingshu Xie Yingying Sun Wenguang Liu Xueqing Ba Xianlu Zeng 《International journal of cancer. Journal international du cancer》2017,140(6):1370-1383
The tumor premetastatic niche initiated by primary tumors is constructed by multiple molecular factors and cellular components and provides permissive condition that allows circulating tumor cells to successfully metastasize. Myeloid‐derived suppressor cells (MDSCs), a population of immature cells in pathological conditions, play a critical role in the formation of the premetastatic niche. However, few researches are focused on the function of monocytic MDSCs (mo‐MDSCs), a subtype of MDSCs, in the construction of the niche. Here, we show that the number of mo‐MDSCs is significantly increased in the premetastatic lungs of tumor‐bearing mice, thus promoting tumor cell arrest and metastasis. Before the arrival of tumor cells, the lung‐recruited mo‐MDSCs produced IL‐1β, thereby increasing E‐selectin expression and promoting tumor cell arrest on endothelial cells. Depletion of mo‐MDSCs in the premetastatic lungs decreased IL‐1β production, resulting in reduced E‐selectin expression. In addition, compared with alveolar macrophages and interstitial macrophages, mo‐MDSCs were the major source of IL‐1β expression in the premetastatic lungs. Cytokine array analyses and transwell experiments revealed that CCL12 recruits mo‐MDSCs to premetastatic lungs. CCL12 knockdown in tumor‐bearing mice significantly decreased mo‐MDSC infiltration into the premetastatic lungs, leading to reduced E‐selectin expression. Overall, the permissive conditions produced by the infiltrated mo‐MDSCs correlated with increased tumor cell arrest and metastasis. These results reveal a novel role of mo‐MDSCs in constructing the premetastatic niche. Thus, inhibition of mo‐MDSCs infiltration may change the premetastatic niche to normal condition and attenuate tumor metastasis. 相似文献
16.
Mixed‐polarization phenotype of ascites‐associated macrophages in human ovarian carcinoma: Correlation of CD163 expression,cytokine levels and early relapse
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Silke Reinartz Tim Schumann Florian Finkernagel Annika Wortmann Julia M. Jansen Wolfgang Meissner Michael Krause Anne‐Marie Schwörer Uwe Wagner Rolf Müller 《International journal of cancer. Journal international du cancer》2014,134(1):32-42
Ovarian cancer is typically accompanied by the occurrence of malignant ascites containing large number of macrophages. It has been suggested that these tumor‐associated macrophages (TAMs) are skewed to alternative polarization (M2) and thereby play an essential role in therapy resistance and metastatic spread. In our study, we have investigated the nature, regulation and clinical correlations of TAM polarization in serous ovarian cancer. Macrophage polarization markers on TAMs and ascites cytokine levels were analyzed for 30 patients and associated with relapse‐free survival (RFS) in a prospective study with 20 evaluable patients. Surface expression of the M2 marker CD163 on TAMs was inversely associated with RFS (p < 0.01). However, global gene expression profiles determined for 17 of these patients revealed a mixed‐polarization phenotype unrelated to the M1/M2 classification. CD163 surface expression also correlated with the ascites levels of IL‐6 and IL‐10 (p < 0.05), both cytokines induced CD163 expression, and their ascites levels showed a clear inverse association with RFS (p < 0.01). These findings define a subgroup of patients with high CD163 expression, high IL‐6 and/or IL‐10 levels and poor clinical outcome. 相似文献
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Endogenous conversion of ω‐6 to ω‐3 polyunsaturated fatty acids in fat‐1 mice attenuated intestinal polyposis by either inhibiting COX‐2/β‐catenin signaling or activating 15‐PGDH/IL‐18
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Young‐Min Han Jong‐Min Park Ji‐Young Cha Migyeong Jeong Eun‐Jin Go Ki Baik Hahm 《International journal of cancer. Journal international du cancer》2016,138(9):2247-2256
Omega‐3 polyunsaturated fatty acids (ω‐3PUFAs) have inhibitory effects in various preclinical cancer models, but their effects in intestinal polyposis have never been examined. As attempts have been made to use nutritional intervention to counteract colon cancer development, in this study we evaluated the effects of ω‐3 PUFAs on intestinal polyposis in the ApcMin/+ mouse model. The experimental groups included wild‐type C56BL/6 mice, ApcMin/+ mice, fat‐1 transgenic mice expressing an n‐3 desaturase to enable ω‐3 PUFA synthesis, and ApcMin/+ × fat‐1 double‐transgenic mice; all mice were 20 weeks of age. Small intestines were collected for gross and pathologic evaluation, including assessment of polyp number and size, followed by immunohistochemical staining and Western blotting. After administration of various concentrations of ω‐3 PUFAs, PUFA levels were measured in small intestine tissue by GC/MS/MS analysis to compare with PUFA synthesis of between C57BL6 and fat‐1mice. As a result, ω‐3 PUFAs significantly attenuated Apc mutation–induced intestinal polyposis accompanied with significant inhibition of Wnt/β‐catenin signaling, COX‐2 and PGE2, but induced significant levels of 15‐PGDH. In addition, significant induction of the inflammasome‐related substrates as IL‐1β and IL‐18 and activation of caspase‐1 was observed in ApcMin/+ × fat‐1 mice. Administration of at least 3 g/60 kg ω‐3 PUFAs was equivalent to ω‐3 PUFAs produced in fat‐1 mice and resulted in significant increase in the expression of IL‐1β, caspase‐3 and IL‐18, as seen in ApcMin/+ × fat‐1 mice. We conclude that ω‐3PUFAs can prevent intestinal polyp formation by inhibition of Wnt/β‐catenin signaling, but increased levels of 15‐PGDH and IL‐18. 相似文献
19.
Elevated p53 promotes the processing of miR‐18a to decrease estrogen receptor‐α in female hepatocellular carcinoma
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Kun‐Huei Yeh Wan‐Hsin Liu Chi‐Ling Chen Ding‐Shinn Chen Pei‐Jer Chen Shiou‐Hwei Yeh 《International journal of cancer. Journal international du cancer》2015,136(4):761-770
The estrogen pathway has long been implicated as a tumor protector in female hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). Our previous study identified that estrogen receptor alpha (ERα) protein is downregulated in 60% of female HCC cases, via a miR‐18a elevation mediated suppression of ERα translation. This study aims to delineate the mechanism underlying the upregulation of miR‐18a in female HCC. The analysis of 77 female HCC specimens revealed that miR‐18a levels were associated with pre‐miR‐18a rather than pri‐miR‐18a levels, suggesting an enhanced processing of pri‐ to pre‐miR‐18a. Among a panel of factors involved in microRNA processing, p53 was identified as a novel regulator for miR‐18a maturation process. Knockdown of p53 by si‐RNA decreased the level of miR‐18a, whereas overexpression of either wild‐type or mutant p53 increased its level. The association between the elevation of miR‐18a and the accumulation of p53, mainly caused by somatic mutations, was confirmed in the clinical specimens of HBV‐related female HCC. By analyzing the association with clinicopathological features, activation of this p53/miR‐18a pathway mainly occurs in younger or noncirrhosis female HCC patients and associated with a trend of worse overall survival. Therefore, this study demonstrated a novel function of elevated/mutant p53 in regulating the amount of ERα protein through its promoting the biogenesis of miR‐18a, which could lead to decrease the tumor‐protective function of the estrogen pathway in female hepatocarcinogenesis. 相似文献
20.
Obesity results in increased circulating levels of specific adipokines, which are associated with colon cancer risk. The disease state is associated with increased leptin, insulin, IGF‐1, and IL‐6. Conversely, adiponectin levels are decreased in obese individuals. Previously, we demonstrated adipokine‐enhanced cell proliferation in preneoplastic, but not normal, colon epithelial cells, demonstrating a differential effect of adipokines on colon cancer progression in vitro. Using a model of late stage carcinoma cancer cell, namely murine MC‐38 colon carcinoma cells, we compared the effect of obesity‐associated adipokines (leptin, insulin, IGF‐1, and IL‐6) on MC‐38 cell proliferation and determined whether adiponectin (full length or globular) could modulate adipokine‐induced cell proliferation. We show that insulin and IL‐6, but not leptin and IGF‐1, induce proliferation in MC‐38 cells. Adiponectin treatment of MC‐38 cells did not inhibit insulin‐induced cell proliferation but did inhibit IL‐6‐induced cell proliferation by decreasing STAT‐3 phosphorylation and activation. Nitric oxide (NO) production was increased in MC‐38 cells treated with IL‐6; co‐treatment with adiponectin blocked IL‐6‐induced iNOS and subsequent NO production. These data are compared to previously reported findings from our laboratory using the YAMC (model normal colon epithelial cells) and IMCE (model preneoplastic) cells. The cell lines are utilized to construct a model summarizing the hormonal consequences of obesity and the impact on the differential regulation of colon epithelial cells along the continuum to carcinoma. These data, taken together, highlight mechanisms involved in obesity‐associated cancers and may lead to potential‐targeted therapies. © 2010 Wiley‐Liss, Inc. 相似文献