IL-6 and STAT3 are required for survival of intestinal epithelial cells and development of colitis associated cancer

By S. Grivennikov, Eliad Karin, J. Terzic, D. Mucida, Guann‐Yi Yu, Sivakumar Vallabhapurapu, J. Scheller, S. Rose‐John, Hilde Cheroutre, L. Eckmann and 1 more. Cancer Cell, 2009

2,165 citations recorded by the source corpus.

Summary Colitis associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Pro-inflammatory cytokines were suggested to regulate pre-neoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB–regulated cytokine which acts on epithelial and immune cells. Using genetic tools we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and pre-malignant intestinal epithelial cells (IEC) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by transcription factor STAT3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-STAT3 cascade is an important regulator of the proliferation and survival of tumor initiating IEC.

Subfields: Cancer Research, Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/8bb8f2dee6e84252f76b4b6a454de52f046e7b9f

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Citations in the corpus

Cancer-related inflammation: common themes and therapeutic opportunities. (2012, background): “IL-6 also has tumor-promoting actions on both malignant and stromal cells in a range of experimental cancer models [43–45], is a downstream effector of oncogenic ras [46] and has been implicated in several human cancers including multiple myeloma [47] and hepatocellular carcinoma [48].”
Immunity, Inflammation, and Cancer (2010, neutral): “In CAC and HCC, the tumor-promoting effect of IL-6 is mainly exerted via STAT3, whose cell-type-specific inactivation in hepatocytes and enterocytes inhibits the development of these malignancies in mice treated with DEN or azoxymethane (AOM) and DSS, respectively (Bollrath et al., 2009; Grivennikov”
Chronic Inflammation and Cytokines in the Tumor Microenvironment (2014, background): “[34] S.”
Coordinated regulation of myeloid cells by tumours (2012, background): “During the early events of colitis-associated cancer, myeloid cells act as tumour promoters by enhancing the proliferation of tumour-initiating cells and by protecting premalignant intestinal epithelial cells from apoptosi”
Tumor self-seeding by circulating cancer cells (2009, background): “Inflammatory cells recruited to the tumor site can also be sources of IL-6 (Balkwill et al., 2005; Grivennikov et al., 2009).”
STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing (2009, result): “Our data are also consistent with two very recently published studies in which IL-6/gp130mediated STAT3 activation during tumor development was shown to drive cell proliferation of enterocytes (Bollrath et al., 2009; Grivennikov et al., 2009).”
Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. (2011, background): “associated colorectal carcinogenesis, for example, myeloid IL-6 activates Stat3 to promote the formation of adenoma and tumors (Bollrath et al., 2009; Grivennikov et al., 2009).”
Signaling in innate immunity and inflammation. (2012, background): “Similarly, IL6 deficiency in hematopoietic cells suppresses colon tumors that develop in response to procarcinogen azoxymethane plus colitis-inducing dextran sulfate sodium (DSS) (Grivennikov et al. 2009).”
An epigenetic switch involving NF-κB, Lin28, let-7 microRNA, and IL6 links inflammation to cell transformation (2009, neutral): “colitis-associated tumorigenesis (Bollrath et al., 2009; Grivennikov et al., 2009).”