IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer

Abstract

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.

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…3). Besides their physiological roles, aberrant activation of the NF-κB pathway is involved in the pathogenesis of a number of human tions, infl ammation-induced tumor promotion may occur early or late in tumor development through production of tumorpromoting cytokines by immune/infl ammatory cells (Moore et al, 1999;Eferl and Wagner, 2003;Yu et al, 2007;Grivennikov et al, 2009;Yu et al, 2009;Grivennikov and Karin, 2010). Angiogenesis, which is required for growth of large tumors, is triggered by tumor hypoxia.…”

“…Most, if not all, solid tumors are infi ltrated with immune and infl ammatory cells (Grivennikov and Karin, 2008). Infl ammation is involved in different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis (Grivennikov et al, 2009). Therefore, cancer-related inflammation (CRI) has been suggested to represent the seventh hallmark of cancer (Colotta et al, 2009) (Fig.…”

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

“…It has been estimated that more than 15% of all malignancies are initiated by chronic inflammatory disease (40)(41)(42)(43)(44)(45). In Table 1, an outline is given of inflammation that has been associated with cancer development: skin inflammation with squamous cell carcinoma, viral hepatitis with liver cancer and inflammatory bowel disease with colorectal cancer.…”

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…Third, specific subsets of Tregs, in particular those expressing activation markers such as CCR4, may exert more robust immunosuppressive functions, and hence be more closely associated with prognosis, than the entire population of Tregs [107]. Fourth, some oncogenic programs, such as those underlying (at least some instances of) lymphoma [108], head and neck cancer [109,110], gastric cancer [111] and colorectal carcinoma [112], involve a prominent pro-inflammatory component. In this setting, Treg-mediated immunosuppression may exert bona fide antitumor functions.…”