The role of IL-6 and IL-23 in colitis associated cancer (88.30)

Abstract Colitis associated cancer (CAC) is the most serious complication of inflammatory bowel diseases (IBD). Pro-inflammatory cytokines regulated by NF-B were suggested to regulate pre-neoplastic growth during CAC tumorigenesis. We tried to dissect the roles of individual cytokines in CAC tumorigenesis. Using genetic tools and a mouse model of azoxymethane/dextrane sodium sulfate induced CAC we demonstrate that IL-6 and IL-23 are critical tumor promoters during early CAC tumorigenesis. IL-6 and IL-23 act on cells of innate and adaptive immunity, particularly on T cells. Additionally, these cytokines have direct and indirect effects on intestinal epithelial (IEC) and neoplastic cells. These effects are mediated by transcription factor STAT3, whose IEC-specific ablation reduces CAC tumorigenicity. We conclude that IL-6 and IL-23 regulate multiple stages of colonic tumorigenesis, particularly tumor initiation and tumor growth. Selective inhibition of these cytokines may be beneficial for treatment and prevention of CAC. Supported by RFA from Crohn`s and Colitis Foundation of America (CCFA #1762) to S.G. and by grants from the NIH and a Jeannik M. Littlefield-AACR grant in metastatic colon cancer to M.K.