| Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane (AOM) and dextran sodium sulfate (DSS) colitis-associated colorectal cancer model (CAC), I show that caspase-1-deficient (Casp1 -/-) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1-deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. I suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.;The microbiota is pivotal in the pathogenesis of IBD-associated inflammation-induced colorectal cancer (CRC), yet mechanisms for these effects remain poorly characterized. Herein, I demonstrate that aberrant inflammasome-induced microbiota plays a critical role in CRC development, where mice deficient in the NLRP6 inflammasome feature enhanced inflammation-induced CRC formation. Intriguingly, WT mice cohoused with inflammasome-deficient mice or with mice lacking IL-18 feature exacerbated inflammation-induced CRC as compared to singly housed WT mice. Enhanced tumorigenesis is dependent upon microbiota-induced CCL5-driven inflammation, which, in turn, promotes epithelial cell proliferation through local activation of the IL-6 pathway, leading to cancer formation. Altogether, our results mechanistically link the altered microbiota to the pathogenesis of inflammation-induced CRC and suggest that, in some conditions, microbiota components may transfer CRC susceptibility between animals. |
