The Role of Inflammation in Colitis-Associated Cancer

Hayley Good, The University of Western Ontario

Abstract

Colitis-associated cancer (CAC) is a major complication associated with Inflammatory bowel disease (IBD). Unfortunately, there are currently few, if any, effective chemopreventative strategies against CAC. Furthermore, the exact mechanism by which inflammation leads to CAC remains poorly understood. In this thesis, we focus on two inflammatory signaling pathways, the cyclooxygenase (COX) and NF-κB pathways, that have been shown to link inflammation and cancer. For instance, non-steroidal anti-inflammatory drugs (NSAIDs) that target COX-1 and/or -2 have previously been shown to be effective in chemoprevention of sporadic colorectal cancer. However, the ability of NSAIDs to prevent CAC has not fully been explored. Using the previously described Dclk1^CreERT2;APC^f/f transgenic mouse model of CAC, we demonstrate that low-dose Aspirin prevents colitis-associated tumorigenesis by inhibiting epithelial-derived COX-1. Moreover, we identify that PGE₂, a major product of COX activity, and phospho-Akt are key inflammatory mediators that promote cellular plasticity of the intestinal epithelium. Specifically, using the Dclk1^CreERT2;APC^f/f mouse model, we have shown that PGE₂ and phospho-Akt are able to stimulate normally quiescent Dclk1+ tuft cells to repopulate the entire colonic crypt. Furthermore, we demonstrate that COX-1-derived PGE₂ and phosho-Akt are upregulated in colitis and cooperate to contribute to inflammation-associated dysplasia through the activation of Wnt signaling. In separate studies, we examined the role of canonical NF-κB signaling in the Dclk1^CreERT2;APC^f/f mouse model of CAC, which has been shown to link inflammation and cancer through the activity of IKKβ. We report the novel observation that IKKβ in Dclk1+ tuft cells serves a protective role in colitis and CAC. In summary, we have identified two novel mechanisms by which inflammation contributes to cancer and have shown that low-dose Aspirin serves as a safe and effective chemopreventative agent for the use against CAC.