A245 THE ROLE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN COLITIS-ASSOCIATED CANCER

Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Canada. A major risk factor for this disease is chronic inflammation. For this reason, patients with inflammatory bowel disease (IBD), such as Crohn’s disease or Ulcerative colitis, require frequent colon cancer screening. Despite the clear link between inflammation and cancer, the exact mechanism by which colitis leads to cancer is unknown. Our group has focused on a rare and ill-defined cell type in the gut known as a tuft cell that uniquely expresses doublecortin-like kinase-1 (Dclk1). Using a novel transgenic mouse model, we have previously shown that Dclk1+ tuft cells are quiescent and long-lived, and remain resistant to proliferation even upon mutation of the tumor suppressor APC. Interestingly, these cells become powerful cancer-initiating cells upon exposure to inflammation, but the mechanism by which inflammation leads to colonic tumors is not known. Intriguingly, Dclk1+ tuft cells express high levels of cyclooxygenase (COX)-1 and -2, the direct enzyme target of non-steroidal anti-inflammatory drugs (NSAIDs) which are known chemopreventative drugs in CRC. In the present study, we aim to determine the effects of COX inhibition by NSAIDs on colitis-associated colorectal cancer. Dclk1CreERT2/APCflox/flox mice were administered tamoxifen to induce an APC mutation in Dclk1-expressing cells. Mice were then exposed to the colitis-inducing agent dextran sodium sulfate (DSS), followed by daily treatment with oral NSAIDs or vehicle for the remainder of the experiment duration. The NSAIDs tested included Aspirin (non-selective COX inhibitor), celecoxib or rofecoxib (COX-2-selective inhibitors), or SC-560 (COX-1-selective inhibitor). Approximately 16 weeks post-tamoxifen, colonic tumour number and size were analyzed to determine the effect of these NSAIDs on tumour initiation and growth, respectively. Extent of inflammation was assessed by myeloperoxidase (MPO) activity and histology, and colonic tissue was taken for measurement of inflammatory mediators by qRT-PCR. Treatment with Aspirin and SC-560, but surprisingly, not celecoxib and rofecoxib, significantly reduced the number of colonic tumours. There was no significant difference in tumour size between vehicle and any of the NSAID-treated groups. Of note, the degree of colitis as assessed by MPO activity and histology was not significantly different between vehicle and NSAID-treated groups. These findings suggest a role for COX-mediated inflammation in colonic tumorigenesis arising from Dclk1+ tuft cells. Our results suggest that COX-1-selective, rather than COX-2-selective, NSAIDs may be useful for chemoprevention of CRC in patients with IBD. CIHR

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