Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Pathology and Laboratory Medicine

Supervisor

Asfaha, Samuel

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 Dclk1CreERT2;APCf/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 Dclk1CreERT2;APCf/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 Dclk1CreERT2;APCf/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.

Summary for Lay Audience

Colorectal cancer is the second most common cause of cancer death in Canada. A major risk factor for this disease is prolonged inflammation of the gastrointestinal tract. This is primarily seen in patients who have Inflammatory bowel disease (IBD), which includes diseases such as Crohn’s disease and Ulcerative colitis. Therefore, patients with IBD are at an increased risk for colitis-associated cancer (CAC). Despite the clear link between inflammation and cancer, exactly how colitis leads to CAC remains largely unknown. Similarly, there are currently few, if any, drugs that can aid in the prevention of CAC. Thus, the aim of this work is to identify how inflammation leads to cancer and determine how we can intervene to prevent this transformation. To do this, we focused on two known inflammatory pathways: the cyclooxygenase (COX) and NF-κB signaling pathways. Non-steroidal anti-inflammatory drugs, such as Aspirin, are some of the most commonly used drugs in the world and are known to inhibit the activity of COX enzymes. We report here the novel finding that low-dose Aspirin is safe and effective against CAC. We further identified that Aspirin works to prevent CAC by downregulating a known key mediator of inflammation, prostaglandin E2 (PGE2). We show that in colitis, PGE2 acts alongside Akt (Protein Kinase B) to stimulate normally non-dividing cells in the colon to give rise to cancer. We further show that PGE2 and Akt promote inflammation-associated cancer by activating a pathway that is known to be abnormally activated in CRC, the Wnt signaling pathway. Furthermore, we identified that the NF-κB pathway serves a protective function against colitis and CAC. Overall, we have identified two novel ways that colitis leads to CAC and have identified that low-dose Aspirin can be safely and effectively used to prevent the transition from IBD to cancer.

Available for download on Tuesday, June 28, 2022

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