Colitis-associated colon cancer (CAC) represents a major form of cancer and a serious medical complication for patients suffering from inflammatory bowel diseases (IBD). Population-based studies indicate that the risk of CAC among patients with ulcerative colitis is 18% at 30 years. A common denominator for these two conditions is the activation of signaling pathways that promote inflammation, cellular proliferation and survival. For instance, signaling cascades that activate the transcription factor NF-kB promote inflammatory conditions and favor cell survival. Interestingly, neoplasia has been observed in some experimental animal models of IBD including the IL-10 gene deleted mouse. The luminal microflora plays a pivotal role in the development of colitis and consequently bacteria may participate in the development of colon cancer in IL- 10-/- mice. In preliminary data, we found that E.feacalis/E.coli dual associated IL-10-/- mice trigger intestinal inflammation and cause colonic dysplasia. This suggests that dysregulated immune responses to enteric commensal bacteria create conditions favorable to the development of both inflammation and dysplasia and cancer. Persistent inflammatory conditions in the intestine may induce genetic and epigenetic events (methylation, hypoacetylation, ect) that transcriptionally silence genes involved in the control of cellular proliferation, growth and survival. Based on these results, we propose that luminal commensal bacterial trigger intestinal inflammation, which then generate an environment favorable to the development of colon cancer. The following specific aims are designed to test our hypothesis.
In AIM I, Identify the signaling pathways associated with inflammation and carcinogenesis in commensal bacteria-associated IL-10-/- mice.
AIM 2, Establish the contribution of myeloid and enterocyte-derived NF-kB dependent mediators responsible for commensal bacterial-induced colitis-associated colon cancer in IL-10-/- mice.
AIM 3, Establish the impact of inflammation on epigenetic changes and development of colon cancer in commensal bacteria-associated IL-10-/- mice. The information gained from this project will be instrumental for the generation of new strategies aimed at preventing and/or treating colitis-associated colon cancer. Rational in lay term: Understanding the impact of luminal bacteria on the development of colitis-associated colon cancer will allow the design of new therapeutic strategies to prevent/treat this pathological condition.
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