Title: Vanilloid receptor-1 regulates neurogenic inflammation in colon and protects mice

Neuroinflammation driven by the vanilloid-type ion channel receptor TRPV-1 is suspected to play a role in the pathophysiology of inflammatory bowel disease. Since inflammatory bowel disease is known to elevate the risk of colon cancer, we examined postulated roles for TRPV-1-driven neuroinflammation in promoting colitis-associated and spontaneous colon cancer development. Using a well-established model of colitisassociated cancer (CAC), we found that mice genetically deficient in TRPV-1 showed a higher incidence and number of tumors in the distal colon. In like manner, genetic deficiency of TRPV-1 in the APC model of spontaneous colon cancer accentuated the number of colonic adenomas formed. Mechanistic analyses in the CAC model revealed an increased infiltration of inflammatory cells into tumors along with elevated expression of IL-6 and IL-11 and activation of the STAT3 and NF-κB signaling pathways. Notably, TPRV-1-deficient mice exhibited a defect in expression of the antiinflammatory neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) which contributed to the generation of a local proinflammatory environment. Together, our findings argue that by limiting neuroinflammatory processes TRPV-1 exerts a protective role that restricts the initiation and progression of colon cancer. on July 25, 2017. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 6, 2012; DOI: 10.1158/0008-5472.CAN-11-3693