Vanilloid Receptor-1 Regulates Neurogenic Inflammation in Colon and Protects Mice from Colon Cancer

Abstract

Neuroinflammation driven by the vanilloid-type ion channel receptor transient receptor potential vanilloid type 1 (TRPV-1) is suspected to play a role in the pathophysiology of inflammatory bowel disease. Because 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 colitis-associated 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 Min/þ 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 the tumors along with elevated expression of interleukin (IL)-6 and IL-11 and activation of the STAT3 and NF-kB signaling pathways. Notably, TPRV-1-deficient mice exhibited a defect in expression of the anti-inflammatory 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. Cancer Res; 72(7);

Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis

“…However, the physiological mechanism of TRPV1 or TRPV3 channel gating in keratinocytes remains unclear. Finally, a protective role for TRPV1-mediated neurogenic inflammation was recently proposed in the etiology of colorectal tumorigenesis (46). Our data suggest that systemic (neonatal) ablation of TRPV1 + sensory neurons did not phenocopy the increased tumorigenesis observed in Apc Min/+ Trpv1 -/-mice ( Figure 7, A-D, and Supplemental Figure 8, C and D).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Confusingly, in adult rats, capsaicin treatment achieved the opposite effect: It worsened experimental colitis (McCafferty et al, 1997). However, a higher incidence of colonic adenomas was recently reported in TRPV1(2/2) mice, leading to the controversial proposal that neurogenic inflammation is, in fact, protective against colorectal carcinogenesis, at least in patients with IBD (Vinuesa et al, 2012).…”

Bladder Cancer and Urothelial Impairment: The Role of TRPV1 as Potential Drug Target

“…The genetic deficiency of TRPV1 was described to induce a higher incidence and number of tumors in the distal colon and an accentuated development of colonic adenomas, in mice affected by colitis-associated cancer and in APCMin−/+ model of spontaneous colon cancer, respectively [72]. …”