Predominant T helper type 2‐inflammatory responses promote murine colon cancers

Abstract

Colon cancer is one of the most serious complications of inflammatory bowel diseases, especially ulcerative colitis (UC). Previous studies have shown that characteristic immunological event during inflammation in UC is the expression of T helper-type 2 (Th2) cell-derived cytokines. In this study, we investigated the influence of a predominant Th2-type cytokine response in colitis on carcinogen-induced colon tumors. Wild type (WT), interferon gamma (IFN-c) gene deficient (2/2) [Th2 dominant] or interleukin (IL)-4 2/2 [Th1-dominant] mice of BALB/c background were used in this study. To compare tumor formation, mice were given the carcinogen azoxymethane (AOM) and intrarectal administration of trinitrobenzene sulfonic acid (TNBS), to induce colitis. Thirtythree weeks after initial treatment, the total colon was examined. When IFN-c 2/2 mice were treated with AOM and TNBS, significantly higher number of tumors were seen (8.4 6 1.7) than in WT (3.3 6 2.9) or IL-4 2/2 (3.1 6 3.4) mice, which received identical treatments. A separate set of experiment, using less doses of AOM and TNBS also showed the higher frequency of tumor formation in IFN-c 2/2 mice than in IL-4 2/2 mice. Histologically, the tumors were well-or moderately-differentiated adenocarcinomas. No invasion into the submucosal or serosal layers of the intestine was seen. In immunohistological staining, some tumors in IFN-c 2/2 mice showed distinct nuclear expression of b-catenin, in contrast to the strong membrane staining seen in tumors of IL-4 2/2 mice. In conclusion, colonic inflammation associated with Th2-donimant cytokine responses enhanced the formation of malignant neoplasms. ' 2005 Wiley-Liss, Inc.

Clinical Impact of Different Classes of Infiltrating T Cytotoxic and Helper Cells (Th1, Th2, Treg, Th17) in Patients with Colorectal Cancer

“…Previously, Th2 response was associated with the tumor immune evasion in mice studies (24,25), or not associated with clinical outcome in human studies (26,27). Our study does not support a major role of Th2 cells on patient's prognosis.…”

Smad7 Expression in T cells Prevents Colitis-Associated Cancer

“…In vivo, IFNg expression protects from tumor in different tumor models (31)(32)(33). In a murine model of CAC, Osawa and colleagues showed that IFNg-deficient mice are more susceptible to develop CAC (34). IFNg expression is also essential for CD8-mediated antitumor activity.…”

Increased Susceptibility to Colitis-Associated Cancer of Mice Lacking TIR8, an Inhibitory Member of the Interleukin-1 Receptor Family

“…A predominant T helper 2 inflammatory response has been implicated in colon cancer and IFNg deficiency increased the frequency of colonic neoplasms (20). The low levels of IFNg observed in Tir8 À/À colons could be indicative of a T helper 2 polarized environment.…”