53 TNF-α Knockout Mice Are Not Protected Against Colitis-Associated Cancer

Abstract

induce colitis-associated CC. Tumor number and size were assessed by endoscopy. Colitis and dysplasia were graded by histology and expression of proinflammatory cytokines was evaluated in mononuclear cells from tumors and tumor free areas by flow-cytometry and real-time pcr. Granzynes B, perforin-1, and FasL mRNA expression was evaluated by realtime pcr. Results: As expected Wt mice developed large and multiple tumors after AOM/ DSS treatment. By contrast, only few and small tumors were seen in Smad7tg mice, despite these animals developed a more pronounced colitis. Consistently, higher expression of IFNgamma, IL-6 and IL-17 was found in the tumor free areas of the Smad7tg mice. Further flow-cytometry analysis of tumor-infiltrating T cells showed a higher expression of high IFN-gamma in both CD4+ and CD8+ T cells from Smad7Tg in comparison to Wt mice. Analysis of CD8+ T-cell-related cytotoxic molecules showed higher expression of Perforin1, Granzyme B and FasL in both tumors and tumor-free areas of the Smad7tg in comparison to the Wt animals. Conclusions: T cell-specific Smad7 over-expression results in a more severe colitis that protects against CC. Our data suggest that high expression of IFN-gamma and cytotoxicity sustained by high Smad7 in T cells could play a role in the regulation of anti-tumor immune responses in the gut.