TWEAK/Fn14 protects against colitis-associated cancer

Inflammatory bowel disease causes chronic, relapsing intestinal inflammation that can lead to the development of colorectal cancer. Members of the TNF superfamily are key regulators of intestinal inflammation. In particular, TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are involved in normal and pathologic intestinal tissue remodeling. In this study, we show that the TWEAK/Fn14 signaling complex plays a protective role during the acute stage of intestinal inflammation and contributes to the prevention of colitis-associated cancer during chronic inflammation through its pro-apoptotic effects. Colitis was in Fn14-/- and Fn14+/+ wild type littermates by administering 3% dextran sodium sulfate (DSS) for 7 days followed by 2 weeks recovery; azoxymethane (AOM) administration followed by 2 cycles of DSS/recovery was used to induce tumors. Reciprocal bone marrow chimeric mice were generated to compare hematopoietic and non-hematopoietic-specific effector tissues. Fn14-/- mice had enhanced susceptibility to colitis compared to Fn14+/+ controls as assessed by endoscopic and histological inflammatory scores, daily weight loss, and mortality rates during recovery after DSS administration. Bone marrow transfer experiments showed that both hematopoietic and non-hematopoietic components are involved in protection against colitis. Tumor lesions were found in the colons of most Fn14-/- mice, but not Fn14+/+ controls. AOM/DSS administration enhanced susceptibility to tumorigenesis in Fn14-/- mice. Overall, these findings show that Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer.

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