Role of SMAD7 in the intestinal epithelium for gut homeostasis and tumor development

Besides the function as an inhibitor of the TGF-ß signaling pathway, polymorphisms of SMAD7 play a crucial role in increasing the risk for the development of colon cancer.  In order to analyze the role of epithelial Smad7for colon cancer development we generated mice with a conditional knockout for Smad7 in intestinal epithelial cells (Smad7^ΔIEC). Smad7^ΔIEC mice were born at mendelian ratio and did not show defects in the postnatal development of the gut. We next subjected Smad7^ΔIEC mice to an experimental model of colitis associated cancer (AOM-DSS model). Surprisingly, Smad7^ΔIEC mice developed fewer tumors in comparison to the control group (Smad7^fl.).  To investigate whether the decreased number of colon tumors in Smad7^ΔIEC mice was dependent on colitis in the AOM-DSS model, we next used a sporadic tumor mouse model (APCmin). Comparison of APCmin^+/- Smad7^ΔIEC and control mice (APCmin^+/-) revealed that APCmin^+/- Smad7^ΔIEC mice not only showed a higher survival rate but also a reduced number of tumors. These findings strongly support our hypothesis that Smad7 plays a crucial role in the development of colon tumors independently from inflammation.