Functional role of Smad7 on intestinal epithelial homeostasis and colorectal cancer development

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Polymorphisms in the Smad7 (mother against decapenthaplegic homolog-7) gene have recently been associated with an increased risk for the development of colorectal cancer. Smad7 is a key regulator of the TGF-beta (transforming growth factor beta) signaling pathway which plays an important role during all stages of tumor genesis via regulation of proliferation, cell death and epithelial cell plasticity. However, recent studies suggest that Smad7 also influences other central pathways (i.e. NF-kappaB and beta-catenin) and cellular processes involved in tumor development and can act independently from TGF-beta. Indeed, our own preliminary data demonstrate that Smad7 though not essential for embryonic gut development or tissue homeostasis in the steady state, is critically involved in colon cancer development, as mice deficient for Smad7 in the intestinal epithelium developed significantly less tumors as compared to controls. In order to better understand the role of Smad7 during different stages of tumor development in the gut, we aim to analyse mice deficient and proficient for Smad7 in established mouse models of colorectal cancer. Moreover, we will investigate the involvement of SMAD7 in TGF-beta-dependent and -independent signalling pathways in the intestinal epithelium. Finally we will extend our studies to cancer associated fibroblast SMAD7 and its involvement in fibroblast-epithelial communication.