Understanding the Role of Smad4 in Intestinal Homeostasis and Tumorigenesis

Abstract

Colorectal carcinoma is the third leading cause of cancer related mortality within the United States. Over 90% of these deaths can be attributed to distant metastasis. Therefore, understanding the signaling perturbations that underlie the development of carcinoma and process of metastasis are paramount in combatting the progression of this disease. Many signaling pathways are dysregulated in the pathogenesis of colorectal carcinoma, but over 80% of sporadic colorectal cancer cases have alterations within the WNT pathway, and over 50% within the TGF-β signaling pathway. Both the WNT and TGF-β pathways are critical in development and intestinal homeostasis. The central mediator of TGF-β signaling pathway is Smad4, a transcription factor that is mutated in approximately 15-30% of colorectal cancer cases. Loss of Smad4 is associated with distant metastasis and overall poor patient prognosis. This body of work uses both in vitro and in vivo models to describe a role for Smad4 in supporting normal epithelial homeostasis within the intestinal tract. These models also describe a new tumor suppressor role of Smad4 wherein Smad4 signaling transcriptionally suppresses WNT pathway activation within intestinal epithelial cells. Overall, these results aid in understanding the biological function of Smad4 signaling in the context of intestinal homeostasis and tumorigenesis and permit further insight into potential therapeutic targets in colorectal carcinoma.