The interplay between intrinsic and extrinsic Wnt signaling in controlling intestinal transformation.

ABSTRACT

The intestinal epithelial layer is the fastest renewing tissue in the human body. Due to its incredible turnover rate, the intestine is especially prone to develop cancer, in particular in the colon. Colorectal cancer (CRC) development is characterized by the stepwise accumulation of mutations over time, of which mutations in the tumor suppressor APC are often very early to occur. Generally, mutations in this gene lead to truncated APC proteins that cannot bind to ß-catenin to promote its degradation, resulting in a constant overstimulation of the Wnt pathway. The level of intrinsic Wnt activation is dependent on the number of functional ß-catenin binding sites remaining within the APC proteins, and the right amount of Wnt signaling is rate-limiting in the formation of polyps. In addition, the intestinal niche provides an extensive spectrum of Wnt ligands, amplifiers and antagonists that locally regulate basal Wnt levels and consequently influence polyp formation propensity. Here we will discuss the crosstalk between transforming epithelial cells and their regional niche in the development of intestinal cancer.