Colorectal cancer is amongst the most threatening diseases of the Western world. It is the second most common type of cancer with one million new cases diagnosed per year worldwide. Although several components of the canonical Wnt signaling pathway are implicated in tumor transformation in the gastrointestinal tract, little is known about their physiological role during intestinal development.
The overwhelming majority of colorectal cancers carry activating mutations in the Wnt signal transduction cascade inducing the initial transformation of crypt epithelial cells. Increased levels of beta-catenin lead to the inappropriate activation of the transcription factor Tcf4 in these colorectal cancer cells. Artificial inhibition of this pathway showed that the inappropriately activated Tcf4 program in these cancer cells is identical to that of crypt progenitor cells. In other words, through mutations in Wnt cascade components, the transformed epithelial cell henceforth behaves as a progenitor cell.
Several studies have found that inhibition of the initiating transforming event in CRC cell lines, i.e. the inappropriate formation of a beta-catenin/Tcf4 complex, drives these cells out of cycle in the face of multiple other acquired mutations in their genome. Tcf4 inhibition actually induces CRC cells to differentiate into a villus epithelial phenotype, essentially completing their life cycle after many years delay. This result implicates the beta-catenin/Tcf4 complex as a valuable target for therapeutic intervention.
To study the role of Tcf4 in colorectal cancer development, a conditional Tcf4-/- knockout mouse model was generated. Thus the Tcf4 gene can be deleted at will in the adult intestinal epithelium of various mouse tumor models to reveal the effects of blocking the Wnt cascade on intestinal tumor development at various stages in cancer progression. Taken together, this study will provide in vivo validation for the utility of blocking the Wnt cascade as a treatment for intestinal neoplasia.
