Role of transforming growth factor beta and Wnt signalling pathways in colon cancer

摘要

The colonic epithelium undergoes constant renewal. The lower sections of colonic crypts contain stem cells and progenitors that undergo cell division and then migrate towards the top of the crypt. Evidence of Wnt pathway activation in lower-crypt localized cells suggests that Wnts are important factors in the regulation of cell division. In contrast to these highly proliferative cells, those found towards the top of the crypt cease division and differentiate. There is evidence of Transforming Growth Factor beta (TGF-beta) activation in differentiated cells of the crypt surface since these cells express TGF-beta, TGF-beta receptors, Smads and PMEPA1, a direct target of the TGF-p pathway. These data suggest a model in which Wnt regulates cell division in the lower region of colon crypts, while TGF-beta regulates cell differentiation at the top of the crypt. However, our recent data suggest that TGF-beta is also active in proliferating crypt cells suggesting that it may also play a role in cell proliferation. Alterations in the signalling of both pathways have been implicated in colon tumours and we have also observed simultaneous activation of TGF-P and Wnt pathways in adenomas derived from several mouse models of gastrointestinal cancers. Thus, there may be considerable interplay between the two pathways in controlling the differentiation of the colonic epithelium during adult homeostasis and in the development of colon cancers.