Molecular interactions in the Vogelstein model of colorectal carcinoma

For about a decade, the model proposed by Fearon and Vogelstein has been the paradigm of the genetic alterations involved in the development of colorectal carcinoma. During this time, much information has become available on the function of the key genes in this model, as well as on their interactions. This review examines the impact of this new knowledge on the Vogelstein model. It is concluded that the model as such still stands and with a few modifications could even be strengthened in that, contrary to the original proposal, the order of genetic events seems to be essential. Crucial molecular events include derangement of the Wnt- and defects in the transforming growth factor beta (TGFbeta)-signalling pathways, which exert a synergistic effect on the cell cycle. Finally, with loss of p53 function, several checks and balances are disrupted, which paves the way to gross chromosomal aberrations and aneuploidy.