Mechanisms of APC-driven tumorigenesis: lessons from mouse models

Colorectal cancer still represents one of the most common causes of morbidi ty and mortality among Western populations. The adenomatous polyposis coli (APC) gene, originally identified as the gene responsible for familial aden omatous polyposis (FAP), an inherited predisposition to multiple colorectal tumors, is now considered as the true "gatekeeper" of colonic epithelial p roliferation. It is mutated in the vast majority of sporadic colorectal tum ors, and inactivation of both APC alleles occurs at early stages of tumor d evelopment in man and mouse. The study of FAP has also led to one of the mo st consistent genotype-phenotype correlations in hereditary cancer. However , great phenotypic variability is still observed not only among carriers of the identical APC mutation from unrelated families but also from within th e same kindred. The generation of several mouse models carrying specific Ap e mutations on the same inbred genetic background has confirmed the genotyp e-phenotype correlations initially established among FAP patients, as well as provided important insights into the mechanisms of colorectal tumor form ation. Here we review the major features of the available animal models for FAP and attempt the formulation of a hypothetical model for APC-driven tum origenesis based on the observed genetic and phenotypic variability in mous e and man.