Fas/CD95 deficiency in Apc^Min/+ mice increases intestinal tumor burden

Background: Fas, a member of the tumor necrosis family, is responsible for initiating the apoptotic pathway when bound to its ligand, Fas-L. Defects in the Fas-mediated apoptotic pathway have been reported in colorectal cancer. Methodology/Principal Findings: In the present study, a variant of the Apc ^Min/+ mouse, a model for the human condition, Familial Adenomatous Polyposis (FAP), was generated with an additional deficiency of Fas (Apc ^Min/+/Fas^lpr) by crossbreeding Apc^Min/+ mice with Fas deficient (Faslpr) mice. One of the main limitations of the Apc ^Min/+ mouse model is that it only develops benign polyps. However, Apc^Min/+/Fas^lpr mice presented with a dramatic increase in tumor burden relative to Apc^Min/+ mice and invasive lesions at advanced ages. Proliferation and apoptosis markers revealed an increase in cellular proliferation, but negligible changes in apoptosis, while p53 increased at early ages. Fas-L was lower in Apc^Min/+/Fas^lpr mice relative to Apc^Min/+ cohorts, which resulted in enhanced inflammation. Conclusions/Significance: This study demonstrated that imposition of a Fas deletion in an Apc^Min/+ background results in a more aggressive phenotype of the Apc^Min/+ mouse model, with more rapid development of invasive intestinal tumors and a decrease in Fas-L levels.