Fas/CD95 Deficiency in ApcMin/+ 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 cross-breeding Apc Min/+ mice with Fas deficient ( Fas lpr ) 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.