Fas/CD95 Deficiency in Apc.sup.Min/+ Mice Increases Intestinal Tumor Burden

• Published in: PloS one 2010-02, Vol.5 (2), p.e9070
• Main Authors: Guillen-Ahlers, Hector, Suckow, Mark A, Castellino, Francis J, Ploplis, Victoria A
• Format: Article
• Language: English
• Subjects: Analysis; Apoptosis; B cells; Cancer; Colorectal cancer; Gastrointestinal diseases; Tumor proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009070

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. In the present study, a variant of the Apc.sup.Min/+ mouse, a model for the human condition, Familial Adenomatous Polyposis (FAP), was generated with an additional deficiency of Fas (Apc.sup.Min/+ /Fas.sup.lpr) by cross-breeding Apc.sup.Min/+ mice with Fas deficient (Fas.sup.lpr) mice. One of the main limitations of the Apc.sup.Min/+ mouse model is that it only develops benign polyps. However, Apc.sup.Min/+ /Fas.sup.lpr mice presented with a dramatic increase in tumor burden relative to Apc.sup.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.sup.Min/+ /Fas.sup.lpr mice relative to Apc.sup.Min/+ cohorts, which resulted in enhanced inflammation. This study demonstrated that imposition of a Fas deletion in an Apc.sup.Min/+ background results in a more aggressive phenotype of the Apc.sup.Min/+ mouse model, with more rapid development of invasive intestinal tumors and a decrease in Fas-L levels.