Fas/CD95 Deficiency in ApcMin/+ Mice Increases Intestinal Tumor Burden |
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Authors: | Hector Guillen-Ahlers Mark A Suckow Francis J Castellino Victoria A Ploplis |
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Institution: | 1. W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America.; 2. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America.; 3. Walther Cancer Research Center, University of Notre Dame, Notre Dame, Indiana, United States of America.; 4. Freimann Life Science Center, University of Notre Dame, Notre Dame, Indiana, United States of America.;Duke-NUS Graduate Medical School, Singapore |
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Abstract: | BackgroundFas, 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 FindingsIn the present study, a variant of the ApcMin/+ mouse, a model for the human condition, Familial Adenomatous Polyposis (FAP), was generated with an additional deficiency of Fas (ApcMin/+/Faslpr) by cross-breeding ApcMin/+ mice with Fas deficient (Faslpr) mice. One of the main limitations of the ApcMin/+ mouse model is that it only develops benign polyps. However, ApcMin/+/Faslpr mice presented with a dramatic increase in tumor burden relative to ApcMin/+ 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 ApcMin/+/Faslpr mice relative to ApcMin/+ cohorts, which resulted in enhanced inflammation.Conclusions/SignificanceThis study demonstrated that imposition of a Fas deletion in an ApcMin/+ background results in a more aggressive phenotype of the ApcMin/+ mouse model, with more rapid development of invasive intestinal tumors and a decrease in Fas-L levels. |
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