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.


RESULTS
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
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.
Guillen-Ahlers
Hector
H
W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America.
Suckow
Mark A
MA
Castellino
Francis J
FJ
Ploplis
Victoria A
VA
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001772:Blood Cell Count; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016019:Survival Analysis; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics*
D025601:Adenomatous Polyposis Coli Protein; D053222:Fas Ligand Protein; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor