2nd Annual BMRP Investigator Meeting - Abstract
Barrier Breakdown in Mice Deficient in Antioxidant Defenses Leads to Ileal Colitis
Robert Steven Esworthy1,a, Fong-Fong Chu1, Peiguo G. Chu2, Jeffrey A. Longmate3, Mark M. Huycke4, Sharon Wilczynski2, and James H. Doroshow1
1Department of Medical Oncology and Experimental Therapeutics, 2Department of Anatomic Pathology and 3Division of Information Sciences, City of Hope National Medical Center (Duarte, California, U.S.A.); 4Department of Veteran Affairs Medical Center and University of Oklahoma Health Sciences Center (Oklahoma City, Oklahoma, U.S.A.)
Two glutathione peroxidase (GPX) isozymes, GPX-1 and GPX-2, are the major enzymes that reduce hydroperoxides in intestinal epithelium. We have previously demonstrated that targeted disruption of both the Gpx1 and Gpx2 genes (GPX-DKO) results in a high incidence of ileocolitis in mice when raised under conventional conditions that include the harboring of Helicobacter species (non-SPF condition).
In this report, we have characterized GPX-DKO mice to have microflora-associated intestinal cancer (25% of mice, largely in ileum) which is correlated with increased pathology/ inflammation. First, germ-free GPX-DKO mice have virtually no inflammation or tumors. Second, after colonizing germ-free mice with commensal microflora without any known pathogens (specific-pathogen-free, SPF), less than 9% of GPX-DKO mice develop tumors in the ilea (3%) or the colons (6%). Low cancer incidence in the ileum is associated with low pathology in young adults and complete resolution of disease by six months of age. Lastly, about one-fourth of non-SPF GPX-DKO mice either at birth or transferred from SPF condition at weaning have predominantly ileal tumors. Nearly 30% of tumors are cancerous with mostly invasive adenocarcinoma and a few signet-ring cell carcinomas.
Based on these results, we concluded that GPX-DKO mice are highly susceptible to bacteria-associated inflammation and cancer. The sensitivity exhibited in these mice suggests that peroxidative stress plays an important role in ileal and colonic inflammation, which can lead to tumorigenesis. The healing of SPF mouse ilea by six months of age and reinitiation of acute disease by contact with soiled bedding from non-SPF mice is being used to determine enzymatic and cellular pathways in acute inflammation and their relationship to oxidative stress.
aPrincipal Investigator