title: Predisposition to colorectal cancer in rats with resolved colitis: role of cyclooxygenase-2-derived prostaglandin d2.
abstract: Colitis markedly increases the risk of developing colon cancer, but the underlying mechanisms are not fully understood. In a rat model of colitis, alterations in epithelial secretion, proliferation, and barrier function persist long after healing has occurred. In the present study, we examined whether rats that have recovered from a bout of colitis are more susceptible to preneoplastic lesions and whether this susceptibility is mediated by cyclooxygenase (COX)-2-derived prostaglandin (PG) D2. Colitis was induced by intracolonic administration of trinitrobenzenesulfonic acid. Six weeks later, weekly treatment with the carcinogen azoxymethane was initiated. Postcolitis rats exhibited significantly more aberrant crypt foci after azoxymethane treatment than controls. The postcolitis rats also exhibited markedly increased colonic PGD2 synthesis and elevated COX-2, H-PGD synthase, and beta-catenin expression. Treatment for 1 week with a selective COX-2 inhibitor or with a selective PGD2 receptor (DP1) antagonist significantly reduced susceptibility of postcolitis rats to aberrant crypt foci development, beta-catenin expression, and mucosal thickness. The results from this animal model suggest that prolonged elevation of COX-2-derived PGD2 synthesis after resolution of colitis may contribute significantly to colitis-associated increases in colon cancer incidence. PGD2 may therefore represent a rational target for therapies directed at reducing the incidence of colitis-associated colorectal cancer.
authors.affiliation: Mucosal Inflammation Research Group, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1, and the Division of Gastroenterology, Kelowna General Hospital, British Columbia, Canada.
authors.forename: Stella R
authors.initials: SR
authors.lastname: Zamuner
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Bak
authors.forename: Pallavi R
authors.initials: PR
authors.lastname: Devchand
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000008:administration & dosage; D003092:Colitis / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000209:etiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis; D054834:Lipocalins; D008297:Male; D015230:Prostaglandin D2 / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D054834:Lipocalins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D051176:beta Catenin; D014302:Trinitrobenzenesulfonic Acid; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D001397:Azoxymethane; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor