title: Cyclooxygenase-2 expression and effect of celecoxib in gastric adenomas of trefoil factor 1-deficient mice.
abstract: Expression of cyclooxygenase-2 (Cox-2) is elevated in gastric adenocarcinomas and precursor lesions leading to this disease. Mice deficient for trefoil factor 1 (TFF1) develop a pyloric adenoma with full penetrance. Because inhibition of Cox-2 suppresses tumor growth in several animal models, we studied expression of Cox-2 and effect of a selective Cox-2 inhibitor celecoxib in gastrointestinal tissues of the TFF1-deficient mice. Cox-2 mRNA and protein were strongly expressed in the pyloric adenomas of the TFF1(-/-) mice as detected by in situ hybridization and immunohistochemistry. Nonneoplastic gastrointestinal tissues of wild-type or TFF1(-/-) mice expressed low or nondetectable levels of Cox-2. Celecoxib (1600 ppm p.o. for 3 months) caused ulceration and inflammation of the adenoma in all treated TFF1(-/-) mice (n = 7). This effect of the drug was adenoma specific, because no histological alterations were observed in the non-neoplastic gastric or intestinal tissues in the TFF1(-/-) or wild-type mice receiving the drug treatment. All untreated TFF1(-/-) mice had an adenoma (n = 7), but none demonstrated the combination of ulceration and inflammation. Our data show that Cox-2 is expressed in gastric adenomas of the TFF1(-/-) mice and suggest that inhibition of Cox-2 disturbs the integrity of the adenoma by promoting ulceration and inflammation. These findings support the effort to initiate clinical studies to investigate the effect of Cox-2 inhibitors as a chemotherapeutic modality for dysplasias of the stomach.
authors.affiliation: Department of Pathology, Helsinki University Central Hospital, and Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Saukkonen
authors.forename: Catherine
authors.initials: C
authors.lastname: Tomasetto
authors.forename: Kirsi
authors.initials: K
authors.lastname: Narko
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Rio
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
mesh_terms: D000236:Adenoma / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity*; D004790:Enzyme Induction; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D005756:Gastritis / Q000139:chemically induced* / Q000209:etiology; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D010455:Peptides / Q000172:deficiency* / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000502:physiology*; D011708:Pylorus / Q000187:drug effects / Q000473:pathology; D011720:Pyrazoles; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000209:etiology; D013449:Sulfonamides / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity*; D000071163:Trefoil Factor-1
chemical_list: D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D010455:Peptides; D011720:Pyrazoles; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013449:Sulfonamides; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib