Cyclooxygenase-2 expression and effect of celecoxib in gastric adenomas of trefoil factor 1-deficient mice

• Published in: Cancer research (Chicago, Ill.) Vol. 63; no. 12; pp. 3032 - 3036
• Main Authors: SAUKKONEN, Kirsi, TOMASETTO, Catherine, NARKO, Kirsi, RIO, Marie-Christine, RISTIMÄKI, Ari
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.06.2003
• Subjects: Adenoma - complications; Adenoma - drug therapy; Adenoma - enzymology; Adenoma - genetics; Angiogenesis Inhibitors - blood; Angiogenesis Inhibitors - therapeutic use; Angiogenesis Inhibitors - toxicity; Animals; Biochemistry, Molecular Biology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Celecoxib; Chemical agents; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - blood; Cyclooxygenase Inhibitors - therapeutic use; Cyclooxygenase Inhibitors - toxicity; Enzyme Induction; Gastric Mucosa - drug effects; Gastric Mucosa - pathology; Gastritis - chemically induced; Gastritis - etiology; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Isoenzymes - antagonists & inhibitors; Isoenzymes - biosynthesis; Isoenzymes - physiology; Life Sciences; Medical sciences; Mice; Mice, Knockout; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - physiology; Peptides - deficiency; Peptides - genetics; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - physiology; Pylorus - drug effects; Pylorus - pathology; Pyrazoles; RNA, Messenger - biosynthesis; RNA, Neoplasm - biosynthesis; Stomach Neoplasms - complications; Stomach Neoplasms - drug therapy; Stomach Neoplasms - enzymology; Stomach Neoplasms - genetics; Stomach Ulcer - chemically induced; Stomach Ulcer - etiology; Sulfonamides - blood; Sulfonamides - therapeutic use; Sulfonamides - toxicity; Trefoil Factor-1; Tumors; Stomach; Prostaglandin-endoperoxide synthase; Dysplasia; Premalignant lesion; Trefoil factor; Enzyme; Rodentia; Enzyme inhibitor; Adenoma; Celecoxib; Anticarcinogen; Gene expression; Non steroidal antiinflammatory agent; Vertebrata; Chemotherapy; Mammalia; Mouse; Animal; Oxidoreductases; Benign neoplasm; Mutation
• ISSN: 0008-5472; 1538-7445; 1538-7445

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.