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Cyclooxygenase-2 Expression and Effect of Celecoxib in Gastric Adenomas of Trefoil Factor 1-deficient Mice¹

Department of Pathology, Helsinki University Central Hospital, and Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, FIN-00014 Helsinki, Finland [K. S., K. N., and A. R.], and Institut de Génétique et de Biologie Moléculaire et Cellulaire, Unité Mixte de Recherche 7104 Centre National de la Recherche Scientifique/U184 Institut National de la Santé et de la Recherche Médicale/Universite Louis Pasteur, BP10142, 67404 Illkirch, C.U. de Strasbourg, France [C. T., M-C. R.]

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.

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