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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenoma / complications
-
Adenoma / drug therapy
-
Adenoma / enzymology*
-
Adenoma / genetics
-
Angiogenesis Inhibitors / blood
-
Angiogenesis Inhibitors / therapeutic use
-
Angiogenesis Inhibitors / toxicity
-
Animals
-
Celecoxib
-
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*
-
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
Substances
-
Angiogenesis Inhibitors
-
Cyclooxygenase 2 Inhibitors
-
Cyclooxygenase Inhibitors
-
Isoenzymes
-
Neoplasm Proteins
-
Peptides
-
Pyrazoles
-
RNA, Messenger
-
RNA, Neoplasm
-
Sulfonamides
-
Tff1 protein, mouse
-
Trefoil Factor-1
-
Cyclooxygenase 2
-
Prostaglandin-Endoperoxide Synthases
-
Celecoxib