Inhibition of cyclooxygenase-2 causes regression of gastric adenomas in trefoil factor 1 deficient mice

• Published in: International journal of cancer Vol. 131; no. 5; pp. 1032 - 1041
• Main Authors: Thiel, Alexandra, Narko, Kirsi, Heinonen, Mira, Hemmes, Annabrita, Tomasetto, Catherine, Rio, Marie-Christine, Haglund, Caj, Mäkelä, Tomi P., Ristimäki, Ari
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: adenoma; Adenoma - metabolism; Adenoma - pathology; Adenoma - prevention & control; Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Cancer; carcinogenesis; Celecoxib; Cell Proliferation; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - physiology; Cyclooxygenase 2 Inhibitors - therapeutic use; cyclooxygenase-2; Enzymes; Female; Fluorescent Antibody Technique; Gastric cancer; Immunoenzyme Techniques; Male; Medical research; Medical sciences; Mice; Mice, Knockout; Peptides - physiology; prostaglandin-endoperoxide synthase 2; Pyrazoles - therapeutic use; Rodents; Stomach - metabolism; Stomach - pathology; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Stomach Neoplasms - prevention & control; Sulfonamides - therapeutic use; Trefoil Factor-1; Tumors; Prostaglandin-endoperoxide synthase; Stomach; Digestive system; Enzyme; Cyclooxygenase 2; Rodentia; cyclooxygenase-2; Enzyme inhibitor; Regression; Cyclooxygenase 2 inhibitor; Adenoma; Celecoxib; Carcinogenesis; Vertebrata; Mammalia; Cancerology; Mouse; Animal; trefoil factor 1; Oxidoreductases; Benign neoplasm; prostaglandin-endoperoxide synthase 2
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27331

Cyclooxygenase‐2 (Cox‐2) expression is a marker of reduced survival in gastric cancer patients, and inhibition of Cox‐2 suppresses gastrointestinal carcinogenesis in experimental animal models. To investigate the role of Cox‐2 in gastric carcinogenesis in vivo, we utilized trefoil factor 1 (Tff1) deficient mice, which model the neoplastic process of the stomach by developing gastric adenomas with full penetrance. These tumors express Cox‐2 protein and mRNA, and we have now investigated the effects of genetic deletion of the mouse Cox‐2 gene [also known as prostaglandin‐endoperoxide synthase 2 (Ptgs2)] and a Cox‐2 selective drug celecoxib. Our results show that genetic deletion of Cox‐2 in the Tff1 deleted background resulted in reduced adenoma size and ulceration with a chronic inflammatory reaction at the site of the adenoma. To characterize the effect of Cox‐2 inhibition in more detail, mice that had already developed an adenoma were fed with celecoxib for 8–14 weeks, which resulted in disruption of the adenoma that ranged from superficial erosion to deep ulcerated destruction accompanied with chronic inflammation. Importantly, mice fed with celecoxib for 16 weeks, followed by control food for 9 weeks, redeveloped a complete adenoma with no detectable inflammatory process. Finally, we determined the identity of the Cox‐2 expressing cells and found them to be fibroblasts. Our results show that inhibition of Cox‐2 is sufficient to reversibly disrupt gastric adenomas in mice.