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Induction of Prostaglandin E₂ Pathway Promotes Gastric Hamartoma Development with Suppression of Bone Morphogenetic Protein Signaling

¹ Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; ² Oncology Department, Banyu Tsukuba Research Institute, Tsukuba, Japan; and ³ Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan

Requests for reprints: Masanobu Oshima, Division of Genetics, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. Phone: 81-76-265-2721; Fax: 81-76-234-4519; E-mail: oshimam{at}kenroku.kanazawa-u.ac.jp.

Key Words: gastric hamartoma • BMP • PGE₂ • COX-2 • juvenile polyposis

Mutations in bone morphogenetic protein (BMP) receptor 1A (BMPR1A) are responsible for a subset of cases of juvenile polyposis (JP) syndrome that develops hamartomatous tumors in the gastrointestinal tract. Mouse genetic studies have shown that suppression of BMP signaling in the intestines causes JP-type hamartoma development. Here, we generated K19-Nog transgenic mice expressing noggin, a BMP antagonist, in gastric epithelium. However, inhibition of BMP signaling did not cause gastric phenotypes. We thus crossed K19-Nog with K19-C2mE mice that expressed Ptgs2 and Ptges in the stomach to generate compound transgenic mice. Expression of Ptgs2 and Ptges results in prostaglandin E₂ (PGE₂) biosynthesis, and both enzymes are induced in most human gastrointestinal tumors. Importantly, K19-Nog/C2mE compound mice developed gastric hamartomas that were morphologically similar to those found in JP with mucin-containing dilated cysts and inflammatory infiltration. Notably, treatment of K19-Nog/C2mE mice with a cyclooxygenase-2 inhibitor, celecoxib, significantly reduced tumor size with suppression of angiogenesis, suggesting that induction of the PGE₂ pathway together with inhibition of BMP signaling is required for gastric hamartoma development. Moreover, microarray analyses revealed that canonical Wnt signaling target genes were not induced in K19-Nog/C2mE hamartomas, indicating that BMP inhibition and PGE₂ induction lead to gastric hamartoma development independent of the Wnt/β-catenin pathway. These results, taken together, suggest that the PGE₂ pathway is an effective preventive target against BMP-suppressed gastric hamartomas, as well as for Wnt/β-catenin–activated adenocarcinomas. [Cancer Res 2009;69(7):2729–33]