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Expressions of Cyclooxygenase-2 and Prostaglandin E-Receptors in Carcinoma of the Gallbladder

Crucial Role of Arachidonate Metabolism in Tumor Growth and Progression¹

Departments of Gastroenterology [T. A., J. S., M. M., N. T.] and Gastrointestinal Surgery [T. K., T. T.], Institute of Clinical Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki 305-8575; Department of Pharmaceutical Research, Mitsubishi Kagaku Bio-Clinical Laboratories, Inc., Itabashi-ku, Tokyo 174-8555 [T. U.]; Department of Pharmacology, National Cardiovascular Center Research Institute, Fujishirodai, Suita, Osaka 565-8565 [M. S., T. T.]; Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, University of Kyoto, Yoshida, Sakyo-ku, Kyoto 606-8501 [Y. S., A. I.]; Cancer Prevention Division, National Cancer Research Institute, Chuo-ku, Tokyo 104-0045 [M. M.]; and Department of Biochemistry and Molecular Oncology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba-shi, Ibaraki 305-8575 Japan [M. M.]

An association of gallbladder carcinoma with cholelithiasis suggests that chronic inflammation may modulate tumorigenesis and/or progression of the carcinoma. An enhanced expression of cyclooxygenase-2 (COX-2) is observed frequently in advanced carcinomas of gastrointestinal tracts, which in turn suggests that potentiated arachidonate metabolism may play a crucial role in tumor biology. In the present study, the expression levels of COX-2 and prostaglandin E receptor subtypes were determined in 16 cases of gallbladder carcinomas of different depths of invasion (pT₁ 3, pT₂ 2, pT₃ 4, and pT₄ 7) to determine the role of arachidonate metabolism in tumor growth and progression. The mRNA levels of COX-2 were increased significantly in pT₃ and pT₄ carcinomas compared with the levels in pT₁ and pT₂ carcinomas. Immunohistochemistry and in situ hybridization revealed the existence of COX-2 mRNA and protein in both the cancerous epithelia and adjacent stroma of pT₁-pT₄ carcinomas. Only in pT₃ and pT₄ carcinomas was intense expression of COX-2 observed in the adjacent stroma. The tissue concentration of PGE₂ was significantly increased in pT₃ and pT₄ carcinomas. The mRNAs of PGE receptor subtypes EP₂, EP₃, and EP₄ were amplified in pT₁-pT₄ gallbladder carcinomas, in which their mRNAs and EP₄ protein were expressed mostly in the cancerous epithelia. Treatment with a specific EP₄ agonist, as well as PGE₂ but not EP₂ and EP₃ agonists, up-regulated the expression of c-fos, an induced growth response gene, and increased colony formation. In advanced gallbladder carcinoma, enhanced expression of COX-2 is observed in the adjacent stroma rather than in the cancerous epithelia, and the stroma is a potent source of PG synthesis. In epithelial-stromal interactions, the increased PGE₂ synthesis in the adjacent stroma and its biological effect via EP₄ on the carcinoma cells may contribute to tumor growth and progression of gallbladder carcinoma.

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