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Clinical Cancer Research Vol. 8, 1157-1167, April 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

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

Crucial Role of Arachidonate Metabolism in Tumor Growth and Progression1

Toru Asano, Junichi Shoda2, Tetsuya Ueda, Toru Kawamoto, Takeshi Todoroki, Manabu Shimonishi, Tadashi Tanabe, Yukihiko Sugimoto, Atsushi Ichikawa, Michihiro Mutoh, Naomi Tanaka and Masanao Miwa

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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