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Transitional Cell Hyperplasia and Carcinomas in Urinary Bladders of Transgenic Mice with Keratin 5 Promoter-Driven Cyclooxygenase-2 Overexpression

¹ Departments of Human Nutrition and Internal Medicine, Ohio State University, Columbus, Ohio; Departments of ² Veterinary Medicine and Surgery and ³ Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁴ Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas; and ⁵ Research Group Eicosanoids and Tumor Development, Deutsches Krebsforschungzentrum, Heidelberg, Germany

Requests for reprints: Karin Müller-Decker, Section Eicosanoids and Tumor Development, A140, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49-6221-424531; Fax: 49-6221-424406; E-mail: K.Mueller-Decker{at}DKFZ.de.

The inducible form of cyclooxygenase (COX), COX-2, is up-regulated in many epithelial cancers and its prostaglandin products increase proliferation, enhance angiogenesis, and inhibit apoptosis in several tissues. Pharmacologic inhibition and genetic deletion studies showed a marked reduction of tumor development in colon and skin. COX-2 has also been strongly implicated in urinary bladder cancer primarily by studies with nonselective COX- and COX-2-selective inhibitors. We now show that forced expression of COX-2, under the control of a keratin 5 promoter, is sufficient to cause transitional cell hyperplasia (TCH) in 17% and 75% of the heterozygous and homozygous transgenic lines, respectively, in an age-dependent manner. TCH was strongly associated with inflammation, primarily nodules of B lymphocytes; some T cells and macrophage infiltration were also observed. Additionally, transitional cell carcinoma was observed in 10% of the K5.COX-2 transgenic mice; no TCH or transitional cell carcinoma was observed in wild-type bladders. Immunohistochemistry for vascular proliferation and vascular endothelial growth factor showed significant increases above that in wild-type urinary bladders. Our results suggest that overexpression of COX-2 is sufficient to cause hyperplasia and carcinomas in the urinary bladder. Therefore, inhibition of COX-2 should continue to be pursued as a potential chemopreventive and therapeutic strategy.

Key Words: Prostaglandins • Bladder Cancer • Cyclooxygenase • Inflammation

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