Transitional cell hyperplasia and carcinomas in urinary bladders of transgenic mice with keratin 5 promoter-driven cyclooxygenase-2 overexpression.
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 approximately 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.
Klein
Russell D
RD
Department of Human Nutrition and Internal Medicine, Ohio State University, Columbus, Ohio, USA.
Van Pelt
Carolyn S
CS
Sabichi
Anita L
AL
Dela Cerda
Jorge
J
Fischer
Susan M
SM
Fürstenberger
Gerhard
G
Müller-Decker
Karin
K
D000818:Animals; D001402:B-Lymphocytes; D002295:Carcinoma, Transitional Cell / Q000201:enzymology* / Q000235:genetics; D049109:Cell Proliferation; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006965:Hyperplasia / Q000201:enzymology* / Q000235:genetics; D007249:Inflammation; D053569:Keratin-15; D053555:Keratin-5; D007633:Keratins / Q000235:genetics*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes; D014158:Transcription, Genetic; D001743:Urinary Bladder / Q000201:enzymology; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C503940:KRT5 protein, human; D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D007633:Keratins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases