Transitional cell hyperplasia and carcinomas in urinary bladders of transgenic mice with keratin 5 promoter-driven cyclooxygenase-2 overexpression

Cancer Res. 2005 Mar 1;65(5):1808-13. doi: 10.1158/0008-5472.CAN-04-3567.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes
  • Carcinoma, Transitional Cell / enzymology*
  • Carcinoma, Transitional Cell / genetics
  • Cell Proliferation
  • Cyclooxygenase 2
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Hyperplasia / enzymology*
  • Hyperplasia / genetics
  • Inflammation
  • Keratin-15
  • Keratin-5
  • Keratins / genetics*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • Neoplasm Staging
  • Promoter Regions, Genetic*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • T-Lymphocytes
  • Transcription, Genetic
  • Urinary Bladder / enzymology
  • Urinary Bladder Neoplasms / enzymology*
  • Urinary Bladder Neoplasms / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • KRT5 protein, human
  • Keratin-15
  • Keratin-5
  • Krt15 protein, mouse
  • Membrane Proteins
  • Vascular Endothelial Growth Factor A
  • Keratins
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases