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Molecular Pathology of Cyclooxygenase-2 in Cancer-induced Angiogenesis

Address correspondence to Egil Fosslien, M.D., Department of Pathology (M/C 847), College of Medicine, University of Illinois at Chicago, 1819 West Polk Street, Chicago, IL 60612, USA; tel 312 996 7323; fax 312 996 7586; e-mail: efosslie{at}uic.edu.

Cancer-induced angiogenesis is the result of increased expression of angiogenic factors, or decreased expression of anti-angiogenic factors, or a combination of both events. For instance, in colon cancer, the malignant cells, the stromal fibroblasts, and the endothelial cells all exhibit strong staining for cyclooxygenase-2 (COX-2), the rate-controlling enzyme in prostaglandin (PG) synthesis. In various cancer tissues, vascular endothelial growth factor (VEGF) and transforming growth factorß (TGF-ß) co-localize with COX-2. Strong COX-2 and VEGF expression is highly correlated with increased tumor microvascular density (MCD); new vessels proliferate in areas of the tumor that express COX-2. Moreover, high MVD is a predictor of poor prognosis in breast and cervical cancers. COX-2 and VEGF expression are elevated in breast and prostate cancer tissues and their cell-lines. In vitro, PGE2 induces VEGF. Supernatants of cultured cells from breast, prostate, and squamous cell cancers contain angiogenic proteins such as COX-2 and VEGF that induce in vitro angiogenesis. A selective COX-2 inhibitor, NS-398, restores tumor cell apoptosis, reduces microvascular density, and reduces tumor growth of PC-3 prostate carcinoma cells xenografted into nude mice. The COX-2 produced by a malignant tumor and COX-2 produced by the surrounding host tissue both contribute to new vessel formation, which explains how selective COX-2 inhibition reduces tumor growth where the tumor COX-2 gene has been silenced by methylation.

Keywords: cancer, angiogenesis, microvascular density, COX-2, PGE2, VEGF, TGF-ß, iNOS, TSP-1, p53, hypoxia, NSAIDs, celecoxib, rofecoxib

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