Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis.
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 factor beta (TGF-beta) 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 VEGE 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.
Fosslien
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Department of Pathology, College of Medicine, University of Illinois at Chicago, 60612, USA. efosslie@uic.edu
D000818:Animals; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases