Cyclooxygenase 2-derived prostaglandin E 2 regulates the angiogenic switch

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Abstract
The first evidence of a potential relationship between the cyclooxygenase 2 (COX-2) enzyme and human cancers was reported in 1994, when COX-2 mRNA levels were found to be markedly elevated in colorectal carcinomas (1). Several subsequent reports verified and extended these findings (2). COX-2 (prostaglandin endoperoxide synthase) converts arachidonic acid to bioactive lipids, including prostaglandins (PGs) and thromboxanes. Considerable evidence suggests that COX-2 may contribute to the development of colorectal cancer as well as other human cancers. For example, in a mouse model of familial adenomatous polyposis, knocking out COX-2 protects against the formation of intestinal polyps, suggesting that COX-2 is involved in adenoma formation (3). Recently, COX-2 transgenic mice have been created to further explore the role of COX-2 in cancer. Transgenic mice with COX-2 expression driven by the keratin-5 promoter did not develop skin cancer spontaneously but were much more sensitive to carcinogen-induced tumor formation, indicating that COX-2 overexpression alone was not sufficient to induce skin cancer (4). However, Hla and colleagues (5) generated COX-2 transgenic mice in which expression was driven by the murine mammary tumor virus (MMTV) promoter. Interestingly, breast carcinomas develop spontaneously in multiparous female MMTV–COX-2 mice. These studies have extended our understanding of the role of cyclooxygenase in carcinogenesis by demonstrating that forced expression of COX-2 alone is sufficient to induce mammary gland cancer. In this issue of PNAS, Chang et al. (6) report studies that studies delineate the molecular mechanism(s) by which COX-2-derived prostaglandin E2 (PGE2) induces tumor-associated angiogenesis, which is required for the initiation and/or progression of mammary cancer in MMTV–COX-2 mice. They observed that PGE2 induced angiogenesis at the earliest stage of tumor development, even before PGE2-induced mammary gland hyperplasia, providing a new understanding of the role of …