Is cyclooxygenase-2 the alpha and the omega in cancer?

Angiogenesis, the development of new blood vessels, is an essential step in the growth of tumors, since the growth of the malignant cells is limited by the availability of nutrients. Recent studies, including one by Williams et al. in this issue of the JCI (1), show that angiogenesis requires cyclooxygenase-2 (COX-2), the enzyme that catalyzes the committed step in the synthesis of prostaglandins. This exciting development suggests that inhibitors of COX-2 may be useful in the treatment of even malignant cancers and may not be restricted to use as chemopreventive agents; the latter application is currently being tested. As with most interesting findings, this report generates at least as many questions as it answers. In recent studies, a number of groups agree that COX-2 is crucial for tumor angiogenesis, but their agreement ends here — is the essential COX-2 found in the carcinomatous epithelial cells, the stromal cells, or the endothelial cells of the neovasculature? The answer, as indicated in Figure ​Figure1,1, seems to be “all of the above”. Figure 1 COX-2 expression in multiple cells in tumors of different stages. The sequence of events shown has been constructed from studies with multiple types of cancer. For example, the work on the earliest events was from mouse and human experiments on adenomatous ... In earlier work, some of the authors of the current report (1) used an in vitro system to examine the role(s) of COX-2 in angiogenesis and reported that colon cancer cells expressing COX-2 induced an angiogenic response in cocultured endothelial cells (2). In this earlier work, they also examined tumor cell xenografts and found that expression of COX-2 by the tumor cells was a key determinant of tumor growth. The implanted cell line grew poorly if there was no COX-2 expression, while cells expressing COX-2 grew to much larger tumors, whose growth could be blocked with a COX-2 inhibitor. In the same study, they found that COX-1 from the host was also important, and they implicated endothelial cells as the target. More recently, Sawaoka et al. implanted COX-2+ or COX-2– tumor cells into mice, which were then treated with inhibitors of COX-1 or -2 (3). When the implanted carcinoma cells were COX-2+, selective inhibitors of COX-2 decreased angiogenesis and tumor growth. However, when the implanted cells were COX-2–, the selective COX-2 inhibitors had no effect on tumor volume or on angiogenesis index. This result confirmed the findings of Tsujii et al. (2) that COX-2 expression in the cancer cell is key to angiogenesis. Likewise, Sawaoka and colleagues found that COX-1 from the host, presumably in endothelial cells, was also required for a complete response (3). The COX field has a record of turning up complications and controversy just when things seem to be clear, and COX function in angiogenesis is no exception. Jones et al. (4) recently reported that a selective inhibitor of COX-2 could block the angiogenic response to growth factors by cultured endothelial cell. This report conflicted with the earlier work suggesting that COX-1 was responsible for the endothelial cell response, and, further, it suggested a different locus for the responsible COX-2 in tumors. In support of this view, Masferrer and coworkers reported that multiple human cancers express COX-2 in the endothelial cells of the neovasculature, as well as the epithelial cells and some inflammatory cells (5). These authors also found that a selective inhibitor of COX-2, but not a selective inhibitor of COX-1, blocked angiogenesis and tumor growth in an implantation model. Based on these experiments, they proposed that COX-2 in host endothelial cells is the target of antiangiogenic therapy, and they employed a corneal model to show that selective inhibition of COX-2 blocks growth factor–dependent angiogenesis. Using a similar corneal model, as well as in vitro experiments, Daniel et al. (6) also concluded that endothelial cell COX-2 acts at an essential step in angiogenesis, and experiments in a different corneal model yielded the same conclusion (7). The expression of COX-2 by endothelial cells was no surprise, as some of the earliest work on human COX-2 expression used these cells (8, 9), but the idea that it contributes to angiogenesis was novel. Prior to the present study (1), the outstanding unanswered questions about COX function in this pathway centered on cell- and enzyme subtype–specificity: Does COX-2 act in the cancer cell, the endothelial cell, or both to control angiogenesis? Does COX-1 contribute as well? The experimental approach of Williams et al. (1) appears ideally suited to address these questions. They implanted Lewis lung carcinoma cells, which generate COX-2+ tumors, into mice that had been genetically engineered to lack either COX-2 or COX-1, and they observed a dramatic suppression of tumor growth and angiogenesis in the animals that lacked COX-2, compared to wild-type mice. The presence or absence of COX-1 made no difference for tumor growth. Williams et al. conclude that COX-2 is required — as everyone now appears to agree — but that it is the COX-2 in the host cells, not the tumor, that matters for tumor growth. Furthermore, they conclude that the relevant COX-2 is expressed not in endothelial cells but in the stromal cells of the tumor. This latter claim is based, first, on the observation that COX-2 occurs in stromal cells, and second, on these researchers’ work with fibroblasts cultured from animals lacking COX expression. Because COX-2–deficient fibroblasts failed to secrete VEGF, an important component of the angiogenic response, the current work identifies a previously unsuspected step in tumor angiogenesis, whereby COX-2 activity in the upstream stromal cell is required to deliver VEGF to the downstream endothelial cell for the latter to generate a new blood vessel.