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Researchers work to block blood vessel growth in tumors
by Leigh MacMillan
Cutting off supply lines is one way to strangle and defeat an enemy army.Vanderbilt University Medical Center researchers are applying that strategy in the war against tumors, which require supply lines—new blood vessels—to support their growth and spread, or metastasis.
Scientists at the Vanderbilt-Ingram Cancer Center have identified an unexpected participant in the process of blood vessel development. Their findings, reported recently in the journal Cancer Research, point to a new target for drugs that inhibit this development, also known as angiogenesis.
Angiogenesis inhibitors may offer certain advantages over standard chemotherapy, including fewer side effects and less risk of drug resistance. More than 20 angiogenesis inhibitors are being tested in clinical trials. The VICC has studied three of these agents.
Previous work from multiple laboratories had suggested that the enzyme cyclooxygenase-2 (COX-2) contributes to the blood vessel development associated with tumors. To determine which of many COX-2 products participate in angiogenesis, Dr. Thomas O. Daniel, Catherine McLaughlin Hakim Professor of Medicine, took advantage of a cultured endothelial cell system developed in his laboratory. The cultured cells migrate in response to angiogenic signals, just as they would in order to form new blood vessels in vivo.
Collaborator Dr. Jason D. Morrow, F. Tremaine Billings Professor of Medicine and Pharmacology, used mass spectrometry to establish that the activated endothelial cells generate the COX-2 products PGE2, thromboxane A2, and PGF2alpha. COX-2 inhibitors developed by Lawrence J. Marnett, Ph.D., Mary Geddes Stahlman Professor of Cancer Research, prevented the formation of all of these products and blocked the cell migration response.
Of the multiple products, only thromboxane A2 turned out to have a functional role in endothelial cell migration.
“Adding back thromboxane A2 under COX-2-inhibited conditions reconstituted cell migration,” said Daniel, who also heads the Vanderbilt Center for Vascular Biology.
Drugs that block the thromboxane A2 receptor also halted endothelial cell migration.
Using a model of angiogenesis in the mouse cornea, Daniel showed that the findings were not limited to cultured cells.
“All of our in vitro observations implicating thromboxane A2 in a COX-2 mediated response were borne out in vivo,” Daniel said. “Whether this will be true in other neovascularization contexts still needs to be determined.”
The studies suggest that thromboxane A2 receptor antagonists will function as angiogenesis inhibitors. A number of such drugs have been developed as anti-thrombotics. “Drugs that were developed and tested, but didn’t make it as better anti-thrombotics, might have applicability in the context of angiogenesis,” Daniel said. “It’s an idea that we will explore with commercial partners.”
Thromboxane A2 receptor-directed drugs may offer advantages over COX-2 inhibitors alone in blocking tumor angiogenesis.
“There are other ways to produce thromboxane A2 in tumors that don’t express a lot of COX-2. Blockers of the thromboxane A2 receptor might be effective in situations when COX-2 inhibitors are not,” Daniel said.
Combinations of drugs attacking different parts of the angiogenesis process, such as thromboxane A2 receptor antagonists and COX-2 inhibitors, may have fewer side effects and be more effective than standard chemotherapy. Anti-angiogenesis agents offer the additional hope for less risk of drug resistance since they target normal endothelial cells rather than genetically unstable tumor cells.
Other colleagues important to the studies were research associate Hua Liu and senior research associate Brenda Crews. The work was supported by the National Institutes of Health, the National Cancer Institute and the T.J. Martell Foundation.