Los Angeles, CA. –– A key protein in the growth and survival of new blood vessels—a process called angiogenesis—can also directly promote the growth and survival of malignant tumor cells, according to research done by scientists at the Keck School of Medicine of the University of Southern California.
"We’ve shown that a protein that everybody knows is an angiogenesis regulator also regulates tumor cells directly," says Parkash Gill, M.D., professor of medicine and pathology at the Keck School and principal investigator on the paper, which was published in the September 15 issue of the journal Blood. "And this observation was not limited to one tumor type but rather to an extensive list of tumors. In other words, this principle has broad applications."
The protein in question, called vascular endothelial growth factor—or VEGF—has attracted a lot of attention for its role in the formation of new blood vessels. Cancer researchers have been particularly keen to find ways to inhibit VEGF’s effects in the body, since cutting off a tumor’s blood supply should stop it from growing and spreading.
But even the best of the new VEGF inhibitors have a hit and miss quality, notes Gill. "Some patients seem to respond," he explains, "while others don’t." In their study, Gill and his colleagues at the Keck School and the USC/Norris Comprehensive Cancer Center showed that the difference might lie in whether the patients’ tumor cells carry on their surface a receptor for the VEGF protein.
The researchers found production of VEGF and expression of a VEGF receptor on cell lines derived from Kaposi’s sarcomas, melanomas, ovarian carcinomas, pancreatic carcinomas and prostate carcinomas. "The coexpression of VEGF and its receptors in some of these tumor cell lines raised the possibility of autocrine growth factor activity," they write.
The best way to test this possibility, explains Gill, was to somehow stop VEGF from binding to the receptors, and see what happened to the tumors. To do this, the team used an inhibitor called VEGF AS-3 that they themselves had recently developed. "It’s a short stretch of DNA that blocks the production of the VEGF protein," explains Gill.
(The VEGF AS-3 inhibitor has been extensively tested in vitro and in animal models of ovarian cancer, prostate cancer, melanoma and Kaposi’s sarcoma, and is expected to begin clinical trials early next year. "One of the more exciting aspects," says Gill, "is that it utilizes chemistry that allows it to be given by mouth.")
When VEGF AS-3 was introduced to the cell lines, the normally proliferative cancer cells were brought to a near-standstill. The inhibitor had similar effects in mouse models of ovarian cancer, prostate cancer, pancreatic cancer and melanoma. In even more recent tests, it has been shown to also have an effect on malignant mesothelioma—a highly virulent, asbestos-related form of cancer.
The discovery that VEGF works directly on tumor cells that display its receptor may allow physicians to predict whether using a VEGF inhibitor as part of the therapy will produce a favorable outcome, says Gill. "We’re going to be able to test for the receptor on the tumor cells directly," he explains, "and thus predict response to VEGF inhibitors. We are now going to be able to sort out who is likely to respond most strongly to these drugs."
Of course, he adds, even those people who don’t carry the VEGF receptor will benefit from VEGF inhibitors, since those drugs will still be able to slow or halt angiogenesis. "When combined with other treatments," says Gill, "the VEGF inhibitors are especially useful because they have a different mechanism of action. We’ve found that they tend to add to each other’s activity—to be additive if not actually synergistic. This may be even more important in patients who are receptor negative, who will only have a blood vessel response to these inhibitors."
The work was supported in part by the National Institutes of Health, the Lynne Cohen Foundation and the University of California.
Rizwan Masood, Jie Cai, Tong Zheng, D. Lynne Smith, David R. Hinton, and Parkash S. Gill. "Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors." Blood, Volume 98, Number 6, 15 September, 2001.
Journal
Blood