Tumor-Starving Protein Identified

Discovery inhibits growth of vessels that feed cancer

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HealthDay Reporter

FRIDAY, June 18, 2004 (HealthDayNews) -- Researchers in Colorado say they have identified a protein that thwarts the growth of new blood vessels that feed and enlarge tumors.

The protein, called fibulin-5, occurs naturally in the body, but researchers say a slightly altered version proved even more effective in arresting blood vessel growth.

The protein works by choking off the nutrient and oxygen supply to tumors, preventing the cancer from growing and spreading to other parts of the body. Researchers believe it could one day be developed as a drug to treat cancer patients.

If further testing bears out its effectiveness, fibulin-5 may join an emerging class of drugs that inhibit angiogenesis, the sprouting of new blood vessels.

"If you can block angiogenesis, you can essentially starve a tumor," explained William P. Schiemann, assistant professor in the cell biology program at National Jewish Medical and Research in Denver and a co-author of the paper, which appears in the June issue of the journal DNA and Cell Biology.

Since the protein can be detected in blood serum and urine, it may also serve as a useful marker in diagnosing cancer status, said Emmanuel Hilaire, a technology transfer specialist at National Jewish.

If fibulin-5 is dropping, it might signal a tumor is preparing to grow or spread, he explained. "You should be able to detect that difference by developing a diagnostic kit."

Harvard University's Dr. Judah Folkman, whose pioneering research in angiogenesis has spawned a booming field of laboratory investigation, said the article is very important because of its many, rather immediate implications.

The study will likely garner great interest, Folkman believes, since it's the first to demonstrate the anti-angiogenic effects of fibulin-5.

"This paper announces a new direction in which many labs may want to follow up immediately," he asserted.

Fibulin-5, a member of a family of proteins that regulate tissue development and repair, interacts with endothelial cells, which are specialized cells that are capable of forming new blood vessels.

To spur new blood vessel growth, cancer cells release special molecules signaling angiogenesis to begin. One of them is called vascular endothelial growth factor (VEGF).

Schiemann and postdoctoral fellow Allan R. Albig wanted to know more about fibulin-5's function. "We approached it with the hypothesis that it's likely regulating some aspect of angiogenesis," Schiemann said.

In cell cultures, the authors showed fibulin-5 levels plummet when endothelial cells begin to form blood vessels. High levels of the protein, they discovered, could prevent new blood vessel growth by frustrating the ability of endothelial cells to move and proliferate.

The study showed that fibulin-5 inhibits blood vessel growth in two ways. For one, it tells the endothelial cells to pay no attention to the incoming pro-angiogenic factor VEGF. Simultaneously, it boosts levels of thrombospondin-1, a naturally occurring protein that can inhibit angiogenesis.

"It prevents acceleration and puts on the brakes," Folkman said. "It's unusual to see a single molecule do two things like that."

The fibulin-5 discovery also may have applications in clinical areas other than cancer. As an example, Folkman cites a 1999 mouse study led by Harvard's Dr. Karen Moulton, an instructor in surgery, showing that the angiogenesis inhibitor endostatin significantly reduced plaque buildup.

Since fibulin-5, like endostatin, is found in the walls of the arteries, "It raises the speculation of whether atherosclerotic plaques have a fibulin deficiency," Folkman said.

In February, the U.S. Food and Drug Administration approved Avastin, a treatment for colorectal cancer and the first drug to choke tumor growth by preventing new blood vessels from forming.

But the scientific quest for the next angiogenesis inhibitor is in full throttle. In the United States, roughly 30 angiogenesis inhibitors are being tested and about 62 different trials are being conducted, Folkman said. Worldwide, at least 50 agents that block blood vessel growth are being tested, he said.

"I think it's important that in order to really develop effective therapies that you're going to have to come at these problems from more than one direction," Schiemann said. "I think you greatly increase your chances of success."

More information

The National Institutes of Health can answer your questions about how angiogenesis works.

SOURCES: William P. Schiemann, Ph.D., assistant professor, Department of Pediatrics, Program in Cell Biology, National Jewish Medical and Research Center, Denver; Emmanuel Hilaire, Ph.D., technology transfer specialist, National Jewish Medical and Research Center; Judah Folkman, M.D., professor of pediatric surgery and professor of cell biology, Harvard Medical School, and senior associate in surgery, Children's Hospital, Boston; June 2004 DNA and Cell Biology

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