And the findings might one day lead to new treatments that could turn cancer into a chronic, though manageable, disease, the researchers say.
A team of American and Canadian scientists reports that tumstatin, a protein discovered two years ago, interferes with the creation of other proteins in cells that line blood vessel walls, halting out-of-control cell growth and stopping angiogenesis.Angiogenesis, or the growth of new blood vessels, has both positive and negative roles in the body. It's a delicate balance that is controlled by angiogenesis-stimulating molecules and angiogenesis inhibitors.
The findings, published in the Jan. 4 issue of Science, suggest that tumstatin is an angiogenesis inhibitor. As such, it plays a key role in maintaining the balance between healthy angiogenesis, which helps repair injuries, and harmful angiogenesis, which occurs in such illnesses as cancer and macular degeneration.
Blood vessels, and their smaller cousins called capillaries, are triple-layered tubes. The inner lining of the tube is made of endothelial cells. They are surrounded by the vascular basement membrane, or "barrel," which supports the tube structure. Finally, these two layers are encased in smooth muscle cells that provide further rigidity.
Until recently, scientists had believed that the barrel had only a structural role. But the research team led by Raghu Kalluri of Beth Israel Deaconess Medical Center in Boston suspected that the barrel was involved in the process of promoting and inhibiting angiogenesis.
The researchers hoped to find out how the barrel helped to control the behavior of the endothelial cells in both a normal blood vessel and in endothelial cells that were trying to divide to support a tumor.
When angiogenesis-stimulating molecules activate the endothelial cells, they secrete enzymes that create tiny holes in the barrel layer. This lets the rapidly dividing cells push through the holes and arrange themselves in lines toward the tumor. Molecules on the surface of the cells called integrins pull the cells toward the tumor. Eventually, these cells form a new blood vessel that feed nutrients to the growing tumor.
But Kalluri says that when tumstatin binds to one of the molecules, called alphaVbeta3 integrin, the molecule's function switches. Instead of accelerating new blood vessel growth, it stops the growth and the spread of the endothelial cells.
Kalluri's team did its research on cells from genetically engineered mice, as well as cells from cows. In the cow cells, for instance, when the researchers added tumstatin to the endothelial cells, they were able to slow angiogenisis by between 25 percent and 45 percent.
By understanding how tumstatin and other anti-angiogenesis proteins work together to halt tumor growth, Kalluri says that it may be possible to tilt the angiogenesis balance in a cancer patient's favor.
"All we're doing is learning what that balance is," says Kalluri. "[We're] trying to help the body do it more effectively, aligning our efforts with our own body to fight something that we don't want to grow."
"The other excitement is that these molecules, even if they don't completely kill the tumor will at least stop tumor growth, giving our body a chance to fight for itself," he adds. The body's own attempts at attacking the cancer could be helped along by surgery or radiation, he says.
As long as a patient continued to take drugs to control the angiogenesis, the cancer could essentially become a chronic, manageable disease similar to heart disease or high blood pressure, Kalluri says. Such therapies could be as little as five years away, he adds.
Kalluri anticipates that tumstatin, which will be tested in future clinical trials, will have few side effects because like other angiogenesis inhibitors, it exists naturally in the body.
Robert Kerbel, the head of molecular and cell biology at the Sunnybrook and Women's College Health Sciences Center in Toronto, says the Science paper is one of the first reports to suggest a clear molecular outline of how tumstatin functions.
"The whole area of [naturally occurring] protein inhibitors has been somewhat controversial as a result of not knowing the precise mechanism of action or what the receptors are for this type of angiogenesis inhibitor," says Kerbel. "It's very interesting that the targets that have been implicated by this study are integrins, such as alphaVbeta3."
What to Do: For more information on angiogenesis, check out the Angiogenesis Foundation, the National Cancer Institute, or this list of angiogenesis links from the WWW Virtual Library of Cell Biology.