Published: Oct. 15, 1997
Updated: Nov. 3, 2004
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By Duke Medicine News and Communications
DURHAM, N.C. -- Researchers at Duke University Medical Center have been able to significantly slow the growth of tumors on rats by preventing the tumors from "signaling" nearby blood vessels to shoot out capillaries to feed the cancer.
They did this by treating the tumors with an inhibitor designed to neutralize a protein on tumor blood vessels called Tie2. A single application of this potion slowed the growth of tumors by 75 percent, compared to animals with untreated tumors.
The researchers said their findings, published in the October issue of the Journal of Clinical Investigation, takes them one step closer to a potential treatment for cancer: halting the growth and spread of tumors by eliminating their ability to hook into the body's blood supply.
"This is the first demonstration that this pathway is crucial for blood vessel growth in tumors, and could be a prime target for anti-angiogenesis tumor therapy," said Charles Lin, primary author of the study.
The research was funded by a National Cancer Institute Special program of Research Excellence in Breast Cancer grant, and other National Institutes of Health funds.
Angiogenesis, the formation of new capillaries from pre-existing blood vessels, is a fundamental process needed for normal growth as well as development of pathologic conditions such as cancer. Without formation of these tiny blood vessels, solid tumors will not grow beyond a few millimeters. But with an enriched environment provided by the new blood vessels, tumors thrive, and scientists say there is a direct correlation between the density of tumor vessels and an adverse prognosis in patients with certain solid tumors, including breast, colon, lung, kidney, bladder and head and neck tumors. Researchers said they are excited about the potential of treating a wide variety of cancers by stopping the process of angiogenesis in the patient. Theoretically, such treatment should only affect tumor formation because once a person has stopped growing, their vessel system is basically stable and only "grows" to repair an injury.
"We believe tumor angiogenesis is a process that can be stopped systemically without harming normal body function," said Dr. Kevin Peters, the study's principal investigator. "The ultimate hope is to make tumors dormant."
Tie2 is a protein receptor found on cells lining blood vessels. When activated by growth factors secreted by tumor cells, Tie2 triggers a series of events in the blood vessel – the vessel wall parts and a new capillary begins to grow, crawling to the tumor to feed it with nutritious blood. While scientists knew that the protein was important for vessel development, because embryonic mice without a Tie2 gene could not develop, they did not know what effect inhibiting the protein in tumors would have.
The Duke scientists reasoned that if they could interrupt the "call" of the tumor to the vessel – that is, the linking of the growth factor to the vessel endothelial cell – then they could prevent the tumor from developing the secondary blood vessels. So they designed a "decoy" for the Tie2 protein receptor whose role it was to bind to growth factor proteins on the tumor, preventing them from latching on to the real Tie2 and activating blood vessel growth.
With the help of Duke researchers Dr. Mark Dewhirst and Siqing Shan, the team then grafted human mammary tumors onto the back of rats to test the solution. They applied the mimic receptor to the tumors on one set of rats, and left the tumors on the "control" rats alone. After 10 days, the tumors on the treated rats, compared to the control rats, was 75 percent smaller, and the tumor vessel length density was reduced by 40 percent.
"It's exciting to see how this one time treatment slowed the growth so substantially," said Lin.
While a preparation that bathes a tumor is not useful for human applications, Lin and Peters said they hope that further study will uncover ways to refine the inhibitor for internal use in clinical trial testing.
Tie2 isn't the first protein identified to be involved in tumor angiogenesis, but it may be the most powerful, Lin and Peters said. Researchers have identified a different class of proteins known as VEGF (vascular endothelial growth factor) involved in the growth of blood vessels, and those findings are now being tested in cancer therapy clinical trials. But Lin said Tie2 appears to come into play further down the vessel formation "pathway," so that by disarming Tie2, VEGF is also inactivated.
The Tie2 pathway might offer another alternative to tumor angiogenesis therapy for those cancers that do not respond to VEGF treatment, Peters said. "Taken together, these studies suggest that, in a clinical setting, it may be important to determine which angiogenic pathway is most likely being used by an individual tumor in order to tailor therapy." The researchers also said that Tie2 may "have broad clinical utility" beyond cancer treatment. "Tie2 is not only an important mediator of tumor angiogenesis, it may also be involved in other forms of pathologic angiogenesis, such as retinal neovascularization, arthritis and atherosclerosis," Lin said.
The researchers are now testing the role of the Tie2 pathway in other disorders, and they are working to perfect the delivery of the experimental inhibitor, possibly through gene therapy approaches.