Holland Lab Discovery Could Lead to New Tumor-Fighting Drugs

Written by Becky Orfinger, Staff Writer, RedCross.org

April 30, 2001 — Although scientists have been researching cancer and its causes for more than a century, more than 500,000 Americans die from the disease each year, and both physicians and patients welcome new treatment options. New research conducted at the American Red Cross Jerome H. Holland Laboratory for Biomedical Sciences in collaboration with scientists at EntreMed, Inc. has identified a molecule that may lead to a novel way to shrink cancerous tumors. Experts have long known that a protein called "tissue factor pathway inhibitor" (TFPI) is a critical component in the process of blood coagulation (clotting). The new study found that TFPI also plays an important role in the process of angiogenesis, or the growth of new blood vessels.

According to Dr. Dudley Strickland, one of the study's authors and head of the Vascular Biology Department at the Holland Lab, there is a link between blood clotting and angiogenesis.

In this illustration, the cancerous tumor (gray mass) has already started to form new blood vessels, or undergo the process of angiogenesis. Photo courtesy of the University of Wisconsin.

"When blood vessels are cut or damaged, causing bleeding, a receptor called 'tissue factor' binds to a coagulation protein known as 'factor VII'. The result is a complex that functions as an enzyme to facilitate clotting. Studies have shown that when TFPI is present, it will bind to the tissue factor/factor VII complex and interrupt the clotting process," he said. "Our work has now shown that in addition to this activity, TFPI can also alter the growth of cells that form new blood vessels, which is important in slowing the progression of cancer," said Strickland

Scientists at EntreMed, Inc., a pharmaceutical company, have been interested in molecules that can interrupt angiogenesis. "Tumors need a supply of oxygen and nutrients in order to thrive," explained Strickland, "both of which come from new blood vessels." As a tumor grows, the number of blood vessels around the tumor increases and serves as the tumor's local blood and oxygen supply.

Antiangiogenic agents, which prevent the formation of these new vessels, are being investigated by several pharmaceutical companies for their potential tumor-shrinking abilities. The renowned cancer researcher Dr. Judah Folkman pioneered angiogenesis research 30 years ago when he recognized that the spread of cancerous tumors were dependent on the growth of new blood vessels. Scientists at EntreMed later developed, and are currently testing, several antiangiogenic drug candidates in clinical trials.

Scientists at the American Red Cross Jerome H. Holland Laboratory for the Biomedical Sciences, pictured above, are researching new ways to fight cancerous tumors.

In collaboration with Strickland and his Holland Lab colleagues, EntreMed scientists hoped to learn more about the specific way that TFPI interacts with molecules involved in the growth of new blood vessels, and then develop even more potent antiangiogenic agents based on their findings. In a Journal of Biological Chemistry article by Hembrough et al., the scientists reported that TFPI works as an antiangiogenic agent by binding not to tissue factor, but to another molecule, the very low density lipoprotein (VLDL) receptor. Strickland said that this is the first time the VLDL receptor — a molecule found on the surface of cells that is involved in cell signaling and transport — has been linked to the angiogenesis process.

"The discovery that the interaction of TFPI with the VLDL receptor regulates the proliferation of blood vessels is an unexpected and exciting finding," said Strickland. "We know that there are a lot of factors that inhibit angiogenesis, but for many of them we have little understanding of how they work. Now that we have identified a role for the VLDL receptor in this process, we can begin to investigate other steps in the biochemical pathway."

Dr. Edward R. Gubish, EntreMed's executive vice president for research and development, said that the identification of the VLDL receptor's critical role in angiogenesis will likely lead to new drugs to help slow the spread of cancer and other diseases in which blood vessels are important, like arthritis and atherosclerosis, the narrowing and thickening of the arteries. "This work provides us with a novel target for the development of new antiangiogenesis and antitumor drugs, and further expands EntreMed's efforts into additional areas of angiogenesis research," said Gubish.

Another illustration of the angiogenesis process, courtesy of Duke University Medical Center.

Strickland said that if the results of future research reinforce the important role that TFPI plays in angiogenesis, it might be possible to create an agent that can mimic its ability to bind to the VLDL receptor and inhibit the formation of new blood vessels. Strickland's own research on the VLDL receptor and the specifics of its interaction with TFPI will continue at the Holland Lab and in colaboration with EntreMed scientists. The next step for the research team is to translate the antiangiogenesis process that they observed in the lab into an in vivo (living) model, said Strickland.

"Discoveries about the specific ways in which antiangiogenic agents work, can eventually provide us with a new understanding of the fundamental processes underlying many diseases, including cancer and atherosclerosis."