New York, NY (May 18, 2004) -- Peering into the mysteries of embryonic development, Weill Cornell Medical College researchers have identified compounds that inhibit the growth of new blood vessels.

If these chemical signaling mechanisms hold true in adult tissue, the discovery could pave the way for therapies to repair damaged heart tissue or, conversely, starve malignant tumors of the blood supply they need to grow.

"We found that a known factor, a known signaling mechanism, is actually inhibiting blood vessel formation. Before this, people didn't know that these factors could do this sort of thing," explained Dr. Takashi Mikawa, Joseph C. Hinsey Professor of Cell and Developmental Biology at Weill Cornell Medical College in New York City.

The study, conducted in an animal model, is published in the May 11 issue of Developmental Cell.

Cancer research reached a new milestone decades ago when it was discovered that the use of specific drugs -- naturally-occurring angiogenesis inhibitors, such as angiostatin and endostatin -- prevented tumors from forming the tiny networks of blood vessels they need to survive and thrive, a process called angiogenesis.

However, in the years since that discovery, anti-angiogenesis drug therapies haven't quite lived up to their promise as a potential cure for cancer. According to Dr. Mikawa, who is also a researcher in Weill Cornell's Center for Vascular Biology, "targeting such inhibitors alone is not perfect, that's known. So other factors may be working."

The search for those "other factors" led Dr. Mikawa's team to the "midline," a central region of the developing embryo. They looked specifically at the area surrounding the notochord -- an elongated cord made up of cells encased in a kind of sheath. In vertebrate embryos, the notochord is the precursor of the backbone, larger skeletal system, and musculature. The area around the notochord shows little or no blood vessel development, creating what the researchers call a blood-cell "nonpermissive zone."

So, in their search for agents that might serve as potential anti-angiogenesis therapies, the notochord "seemed like a good place to start," according to Dr. Mikawa. His team hypothesized that the notochord might be expressing chemicals that work to inhibit blood vessel formation.

"We tested it, and our hypothesis was right," Dr. Mikawa said.

In experiments involving quail embryos, the researchers quickly discovered that the notochord was more than just a physical barrier to the migration of blood cells, as was previously assumed. In fact, it appears to play a much more active role, emitting two chemicals, Chordin and Noggin, that effectively block BMP (Bone Morphogenic Protein) signaling.

The data also suggest that BMP promotes the development and migration of blood vessel precursor cells, a process that eventually gives rise to the cardiovascular system.

"Vessel formation depends not only on positive signals but also negative signals," Dr. Mikawa explained. Until the Weill Cornell scientists' discovery of the suppressive role of Chordin and Noggin, "we didn't know much about the negative side," he said.

The next step is to see if these mechanisms work in adult tissues to either spur or suppress neovascularization, the growth of new vessels.

"We know that Noggin, for example, is an inhibitor of blood vessel cell migration and blood vessel formation, and we know that BMP is a competitor," Dr. Mikawa said. "Now we can start to find out whether BMP signaling is playing a role in angiogenesis and neovascularization -- that's a new question."

The discoveries hold within them the promise of exciting new treatments for cancer and heart disease. For example, "we can start asking about the repair of the vascular system, repair to damaged hearts," Dr. Mikawa explained. "Also, tumor angiogenesis -- that's another area we have to pursue -- whether this new signaling is playing a role or not. Those will be future directions."

Collaborating on the research were David E. Reese (postdoctoral associate) and Christopher E. Hall (research technician) of Weill Cornell Medical College.

The study was funded in part by grants from the National Institutes of Health and the Tolly Vinick Foundation.

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