New pathway identified in angiogenesis

December 14, 2004

COLUMBUS, Ohio - Scientists have discovered a new biological pathway that may be useful in regulating angiogenesis, the process the body uses to build new blood vessels. The findings, published in the December issue of the journal Immunity, may offer clinicians a new way to intervene in a broad range of diseases and disorders, including cancer, heart and lung disease, wound healing and transplantation.

Angiogenesis is a normal function in the body, but it's not always helpful. For example, while it is critical to normal embryonic development and beneficial in wound healing and recovery from heart disease, it can be harmful when it creates new feeder lines that help cancerous tumors grow and spread.

Investigators in The Ohio State University Davis Heart and Lung Research Institute say angiogenesis appears to be manageable by stimulating monocytes - certain white blood cells in the immune system - with high doses of a naturally occurring growth factor in the body called GM-CSF (granulocyte-macrophage colony stimulating factor).

GM-CSF stimulates monocytes to produce soluble receptors for VEGF (vascular endothelial growth factor), the substance tumors secrete to signal nearby blood vessels to build connectors to them.

"When tumors reach a certain size, they need more oxygen and nutrients to continue to grow. New blood vessels play an important role in tumor metastases, and it is the tumor's production of VEGF that is the key driver of new blood vessel formation," says Clay Marsh, director of the division of pulmonary, critical care and sleep medicine in the department of internal medicine at Ohio State and senior author of the study.

But he says that soluble VEGF receptors produced by the stimulated monocytes act like sponges, soaking up all of the available VEGF, so the signal to build new blood vessels never gets through.

"In essence, we think we have found a new way to block angiogenesis," says Marsh.

The approach takes advantage of a well-known principle of immunity: When a tumor or inflammation occurs, the body alerts monocytes and macrophages (other infection-fighting white blood cells) to rush to the site to contain it.

"We are taking advantage of the fact that the monocytes are already in place. We just give them additional growth factor to boost the production of soluble VEGF receptors to block angiogenesis."

Earlier pieces of the pathway have been identified and described, but this is the first time it has been conceptualized as a process that could be utilized to actually manipulate angiogenesis, says Marsh.

Marsh, working with Tim Eubank, a post-doctoral fellow in his laboratory, conducted initial studies stimulating monocytes with GM-CSF in a test tube, measuring the impact of the soluble VEGF receptors on endothelial cell tube formation, the first step in new blood vessel growth.

Ryan Roberts, an MD/PhD student, later assisted the team in performing similar studies in mice. They implanted the mice with Matrigel plugs, tiny bits of mouse tissue engineered to mimic a tumor, then added VEGF and GM-CSF to them.

In both sets of studies they found that the stimulated monocytes produced enough soluble VEGF receptors to inhibit angiogenesis.

The research team says their next step will be to test the process in mice with mammary tumors. They plan on injecting the mice with GM-CSF at the tumor site, a therapeutic strategy that would maximize the effects of the growth factor, but keep it localized at the same time.

"Our findings are especially intriguing because GM-CSF is naturally produced by the body. We use a lot more of it than what might be normally present at a tumor site, but it appears to be safe and well tolerated in the animals we've studied," says Marsh.

The findings come at a time when new methods to thwart angiogenesis are sorely needed. So far, the small handful of drugs and targeted therapies engineered to block the process have had only limited success.

Additional investigators from Ohio State who worked on the study include Michelle Galloway, Yijie Wang and David Cohn.
-end-
The project was supported by grants from the National Institutes of Health, the American Lung Association Johnie Walker Murphy Career Investigator Award and the Kelly Clark Memorial Fund.

Contact: Michelle Gailiun, Medical Center Communications, 614-293-3737, or Gailiun.1@osu.edu.

Ohio State University

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