Researchers identify protein promoting vascular tumor growth

09/29/04

COLUMBUS, Ohio Researchers have discovered a new mechanism responsible for the growth of blood vessel tumors that can cause facial deformities in infants and young children, paving the way for an antibody-based treatment to remove cells that fuel the tumors' growth.

Blood vessel tumors require macrophages, a type of white blood cells, to develop. In studying these cells' role in tumor development, Ohio State University medical researchers determined that a protein called MCP-1 "recruits" macrophages to the vascular tumor site.

This means that therapies to eliminate the MCP-1 protein could be a key to healing or preventing the tumors and possibly others in which MCP-1 is expressed.

The results are published in the October issue of the American Journal of Physiology (Cell).

Blood vessel tumors affect up to 3 percent of all children, typically resulting in a prominent red mass on the head and neck. Up to one in four patients with hemangioendotheliomas, or HEs, the type of tumor used in these studies, die of anemia associated with the tumors.

The findings present the first evidence that MCP-1 and macrophages are needed for these tumors to grow, and the first evidence that anti-MCP-1 therapy prevents vascular tumor development in animals with intact immune systems, said Gayle Gordillo, lead author of the study, assistant professor of plastic surgery and an investigator in the Davis Heart and Lung Research Institute at Ohio State University Medical Center.

When MCP-1 recruits macrophages to the tumor site, it stimulates new blood vessel development, or angiogenesis, in endothelial cells that make up the lining of blood vessels. That proliferation can cause the tumors to grow because new vessels develop and allow blood to collect in the lesion. Gordillo, in partnership with Heart and Lung Research Institute investigators Chandan Sen and Sashwati Roy, determined MCP-1's role in recruiting macrophages by observing tumor responses to an MCP-1 neutralizing antibody in mice when varying levels of macrophages were present.

"Our observations specifically link MCP-1 and macrophages as key contributors to the development of these tumors. MCP-1's essential role in supporting proliferation of HEs indicates that accessory cells, such as macrophages, play a significant role in facilitating the growth of these tumors," Gordillo said. "Antibody-based therapy that blocks MCP-1 may be effective in substantially limiting the incidence and quality of the malformation."

A new treatment option is needed because current therapies including steroids and alpha interferon have a number of high-risk side effects. Steroids suppress the immune system, stunt growth and development, and cause weight gain and irritability. Use of alpha interferon as a medication in children can cause irreversible neurologic damage. Surgical removal is too dangerous because of potential bleeding complications and skin loss.

"Most of these tumors show up in the first month of life. About 90 percent go away by themselves over time, but until they do, children are forced to accept a period of deformity, sometimes up to age 9," Gordillo said.

In addition to her Ohio State posts, Gordillo is director of the Hemangioma and Vascular Malformations Clinic at Columbus Children's Hospital, where she sees patients with HEs and other vascular tumors.

Sen, director of the laboratory of molecular medicine in OSU's Heart and Lung Research Institute, said this research lays the foundation for clinical trials testing the effectiveness of both antibody-based therapies and, even sooner, an experimental nutritional intervention for vascular malformations.

"Previous work in our lab has shown that a certain form of berry extract significantly regulates MCP-1 function," said Sen, who served as a mentor to Gordillo on this research.

The trick will be regulating MCP-1 levels safely, because the protein also is called to action to help wounds heal. Macrophages recruited in these cases make free radicals and promote angiogenesis that is beneficial in the wound-healing process.

"There are times when you want to promote angiogenesis, but not with tumors, because it contributes to tumor growth," Gordillo said. "MCP-1 can be brought in as a repair response to help people with wounds, but it can make negative contributions to the health and well-being of people with tumors."

Because angiogenesis is implicated in the development of other kinds of tumors and chronic inflammatory conditions, OSU scientists say the findings of this study suggest anti-MCP-1 therapy may be a useful approach for other diseases. "This study's identification of the role of MCP-1 expression has obvious potential for other tumors, as well," Gordillo said. "The concept could be applicable to a broad variety of tumors in which we know MCP-1 is expressed."

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