Re-educated immune cells may reduce breast cancer spread

Abstract

Researchers at Ohio State University Medical Center have discovered a novel strategy for reducing the growth and spread of breast cancer tumors by slowing the metastasis or spread of tumor-associated inflammatory cells.

"We found that we could 're-educate' macrophages within the tumor so that rather than promote new blood vessel formation they will block it," says Dr. Clay B. Marsh, director of Ohio State Medical Center's Center for Critical Care and senior author of the study, which appeared in March, 2009 in the journal Cancer Research.

Macrophages produce a protein called vascular endothelial growth factor (VEGF) that drives the new blood vessel formation necessary for tumor growth and metastases. "We were able to manipulate the macrophages to produce a soluble receptor for VEGF," said Marsh, also a member of Ohio State's Comprehensive Cancer Center. "This receptor binds with and absorbs the VEGF in the tumor so that it can't stimulate tumor growth and spread."

Using a mouse model that mimicks human breast cancer, the researchers injected the growth factor granulocyte macrophage colony-stimulating factor (GM-CSF) directly into the tumors. Treated mice showed a significant reduction in breast cancer tumor size, fewer lung metastases and increased survival.

The data also showed that GM-CSF reprogrammed the tumor-associated macrophages to slow tumor progression by increasing levels of VEGF within the tumor, starving the tumors of oxygen and nutrients, and preventing the development of new blood vessels or angiogenesis.

According to Marsh, human breast cancer patients with high VEGF and low soluble VEGF receptor have a much worse outcome than if the reverse is found. These patients do not have enough soluble VEGF receptor to soak up the VEGF, so tumors attract new blood vessels and flourish.

Marsh and his team plan to study whether the soluble VEGF receptor is made by macrophages in human tumors when the soluble VEGF receptor is high and using the same method reported in this animal study to treat human breast cancer.

A macrophage is a type of immune cell that plays a significant role in normal breast tissue development and makes up to 35 percent of inflammatory cells in breast tumors. These tumor-associated macrophages can facilitate tumor invasion and angiogenesis, which is necessary for tumor progression. Tumors are unable to grow or spread without blood vessel formation which supplies oxygen and nutrients.

Along with Marsh, other Ohio State researchers who were involved in the study were co-first authors Tim D. Eubank and Ryan D. Roberts, Mahmood Khan, Jennifer M. Curry, Gerard J. Nuovo and Periannan Kuppusamy.

Funding from the National Institutes of Health and the Department of Defense Congressionally Directed Medical Research Program supported this research.

Contact: Sherri L. Kirk 614-293-3737, or

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