Discovery of novel mechanism controlling tumor growth in the brain

As survival rates among some patients with cancer continue to rise, so does the spread of these cancers to the brain - as much as 40 percent of all diagnosed brain cancers are considered metastatic, having spread from a primary cancer elsewhere in the body.

Now, scientists from The Scripps Research Institute have discovered a molecular mechanism that plays a pivotal role in controlling cancer growth in the brain. The discovery could provide a basis for potentially effective therapies for the treatment of brain metastasis.

The study was published in an online Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS) the week of June 8, 2009.

"Our study could have a broad impact because it explains at a molecular level how metastatic lesions thrive in the brain," said Scripps Research Associate Professor Brunhilde Felding-Habermann, who led the research. "This offers a potential target for inhibiting the growing problem of brain metastasis."

For tumor cells that have invaded the brain, Felding-Habermann and her colleagues found that when activated, a tumor cell receptor known as integrin αvβ3 increased the supply of a growth factor involved in the development of new blood vessels ("angiogenesis") necessary for tumor expansion within the brain tissue. In contrast, the same receptor did not influence tumor growth at the primary cancer site, in this case, the breast.

"The fact that we uncovered a link between activated αvβ3 and angiogenesis is quite striking," said Senior Research Associate Mihaela Lorger, the first author of the study. "In addition, our study showed that that the ability of tumor cell αvβ3 to enhance angiogenesis depends very much on the microenvironment."

This receptor's varying effects on tumor cells depending on their location in the body reinforces a principle that the Felding-Habermann lab uncovered a few years ago.

"For tumor cells, it's not just the presence of the receptor on the cells, but the conformation or shape of the molecule that determines how well tumor cells can do within different tissues" Felding-Habermann said. "The shape of the molecule can increase or reduce the receptor's affinity for its natural ligands."

In the new study, which was conducted in mouse models, the scientists showed that activated αvβ3 on tumor cells leads to angiogenesis in the brain by elevating the expression of the VEGF, a protein that is critical to the formation of new blood vessels.

Tumor cells normally try to recruit more blood vessels when oxygen supply runs low. When oxygen and nutrients get scarce, many tumor cells die and tumor growth slows down until new vessels have formed. But in the brain, activated αvβ3 promotes rapid tumor growth by enabling tumor cells to attract new blood vessels continuously, even when oxygen is still abundant.

The scientists plan to follow up on their new findings by testing if activated αvβ3 on tumor cells also supports brain metastasis of other types of cancer, and by investigating if targeting the activated form of αvβ3 can inhibit metastatic brain disease.

In addition to Felding-Habermann and Lorger, other authors of the study, "Activation of Tumor Cell Integrin αvβ3 Controls Angiogenesis And Metastatic Growth in the Brain," include Joseph S. Krueger, Melissa O'Neal, and Karin Staflin of The Scripps Research Institute.

The study was supported by The National Institutes of Health, the University of California Breast Cancer Research Program, S.G. Komen, and the Government of Sweden.