Novel pathway identifies rapamycin as tumor angiogenesis...( New research has uncovered a signaling...)

New research has uncovered a signaling pathway sufficient to induce formation of abnormal tumor-like blood vessels in otherwise healthy, normal tissues. These changes in vasculature were reversible and could be blocked by rapamycin, a compound that is currently in clinical use as an immunosuppressant and under investigation as an anticancer therapy. The findings appear in the August issue of Cancer Cell, published by Cell Press.

Compared to normal blood vessels, blood vessels associated with tumors are large, twisted, and leaky. Previous research has shown that overexpression of the cytokine VEGF-A leads to formation of tumor-like blood vessels. Dr. Laura E. Benjamin, from Beth Israel Deaconess Medical School and Harvard Medical School, and colleagues observed that tumor blood vessel cells exhibit activation of a signaling molecule, called Akt, that acts downstream of VEGF-A and has been linked to blood vessel cell survival. To investigate the function of Akt, the researchers used transgenic mice that expressed activated Akt in normal endothelial cells without the complicating influence of tumor cells.

Activation of Akt stimulated formation of abnormal blood vessels in healthy, normal tissues. The Akt-induced vessels had the same structural and functional abnormalities seen in tumor blood vessels. Simply removing or inhibiting the activated Akt was sufficient to reverse the vascular changes. Treatment with rapamycin, a compound with antiproliferative and immunosuppressive properties known to decrease Akt activation, blocked Akt-driven changes in blood vessels. Rapamycin also reduced tumor growth and abnormal vasculature in a mouse tumor model.

"Rapamycin inhibited tumor growth and tumor vascular permeability, which we hypothesize are in part due to effects of rapamycin on endothelial Akt activation. These findings indicate a possible clinical utility of rapamycin as an angiogenesis inhibitor and support a novel pathway for rapamycin
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
14-Aug-2006