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Endothelial Akt Signaling Is Rate-Limiting for Rapamycin Inhibition of Mouse Mammary Tumor Progression

¹ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School; ² Whitaker Cardiovascular Institute, Boston University School of Medicine; and ³ Departments of Anatomy and Cellular Biology/Radiation Oncology, Tufts University School of Medicine/New England Medical Center, Boston, Massachusetts

Requests for reprints: Laura E. Benjamin, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. Phone: 617-667-5964; Fax: 617-667-3591; E-mail: lbenjami{at}bidmc.harvard.edu.

Chronic activation of Akt signaling in the endothelium recapitulates the salient features of a tumor vasculature and can be inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. This led to the hypothesis that the antitumor efficacy of rapamycin may be partially dependent on its ability to inhibit endothelial Akt signaling, making rapamycin an antiangiogenic agent and endothelial Akt pathway inhibitor. Dose-response studies with rapamycin showed that primary human endothelial cells and fibroblasts had a bimodal Akt response with effective reductions in phosphorylated Akt (pAkt) achieved at 10 ng/mL. In contrast, rapamycin increased pAkt levels in tumor cell lines. When tumor-bearing mice were treated with rapamycin doses comparable to those used clinically in transplant patients, we observed strong inhibition of mammary tumor growth. To test whether Akt activation in the endothelium was rate-limiting for this antitumor response, we engineered mouse mammary tumor virus–polyoma virus middle T antigen mice with endothelial cell–specific expression of constitutively activated Akt. We observed that the antitumor efficacy of rapamycin was reduced in the presence of elevated endothelial Akt activation. Just as we observed in MCF7 cells in vitro, rapamycin doses that were antiangiogenic resulted in increased pAkt levels in total mouse mammary tumor virus–polyoma virus middle T antigen tumor lysates, suggesting that tumor cells had an opposite Akt response following mammalian target of rapamycin inhibition compared with tumor endothelial cells. Together, these data support the hypothesis that endothelial Akt signaling in the tumor vasculature is an important target of the novel anticancer drug rapamycin. [Cancer Res 2007;67(11):5070–5]

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				Correction: Rapamycin Is an Endothelial Akt Inhibitor Cancer Res., July 1, 2007; 67(13): 6528 - 6528. [Full Text] [PDF]