Etiology and Pathogenesis > Tumor Biology | Treatment > Rapamycin

Cancer Cell, Vol 10, 159-170, August 2006. Published: August 14, 2006.

Abstract
Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin

Thuy L. Phung,1 Keren Ziv,2 Donnette Dabydeen,1 Godfred Eyiah-Mensah,1 Marcela Riveros,1 Carole Perruzzi,1 Jingfang Sun,1 Rita A. Monahan-Earley,1 Ichiro Shiojima,3 Janice A. Nagy,1 Michelle I. Lin,4 Kenneth Walsh,3 Ann M. Dvorak,1 David M. Briscoe,5 Michal Neeman,2 William C. Sessa,4 Harold F. Dvorak,1 and Laura E. Benjamin1,*

1Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215. 2Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. 3Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118. 4Department of Pharmacology and Program in Vascular Cell Signaling and Therapeutics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536. 5Transplantation Research Center, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115 -- *Corresponding author: Laura E. Benjamin lbenjami@bidmc.harvard.edu -- Received: October 5, 2005. Revised: February 19, 2006. Accepted: July 18, 2006. Published: August 14, 2006.


Endothelial cells in growing tumors express activated Akt, which when modeled by transgenic endothelial expression of myrAkt1 was sufficient to recapitulate the abnormal structural and functional features of tumor blood vessels in nontumor tissues. 
Sustained endothelial Akt activation caused increased blood vessel size and generalized edema from chronic vascular permeability, while acute permeability in response to VEGF-A was unaffected. 
These changes were reversible, demonstrating an ongoing requirement for Akt signaling for the maintenance of these phenotypes. 
Furthermore, rapamycin inhibited endothelial Akt signaling, vascular changes from myrAkt1, tumor growth, and tumor vascular permeability. 
Akt signaling in the tumor vascular stroma was sensitive to rapamycin, suggesting that rapamycin may affect tumor growth in part by acting as a vascular Akt inhibitor.

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