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A Double Hit to Kill Tumor and Endothelial Cells by TRAIL and Antiangiogenic 3TSR

¹ Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center, and ² Biological and Biomedical Sciences Program, Harvard Medical School, Boston, Massachusetts and ³ Oncology Research Department, Human Genome Sciences, Rockville, Maryland

Requests for reprints: Roya Khosravi-Far, 3 Blackfan Circle, Boston, MA 02215. Phone: 617-735-2441; Fax: 617-735-2475; E-mail: rkhosrav{at}bidmc.harvard.edu.

Key Words: angiogenesis • apoptosis • Lexatumumab • thrombospondin-1 • TRAIL • VEGF

As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH₂-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels. [Cancer Res 2009;69(9):3856–65]

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