Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates In vivo Angiogenesis through a CD36-Dependent Mechanism

Laboratory of Molecular Neuro-Oncology, Departments of ¹Neurosurgery, ²Pathology, ³Hematology/Oncology, and ⁴Radiology, and ⁵Winship Cancer Institute, Emory University, School of Medicine, Atlanta, Georgia; and ⁶Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio

^* To whom correspondence should be addressed. E-mail: evanmei{at}emory.edu.

	Abstract

Angiogenesis is a critical physiologic process that is appropriated during tumorigenesis. Little is known about how this process is specifically regulated in the brain. Brain angiogenesis inhibitor-1 (BAI1) is a brain-predominant seven-transmembrane protein that contains five antiangiogenic thrombospondin type-1 repeats (TSR). We recently showed that BAI1 is cleaved at a conserved proteolytic cleavage site releasing a soluble, 120 kDa antiangiogenic factor called vasculostatin (Vstat120). Vstat120 has been shown to inhibit in vitro angiogenesis and suppress subcutaneous tumor growth. Here, we examine its effect on the intracranial growth of malignant gliomas and further study its antitumor mechanism. First, we show that expression of Vstat120 strongly suppresses the intracranial growth of malignant gliomas, even in the presence of the strong proangiogenic stimulus mediated by the oncoprotein epidermal growth factor receptor variant III (EGFRvIII). This tumor-suppressive effect is accompanied by a decrease in tumor vascular density, suggesting a potent antiangiogenic effect in the brain. Second, and consistent with this interpretation, we find that treatment with Vstat120 reduces the migration of cultured microvascular endothelial cells in vitro and inhibits corneal angiogenesis in vivo. Third, we show that these antivascular effects critically depend on the presence of the cell surface receptor CD36 on endothelial cells in vitro and in vivo, supporting the role of Vstat120 TSRs in mediating these effects. These results advance the understanding of brain-specific angiogenic regulation, and suggest that Vstat120 has therapeutic potential in the treatment of brain tumors and other intracerebral vasculopathies. [Cancer Res 2009;69(3):1212–20]

Key Words: Brain angiogenesis inhibitor 1 (BAI1), Vasculostatin, brain tumor, glioma

This article has been cited by other articles:

				R. L. Silverstein and M. Febbraio CD36, a Scavenger Receptor Involved in Immunity, Metabolism, Angiogenesis, and Behavior Sci. Signal., May 26, 2009; 2(72): re3 - re3. [Abstract] [Full Text] [PDF]