Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism

• Authors: Balveen Kaur, Emory University; Sarah M Cork, Emory University; Eric M Sandberg, Emory University; Narra S Devi, Emory University; Zhaobin Zhang, Emory University; Philip A Klenotic, Cleveland Clinic; Maria Febbraio, Cleveland Clinic; Hyunsuk Shim, Emory University; Hui Mao, Emory University; Carol Tucker-Burden, Emory University; Roy L Silverstein, Cleveland Clinic; Daniel J Brat, Emory University; Jeffrey James Olson, Emory University; Erwin Van Meir, Emory University
• Journal Title: Cancer Research
• Volume: Volume 69, Number 3
• Publisher: American Association for Cancer Research | 2009-02-01, Pages 1212-1220
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/0008-5472.CAN-08-1166
• Subjects: Biology, Cell; Health Sciences, Oncology
• Keywords: Brain Angiogenesis Inhibitor 1 (BAI1); Vasculostatin; brain tumor; glioma

Abstract

Angiogenesis is a critical physiological 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 primarily brain specific seven-transmembrane protein that contains five anti-angiogenic thrombospondin type-1 repeats (TSR). We recently showed that BAI1 is cleaved at a conserved proteolytic cleavage site releasing a soluble, 120 kDa anti-angiogenic factor called Vasculostatin (Vstat120). Vstat120 has been shown to inhibit in vitro angiogenesis and suppress subcutaneous tumor growth. Here, we examine its effect on intracranial growth of malignant gliomas and further study the mechanism of its anti-tumor effects. First, we show that expression of Vstat120 strongly suppresses the intracranial growth of malignant gliomas, even in the presence of the strong pro-angiogenic stimulus mediated by the oncoprotein Epidermal Growth Factor Receptor variant III (EGFRvIII). This tumor suppressive effect is accompanied by a decrease in vascular density in the tumors, suggesting a potent anti-angiogenic 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 demonstrate that these anti-vascular effects are critically dependent on the presence of the cell surface receptor CD36 on endothelial cells in vitro and in vivo, supporting a role of the 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 intra-cerebral vasculopathies.