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Author Notes:

Corresponding Author: Erwin G Van Meir, Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Rd. NE, C5078, Atlanta, GA 30322, USA, email: evanmei@emory.edu, Phone: +1 (404) 778-5563, Fax: +1 (404) 778-5550

New address: Dardinger Laboratory of Neuro-oncolgy and Neurosciences, James Comprehensive Cancer Center, Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, 43210, U.S.A.

Author contributions: BK performed and coordinated experiments in collaboration with NSD, ZZ and JJO for the rodent glioma models, HS and HM for the rat brain imaging, DJB and EMS for the quantification of tumor vascular density, EMS and SMC for in vitro angiogenesis assays, EMS and MF for the mouse corneal experiments, PK and RLS for the GST binding experiments, SMC and CTB for analysis of Vstat120 in clones and CD36 in endothelial cells and brain sections. BK and EGVM conceived project, established collaborations, designed research, interpreted results and wrote the manuscript. All authors read the manuscript.

Subjects:

Research Funding:

National Institute of Neurological Disorders and Stroke : NINDS

National Cancer Institute : NCI

National Heart, Lung, and Blood Institute : NHLBI

Keywords:

  • Brain Angiogenesis Inhibitor 1 (BAI1)
  • Vasculostatin
  • brain tumor
  • glioma

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

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Journal Title:

Cancer Research

Volume:

Volume 69, Number 3

Publisher:

, Pages 1212-1220

Type of Work:

Article | Post-print: After Peer Review

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.
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