title: Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism.
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.
authors.affiliation: Department of Neurosurgery, Laboratory of Molecular Neuro-Oncology, Winship Cancer Institute, Emory University, School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Cork
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sandberg
authors.forename: Narra S
authors.initials: NS
authors.lastname: Devi
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Philip A
authors.initials: PA
authors.lastname: Klenotic
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.forename: Carol
authors.initials: C
authors.lastname: Tucker-Burden
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000628:therapy*; D018955:CD36 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016510:Corneal Neovascularization / Q000188:drug therapy; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000628:therapy; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C468226:ADGRB1 protein, human; D042501:Angiogenic Proteins; D018955:CD36 Antigens; D018076:DNA, Complementary; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled