title: Mechanisms of glioma formation: iterative perivascular glioma growth and invasion leads to tumor progression, VEGF-independent vascularization, and resistance to antiangiogenic therapy.
abstract: As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Baker
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Viveka Nand
authors.initials: VN
authors.lastname: Yadav
authors.affiliation: Center for Scientific Computation and Mathematical Modeling, University of Maryland, College Park, MD 20742, USA; School of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ 85281, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Motsch
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Koschmann
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Anda-Alexandra
authors.initials: AA
authors.lastname: Calinescu
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mineharu
authors.affiliation: Dept. of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sandra Ines
authors.initials: SI
authors.lastname: Camelo-Piragua
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Orringer
authors.affiliation: Dept. of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Serguei
authors.initials: S
authors.lastname: Bannykh
authors.affiliation: Dept. of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Wesley S
authors.initials: WS
authors.lastname: Nichols
authors.affiliation: Depts. of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: deCarvalho
authors.affiliation: Depts. of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
authors.affiliation: Dept. of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Dept. of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: pedrol@umich.edu.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
mesh_terms: D000465:Algorithms; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001706:Biopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A