title: Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model.
abstract: Glioblastomas are highly vascularized tumors with a prominent infiltration of macrophages/microglia whose role in promoting glioma growth, invasion, and angiogenesis has not been fully elucidated.
  
  
  
  The contribution of myeloid-derived vascular endothelial growth factor (VEGF) to glioma growth was analyzed in vivo in a syngeneic intracranial GL261 glioma model using a Cre/loxP system to knock out the expression of VEGF-A in CD11b + myeloid cells. Changes in angiogenesis-related gene expression profile were analyzed in mutant bone marrow-derived (BMD) macrophages in vitro. Furthermore, we studied the influence of macrophages on GL261 growth, invasiveness, and protein expression profile of angiogenic molecules as well as the paracrine effect of mutant macrophages on angiogenesis in vitro.
  
  
  
  Myeloid cell-restricted VEGF-A deficiency leads to a growth delay of intracranial tumors and prolonged survival. The tumor vasculature in mutant mice was more regular, with increased pericyte coverage. Expression analysis revealed significant downregulation of VEGF-A and slight upregulation of TGFβ-1 in BMD macrophages from mutant mice. Endothelial tube formation was significantly decreased by conditioned media from mutant macrophages. The expression of angiogenesis-related proteins in GL261 glioma cells in co-culture experiments either with wild-type or mutant macrophages remained unchanged, indicating that effects observed in vivo are due to myeloid-derived VEGF-A deficiency.
  
  
  
  Our results highlight the importance of VEGF derived from tumor-infiltrating myeloid cells for initiating vascularization in gliomas. The combination of antiangiogenic agents with myeloid cell-targeting strategies might provide a new therapeutic approach for glioblastoma patients.
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Nadja
authors.initials: N
authors.lastname: Osterberg
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Jean
authors.initials: J
authors.lastname: Vacher
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Simone
authors.initials: S
authors.lastname: Gaedicke
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Astrid
authors.initials: A
authors.lastname: Weyerbrock
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Soroush
authors.initials: S
authors.lastname: Doostkam
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Hans-Eckart
authors.initials: HE
authors.lastname: Schaefer
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Department of Neurosurgery, Freiburg University Medical School, Freiburg, Germany (N.O., A.W., M.R.M.); Department of Pathology, University of California San Diego, San Diego, California (N.F.); Department of Medicine, Institut de Recherches Cliniques de Montréal, Université de Montréal, Quebec, Canada (J.V.); Department of Radiation Oncology, University Hospital Freiburg, Germany (S.G., G.N.); Department of Neuropathology, Freiburg University Medical School, Freiburg, Germany (S.D.); Department of Pathology, Freiburg University Medical School, Freiburg, Germany (H.-E.S.); Institute of Neurology (Edinger Institute), Frankfurt University Medical School, Frankfurt, Germany (K.H.P).
authors.forename: Marcia Regina
authors.initials: MR
authors.lastname: Machein
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005910:Glioma / Q000098:blood supply / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: VEGF; angiogenesis; glioma; macrophages; microglia