title: The role of angiogenesis in Group 3 medulloblastoma pathogenesis and survival.
abstract: BACKGROUND
  Of the 4 medulloblastoma subgroups, Group 3 is the most aggressive but the importance of angiogenesis is unknown. This study sought to determine the role of angiogenesis and identify clinically relevant biomarkers of tumor vascularity and survival in Group 3 medulloblastoma.
  
  
  METHODS
  VEGFA mRNA expression and survival from several patient cohorts were analyzed. Group 3 xenografts were implanted intracranially in nude rats. Dynamic susceptibility weighted (DSC) MRI and susceptibility weighted imaging (SWI) were obtained. DSC MRI was used to calculate relative cerebral blood volume (rCBV) and flow (rCBF). Tumor vessel density and rat vascular endothelial growth factor alpha (VEGFA) expression were determined.
  
  
  RESULTS
  Patient VEGFA mRNA levels were significantly elevated in Group 3 compared with the other subgroups (P < 0.001) and associated with survival. Xenografts D283, D341, and D425 were identified as Group 3 by RNA hierarchical clustering and MYC amplification. The D283 group had the lowest rCBV and rCBF, followed by D341 and D425 (P < 0.05). These values corresponded to histological vessel density (P < 0.05), rat VEGFA expression (P < 0.05), and survival (P = 0.002). Gene set enrichment analysis identified 5 putative genes with expression profiles corresponding with these findings: RNH1, SCG2, VEGFA, AGGF1, and PROK2. SWI identified 3 xenograft-independent categories of intratumoral vascular architecture with distinct survival (P = 0.004): organized, diffuse microvascular, and heterogeneous.
  
  
  CONCLUSIONS
  Angiogenesis plays an important role in Group 3 medulloblastoma pathogenesis and survival. DSC MRI and SWI are clinically relevant biomarkers for tumor vascularity and overall survival and can be used to direct the use of antivascular therapies for patients with Group 3 medulloblastoma.
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Thompson
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Talaignair
authors.initials: T
authors.lastname: Venkatraman
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lascola
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kristen W
authors.initials: KW
authors.lastname: Yeom
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yingmiao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Picard
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000000981:diagnostic imaging / Q000401:mortality / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008527:Medulloblastoma / Q000000981:diagnostic imaging / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000473:pathology*; D059906:Neuroimaging / Q000379:methods; D051381:Rats; D011923:Rats, Nude; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000096:biosynthesis
chemical_list: D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Group 3; VEGF; angiogenesis; dynamic susceptibility contrast MRI; medulloblastoma