title: Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy.
abstract: OBJECTIVE
  To identify mechanisms and mediators of resistance to antiangiogenic therapy in human glioblastoma.
  
  
  METHODS
  We carried out microarray gene expression analysis and immunohistochemistry comparing 21 recurrent glioblastomas progressing during antiangiogenic treatment with VEGF neutralizing antibody bevacizumab to paired pretreatment tumors from the same patients.
  
  
  RESULTS
  Microarray analysis revealed that bevacizumab-resistant glioblastomas (BRG) had two clustering patterns defining subtypes that reflect radiographic growth patterns. Enhancing BRGs (EBRG) exhibited MRI enhancement, a long-established criterion for glioblastoma progression, and expressed mitogen-activated protein kinases, neural cell adhesion molecule-1 (NCAM-1), and aquaporin 4. Compared with their paired pretreatment tumors, EBRGs had unchanged vascularity and hypoxia, with increased proliferation. Nonenhancing BRGs (NBRG) exhibited minimal MRI enhancement but had FLAIR-bright expansion, a newer criterion for glioblastoma recurrence since the advent of antiangiogenic therapy, and expressed integrin α5, laminin, fibronectin1, and PDGFRβ. NBRGs had less vascularity, more hypoxia, and unchanged proliferation than their paired pretreatment tumors. Primary NBRG cells exhibited more stellate morphology with a 3-fold increased shape factor and were nearly 4-fold more invasive in Matrigel chambers than primary cells from EBRGs or bevacizumab-naive glioblastomas (P < 0.05).
  
  
  CONCLUSIONS
  Using microarray analysis, we found two resistance patterns during antiangiogenic therapy with distinct molecular profiles and radiographic growth patterns. These studies provide valuable biologic insight into the resistance that has limited antiangiogenic therapy to date.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: DeLay
authors.forename: Arman
authors.initials: A
authors.lastname: Jahangiri
authors.forename: W Shawn
authors.initials: WS
authors.lastname: Carbonell
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Hu
authors.forename: Sean
authors.initials: S
authors.lastname: Tsao
authors.forename: Maxwell Wing
authors.initials: MW
authors.lastname: Tom
authors.forename: Jesse
authors.initials: J
authors.lastname: Paquette
authors.forename: Taku A
authors.initials: TA
authors.lastname: Tokuyasu
authors.forename: Manish K
authors.initials: MK
authors.lastname: Aghi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D051401:Aquaporin 4 / Q000096:biosynthesis / Q000235:genetics; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019002:CD56 Antigen / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005353:Fibronectins / Q000096:biosynthesis; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D039482:Integrin alpha5 / Q000096:biosynthesis; D007797:Laminin / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D051401:Aquaporin 4; D019002:CD56 Antigen; C067625:FN1 protein, human; D005353:Fibronectins; D039482:Integrin alpha5; D007797:Laminin; C522918:NCAM1 protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D020797:Receptor, Platelet-Derived Growth Factor beta; D020928:Mitogen-Activated Protein Kinases