title: Selective coexpression of VEGF receptor 2 in EGFRvIII-positive glioblastoma cells prevents cellular senescence and contributes to their aggressive nature.
abstract: In glioblastoma (GBM), the gene for epidermal growth factor receptor (EGFR) is frequently amplified. EGFR mutations also are common, including a truncation mutation that yields a constitutively active variant called EGFR variant (v)III. EGFRvIII-positive GBM progresses rapidly; however, the reason for this is not clear because the activity of EGFRvIII is attenuated compared with EGF-ligated wild-type EGFR. We hypothesized that EGFRvIII-expressing GBM cells selectively express other oncogenic receptors that support tumor progression.
  
  
  
  Mining of The Cancer Genome Atlas prompted us to test whether GBM cells in culture, which express EGFRvIII, selectively express vascular endothelial growth factor receptor (VEGFR)2. We also studied human GBM propagated as xenografts. We then applied multiple approaches to test the effects of VEGFR2 on GBM cell growth, apoptosis, and cellular senescence.
  
  
  
  In human GBM, EGFR overexpression and EGFRvIII positivity were associated with increased VEGFR2 expression. In GBM cells in culture, EGFRvIII-initiated cell signaling increased expression of VEGFR2, which prevented cellular senescence and promoted cell cycle progression. The VEGFR-selective tyrosine kinase inhibitor cediranib decreased tumor DNA synthesis, increased staining for senescence-associated β-galactosidase, reduced retinoblastoma phosphorylation, and increased p27(Kip1), all markers of cellular senescence. Similar results were obtained when VEGFR2 was silenced.
  
  
  
  VEGFR2 expression by GBM cells supports cell cycle progression and prevents cellular senescence. Coexpression of VEGFR2 by GBM cells in which EGFR signaling is activated may contribute to the aggressive nature of these cells.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Karra A
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Gilder
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lam
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Na
authors.initials: N
authors.lastname: Du
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Banki
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Aran
authors.initials: A
authors.lastname: Merati
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Donald P
authors.initials: DP
authors.lastname: Pizzo
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Scott R
authors.initials: SR
authors.lastname: VandenBerg
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California (all authors).
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis*; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*
chemical_list: C410723:epidermal growth factor receptor VIII; C512478:EGFR protein, human; D066246:ErbB Receptors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: EGF receptor; EGFRvIII; VEGF receptor-2; cellular senescence; glioblastoma