title: EGF and bFGF promote invasion that is modulated by PI3/Akt kinase and Erk in vestibular schwannoma.
abstract: OBJECTIVE
  Vestibular schwannomas (VSs) are slow-growing benign tumors but, on rare occasion, can invade adjacent cranial nerves, causing significant morbidity, especially in association with neurofibromatosis 2 (NF2). We aimed to determine the role of the growth factors EGF, bFGF, and the hormone, Epo, in promoting such invasive behavior in VS, as well as their mechanisms of action.
  
  
  METHODS
  Immunohistochemical staining showed expression of EGFR, bFGF, Epo, EpoR in archived VS tissue. Western blots and immunofluorescence showed expression of EGFR, EpoR and FGF in HEI-193, an immortalized cell line derived from human NF2-related VS. Matrigel invasion assays were used to study the effect of Epo, FGF and bFGF on invasive behavior in HEI-193. Western blotting showed levels of phospho-Akt and phospho-Erk in HEI-193 upon addition of growth factors plus PI3K or MEK inhibitors. Quantitative RT-PCR was performed to determine the expression of MMP2 and MMP9 after treatment with growth factors.
  
  
  RESULTS
  EGFR, bFGF, Epo and EpoR were expressed in VS tissue and HEI193. Addition of EGF and bFGF increased cellular invasion by 10 and 3.5-fold, respectively. Epo had minimal effect on invasion. Results indicated that Erk is involved in bFGF but not EGF-induced invasion, while Akt is involved in both pathways. EGF treatment moderately induced MMP9, but is unlikely to account for the observed invasion.
  
  
  CONCLUSIONS
  Activation of EGFR and FGFR may promote invasive behavior in VS through ERK and Akt signaling pathways. Further investigation will be necessary to elucidate their potential as useful targets in the treatment of VS.
authors.affiliation: Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California-San Diego and the VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Blair
authors.forename: Alan
authors.initials: A
authors.lastname: Kiang
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang-Rodriguez
authors.forename: Michael Andrew
authors.initials: MA
authors.lastname: Yu
authors.forename: Joni K
authors.initials: JK
authors.lastname: Doherty
authors.forename: Weg M
authors.initials: WM
authors.lastname: Ongkeko
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D003094:Collagen; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004921:Erythropoietin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009361:Neoplasm Invasiveness / Q000473:pathology; D009464:Neuroma, Acoustic / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D003094:Collagen; D004338:Drug Combinations; D004815:Epidermal Growth Factor; D004921:Erythropoietin; D048049:Extracellular Signal-Regulated MAP Kinases; D016222:Fibroblast Growth Factor 2; D007797:Laminin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C059485:matrigel