title: Fibroblast growth factor receptor-3 expression in meningiomas with stimulation of proliferation by the phosphoinositide 3 kinase-Akt pathway.
abstract: OBJECTIVE
  Fibroblast growth factor receptors (FGFRs)-1, -2, and -3 are expressed in the developing brain and may participate in CNS neoplasia. Fibroblast growth receptor-3 has not been demonstrated in the human CNS or its tumors. Nonetheless, it has been implicated in the pathogenesis of several other forms of neoplasia.
  
  
  METHODS
  Twenty-four human meningiomas were evaluated using Western blot analysis for expression of FGFR3, its ligand acidic FGF, and concomitant phosphorylation/activation of p44/42 mitogen-activated protein kinase (MAPK), Akt, and STAT3. Mutations in exons 7 and 10 of the FGFR3 gene were analyzed by polymerase chain reaction in 10 meningiomas. Primary meningioma cells cultured from 10 human meningiomas were also treated with acidic FGF and evaluated for cell proliferation or activation/phosphorylation of p44/42 MAPK, Akt, and STAT3.
  
  
  RESULTS
  Immunoblotting demonstrated the presence of FGFR3 in 12 (71%) of 17 primarily fibroblastic and transitional WHO Grade I meningiomas. The FGFR3 was detected in 4 (80%) of 5 WHO Grade II, and 2 of 2 Grade III tumors. Acidic FGF was detected in 3 (18%) of 17 Grade I, 1 (20%) of 5 Grade II, and 1 (50%) of 2 Grade III meningiomas. In WHO Grade I meningiomas, 3 of 6 tumors with no detectable FGFR3 had no detectable p-STAT3. In WHO Grades II and III meningiomas, FGFR3 expression was associated with p-STAT3, p-Akt, and p-p44/42 MAPK expression. No mutations were demonstrated in exons 7 or 10 by polymerase chain reaction in any meningioma. Treatment with acidic FGF, a ligand for FGFR3, stimulated meningioma cell proliferation and activation of Akt and STAT3 in primary meningioma cell cultures.
  
  
  CONCLUSIONS
  These findings suggest that FGFR3 and acidic FGF are expressed in adult human leptomeninges as well as WHO Grades I and II meningiomas. Fibroblast growth factor receptor-3 activation stimulates meningioma cell proliferation by activation of the phosphoinositide 3 kinase-Akt-PRAS40-mTOR and STAT3 pathways.
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of Rochester Medical Center, Rochester, New York 14623, USA. mahlon_johnson@urmc.rochester.edu
authors.forename: Mahlon D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Mary J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Webster
authors.initials: W
authors.lastname: Pilcher
authors.forename: Jay E
authors.initials: JE
authors.lastname: Reeder
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics / Q000473:pathology; D008579:Meningioma / Q000201:enzymology* / Q000235:genetics*; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014944:World Health Organization
chemical_list: D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt