title: Radiation effects on human leptomeningeal cell response to cerebrospinal fluid and PDGF-BB.
abstract: OBJECTIVE
  The pathogenesis of meningiomas remains largely unknown, but there is evidence that exposure radiation increases the risk of meningiomas. We therefore evaluated whether radiation stimulates human leptomeningeal cell proliferation and activates growth regulatory pathways.
  
  
  METHODS
  Cultures from six human primary leptomeningeal cells were established and irradiated with 0.5, 1 or 2 Gy. Cells were subsequently maintained for approximately 3-6 months and then treated with the mitogen, platlet-derived growth factor-BB (PDGF-BB), or human cerebrospinal fluid (CSF) obtained from patients with no neurological disease. Cell proliferation was evaluated by CyQUANT, and changes in the regulatory activation levels of signal transducer and activator of transcription (STAT3), mitogen-activated protein kinase kinase 1/2 (MEK1/2), mitogen activated protein kinase (MAPK 44/42), Akt, and mammalian target of rapamycin (mTOR) were assessed by Western blot.
  
  
  RESULTS
  At both 3 and 6 months post-irradiation, CSF stimulated cell proliferation in all six leptomeningeal cultures. At 3 months, radiation was associated with an increase in STAT3, MEK 1/2, p44/42 MAPK and variable Akt activation, and at 6 months, STAT3, p44/42 MAPK, variable Akt and mTOR activation was observed in response to PDGF-BB and CSF.
  
  
  CONCLUSIONS
  Irradiation of fetal leptomeningeal cells was associated with loss of heterozygosity of 1p36 and persistent sensitization leading to upregulation in growth pathways in response to PDGF and CSF. These findings suggest a mechanistic basis for radiation's role in meningioma initiation.
authors.affiliation: Department of Pathology, Division of Neuropathology, University of Rochester Medical Center, Rochester, NY, USA. mahlon_johnson@urmc.rochester.edu
authors.forename: Mahlon D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Mary
authors.initials: M
authors.lastname: O'Connell
authors.forename: M Anwar
authors.initials: MA
authors.lastname: Iqbal
authors.forename: Jacqueline P
authors.initials: JP
authors.lastname: Williams
mesh_terms: D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D008578:Meninges / Q000187:drug effects* / Q000502:physiology* / Q000528:radiation effects*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin