title: Cerebrospinal fluid stimulates leptomeningeal and meningioma cell proliferation and activation of STAT3.
abstract: The role of cerebrospinal fluid (CSF) in the pathogenesis of meningiomas is unknown. Cell cultures from three human leptomeninges, five WHO grade I and seven grade II meningiomas were treated with remnant CSF from 22 patients with no central nervous system disease and normal cell indices. Cells were evaluated by CyQUANT for DNA synthesis/cell proliferation and by western blots for phosphorylation/activation of growth regulatory pathways activated in meningiomas including JAK1-STAT3, MEK1-p44/42MAPK, Akt-mTOR and Rb. Analysis of Caspase 3 activation and survivin was also performed. Finally, the effects of PDGF neutralizing antibody and cucurbitacin, a STAT3 inhibitor on CSF stimulation were tested. Compared to controls and the mitogen PDGF-BB, various CSF samples significantly stimulated DNA synthesis/cell proliferation in 20 and 22 week leptomeningeal cultures and all of the grade I and II meningioma cells tested. Collectively CSF samples, from multiple different patients, stimulated DNA synthesis in tests of 23 of 32 grade I and 18 of 28 grade II meningioma cells. CSF stimulated phosphorylation/activation of STAT3 and reduced p44/42 MAPK in the leptomeningeal, all three grade I and 1 of three grade II meningioma cells. CSF did not affect Caspase 3 activity or survivin levels. PDGF neutralizing antibody had no effect on CSF stimulation but cucurbitacin blocked PDGF and CSF stimulation. While there are limitations to the CSF available since they were not from "normal" volunteers, the studies suggest that, in some settings, CSF is potentially mitogenic to leptomeningeal and meningioma cells and may act, in part, via activation of STAT3.
authors.affiliation: Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 626, Rochester, NY 14642, 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: Michael
authors.initials: M
authors.lastname: Facik
authors.forename: Paul
authors.initials: P
authors.lastname: Maurer
authors.forename: Babak
authors.initials: B
authors.lastname: Jahromi
authors.forename: Webster
authors.initials: W
authors.lastname: Pilcher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000077214:Becaplermin; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004261:DNA Replication; D005260:Female; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D008577:Meningeal Neoplasms / Q000134:cerebrospinal fluid* / Q000378:metabolism / Q000473:pathology*; D008579:Meningioma / Q000134:cerebrospinal fluid* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016160:Retinoblastoma Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D000077214:Becaplermin; C482128:MAP2K2 protein, human; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D053148:Caspase 3