title: Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development.
abstract: We investigated the significance of PI3K/AKT/mTOR pathway and its interactions with MAPK, JAK/STAT and Notch pathways in meningioma progression. Paraffin-embedded tissue from 108 meningioma patients was analysed for the presence of mutations in PIK3CA and AKT1. These were correlated with the expression status of components of the PI3K/AKT/mTOR pathway, including p85α and p110γ subunits of PI3K, phosphorylated (p)-AKT, p-mTOR, p-p70S6K and p-4E-BP1, as well as of p-ERK1/2, p-STAT3 and Notch-1, clinicopathological data and patient survival. A mutation in PIK3CA or AKT1 was found in around 9 % of the cases. Higher grade meningiomas displayed higher nuclear expression of p-p70S6K; higher nuclear and cytoplasmic expression of p-4E-BP1 and of Notch-1; lower cytoplasmic expression of p85αPI3K, p-p70S6K and p-ERK1/2; and lower PTEN Histo-scores (H-scores). PTEN H-score was inversely correlated with recurrence probability. In univariate survival analysis, nuclear expression of p-4E-BP1 and absence of p-ERK1/2 expression portended adverse prognosis, whereas in multivariate survival analysis, p-ERK1/2 expression emerged as an independent favourable prognostic factor. Treatment of the human meningioma cell line HBL-52 with the PI3K inhibitor LY294002 resulted in reduction of p-AKT, p-p70S6K and p-ERK1/2 protein levels. The complex interactions established between components of the PI3K/AKT/mTOR pathway, or with components of the MAPK, JAK/STAT and Notch-1 pathways, appear to be essential for facilitating and fuelling meningioma progression.
authors.affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, 115 27, Athens, Greece, elhabere@yahoo.com.
authors.forename: Elias A
authors.initials: EA
authors.lastname: El-Habr
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.forename: Eleni-Andriana
authors.initials: EA
authors.lastname: Trigka
authors.forename: Joanna
authors.initials: J
authors.lastname: Sakalidou
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.forename: Ilenia
authors.initials: I
authors.lastname: Chatziandreou
authors.forename: Anastasia
authors.initials: A
authors.lastname: Spyropoulou
authors.forename: Rigas
authors.initials: R
authors.lastname: Soldatos
authors.forename: Georgia
authors.initials: G
authors.lastname: Tomara
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Petraki
authors.forename: Vassilis
authors.initials: V
authors.lastname: Samaras
authors.forename: Athanasios
authors.initials: A
authors.lastname: Zisakis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Varsos
authors.forename: George
authors.initials: G
authors.lastname: Vrettakos
authors.forename: Efstathios
authors.initials: E
authors.lastname: Boviatsis
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.forename: Angelica A
authors.initials: AA
authors.lastname: Saetta
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
mesh_terms: D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008579:Meningioma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051881:Receptor, Notch1; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D053612:Janus Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051881:Receptor, Notch1; D050791:STAT Transcription Factors; D058570:TOR Serine-Threonine Kinases; C497761:NOTCH1 protein, human; C546842:MTOR protein, human