@article{3087960,
    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",
    author = "El-Habr, E.A. and Levidou, G. and Trigka, E.-A. and Sakalidou, J. and Piperi, C. and Chatziandreou, I. and Spyropoulou, A. and Soldatos, R. and Tomara, G. and Petraki, K. and Samaras, V. and Zisakis, A. and Varsos, V. and Vrettakos, G. and Boviatsis, E. and Patsouris, E. and Saetta, A.A. and Korkolopoulou, P.",
    journal = "Virchows Archiv",
    year = "2014",
    volume = "465",
    number = "4",
    pages = "473-485",
    publisher = "Springer-Verlag",
    issn = "0945-6317, 1432-2307",
    doi = "10.1007/s00428-014-1641-3",
    keywords = "epithelial membrane antigen;  glial fibrillary acidic protein;  initiation factor 4E binding protein 1;  Janus kinase;  mammalian target of rapamycin;  mitogen activated protein kinase;  mitogen activated protein kinase 1;  mitogen activated protein kinase 3;  Notch1 receptor;  phosphatidylinositol 3 kinase;  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase;  protein;  protein akt1;  protein kinase B;  protein p110;  protein p110 gamma;  protein p85;  protein p85 alpha;  protein pik3ca;  protein S 100;  STAT3 protein;  unclassified drug;  Janus kinase;  mitogen activated protein kinase kinase;  MTOR protein, human;  NOTCH1 protein, human;  Notch1 receptor;  phosphatidylinositol 3 kinase;  protein kinase B;  STAT protein;  target of rapamycin kinase, adult;  Article;  cancer patient;  cancer radiotherapy;  cancer surgery;  cancer survival;  controlled study;  exon;  female;  gene mutation;  human;  human tissue;  immunoreactivity;  major clinical study;  male;  meningioma;  multimodality cancer therapy;  overall survival;  protein expression;  protein phosphorylation;  protein protein interaction;  retrospective study;  signal transduction;  brain tumor;  disease course;  immunohistochemistry;  meningioma;  metabolism;  mortality;  mutation;  pathology;  physiology;  prognosis;  tumor cell line;  Western blotting, Blotting, Western;  Brain Neoplasms;  Cell Line, Tumor;  Disease Progression;  Female;  Humans;  Immunohistochemistry;  Janus Kinases;  Male;  Meningioma;  Mitogen-Activated Protein Kinase Kinases;  Mutation;  Phosphatidylinositol 3-Kinases;  Prognosis;  Proto-Oncogene Proteins c-akt;  Receptor, Notch1;  Signal Transduction;  STAT Transcription Factors;  TOR Serine-Threonine Kinases",
    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. © 2014, Springer-Verlag Berlin Heidelberg."
}