title: Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM).
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM.
  
  
  METHODS
  Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil-lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis.
  
  
  RESULTS
  Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p = 0.04) and overall survival (OS: 23.4 vs 5.6 months; p = 0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p = 0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p = 0.02 and p = 0.04 respectively), but pS6 only showed a trend (p = 0.8).
  
  
  CONCLUSIONS
  This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.
authors.affiliation: Medical Oncology Service/Vall d'Hebron University Hospital, Barcelona, Spain. scedres@vhebron.net
authors.forename: S
authors.initials: S
authors.lastname: Cedrés
authors.forename: M A
authors.initials: MA
authors.lastname: Montero
authors.forename: P
authors.initials: P
authors.lastname: Martinez
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.forename: V
authors.initials: V
authors.lastname: Rodríguez-Freixinós
authors.forename: D
authors.initials: D
authors.lastname: Torrejon
authors.forename: A
authors.initials: A
authors.lastname: Gabaldon
authors.forename: M
authors.initials: M
authors.lastname: Salcedo
authors.forename: S
authors.initials: S
authors.lastname: Ramon Y Cajal
authors.forename: E
authors.initials: E
authors.lastname: Felip
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins; D018572:Disease-Free Survival; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D015999:Multivariate Analysis; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010997:Pleural Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D012189:Retrospective Studies; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D018709:Statistics, Nonparametric
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019893:Ribosomal Protein S6 Kinases; C087000:EIF4EBP1 protein, human; C499517:FOXO3 protein, human; C494929:PTEN protein, human