Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM)

Lung Cancer. 2012 Jul;77(1):192-8. doi: 10.1016/j.lungcan.2012.02.022. Epub 2012 Mar 27.

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.

Patients and 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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Aged
  • Aged, 80 and over
  • Cell Cycle Proteins
  • Disease-Free Survival
  • Female
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mesothelioma / diagnosis
  • Mesothelioma / metabolism*
  • Mesothelioma / mortality
  • Middle Aged
  • Multivariate Analysis
  • PTEN Phosphohydrolase / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / metabolism
  • Pleural Neoplasms / diagnosis
  • Pleural Neoplasms / metabolism*
  • Pleural Neoplasms / mortality
  • Prognosis
  • Retrospective Studies
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction*
  • Statistics, Nonparametric

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Phosphoproteins
  • Ribosomal Protein S6 Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human