Plasma cell membrane localization of c-MET predicts longer survival in patients with malignant mesothelioma: a series of 157 cases from the MESOPATH Group

J Thorac Oncol. 2012 Mar;7(3):599-606. doi: 10.1097/JTO.0b013e3182417da5.


Introduction: By regulating cell functions such as growth, survival, motility/migration, and invasion, the c-mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase/hepatocyte growth factor (HGF) axis accounts for a critical pathway in malignant pleural mesothelioma.

Methods: Overall survival correlations of c-MET and phospho-c-MET immunostainings were investigated in 157 malignant pleural mesothelioma patients for whom paraffin-embedded specimens were referred to our center for pathological diagnosis certification (MESOPATH French National group). Subcellular localization of the activated c-MET receptor after HGF stimulation was assessed in nontumorogenic cell lines.

Results: Positive c-MET expression was found in 119 samples (75.8%), more frequently in the epithelioid subtype (p < 0.0001). Among those 119 positive c-MET specimens, 77 (64.7%) were also positive for phospho-c-MET. Both c-MET and phospho-c-MET scoring were independent of patient gender or age. Phospho-c-MET scoring or localization did not associate with survival. Conversely, patients with a c-MET immunohistochemical staining intensity higher than 1, but exclusively confined to plasma membrane, had a median overall survival of 25 months versus 13 months for all other patients. Only exclusive plasma membrane staining remained significantly associated with a worse prognosis in multivariate analysis (hazard ratio = 2.9, 95% confidence interval 1.0-8.2, p = 0.043). Using the HBEC3 immortalized epithelial cell lines treated with HGF, we showed the physiological relevance of phospho-c-MET nuclear translocation.

Conclusions: Our results lighten that, disregarding the intracellular c-MET receptor traffic, only c-MET plasma membrane localization could be a relevant prognosis biomarker in malignant pleural mesothelioma. Whether patients with c-MET plasma membrane immunostaining could beneficiate from c-MET-targeted therapies remains to be established in prospective trials.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Blotting, Western
  • Cell Membrane / metabolism*
  • Cell Movement
  • Cytoplasm / metabolism
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mesothelioma / metabolism
  • Mesothelioma / mortality*
  • Mesothelioma / pathology
  • Middle Aged
  • Phosphorylation
  • Plasma Cells / metabolism*
  • Pleural Effusion, Malignant / metabolism
  • Pleural Effusion, Malignant / mortality*
  • Pleural Effusion, Malignant / pathology
  • Prospective Studies
  • Proto-Oncogene Proteins c-met / metabolism*
  • Subcellular Fractions
  • Tumor Cells, Cultured


  • MET protein, human
  • Proto-Oncogene Proteins c-met