title: Plasma cell membrane localization of c-MET predicts longer survival in patients with malignant mesothelioma: a series of 157 cases from the MESOPATH Group.
abstract: BACKGROUND
  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.
authors.affiliation: MESOPATH Center, Caen, France.
authors.forename: Guénaëlle
authors.initials: G
authors.lastname: Levallet
authors.forename: Mélissa
authors.initials: M
authors.lastname: Vaisse-Lesteven
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Le Stang
authors.forename: Anabelle Gilg Soit
authors.initials: AG
authors.lastname: Ilg
authors.forename: Patrick
authors.initials: P
authors.lastname: Brochard
authors.forename: Philippe
authors.initials: P
authors.lastname: Astoul
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Pairon
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bergot
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
authors.forename: Francoise
authors.initials: F
authors.lastname: Galateau-Sallé
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008654:Mesothelioma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D008875:Middle Aged; D010766:Phosphorylation; D010950:Plasma Cells / Q000378:metabolism*; D016066:Pleural Effusion, Malignant / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D011446:Prospective Studies; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met