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.
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 mesotheliomapatients 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.
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Authors: R Montagne; M Berbon; L Doublet; N Debreuck; A Baranzelli; H Drobecq; C Leroy; N Delhem; H Porte; M-C Copin; E Dansin; A Furlan; D Tulasne Journal: Cell Death Dis Date: 2015-05-21 Impact factor: 8.469
Authors: Guntulu Ak; Sandra C Tomaszek; Farhad Kosari; Muzaffer Metintas; James R Jett; Selma Metintas; Huseyin Yildirim; Emine Dundar; Jie Dong; Marie Christine Aubry; Dennis A Wigle; Charles F Thomas Journal: Biomed Res Int Date: 2015-02-01 Impact factor: 3.411
Authors: Samer Al-Saad; Elin Richardsen; Thomas K Kilvaer; Tom Donnem; Sigve Andersen; Mehrdad Khanehkenari; Roy M Bremnes; Lill-Tove Busund Journal: PLoS One Date: 2017-07-25 Impact factor: 3.240
Authors: William F Maguire; John C Schmitz; Jonas Scemama; Ken Czambel; Yan Lin; Anthony G Green; Shaoyu Wu; Huang Lin; Shannon Puhalla; John Rhee; Ronald Stoller; Hussein Tawbi; James J Lee; John J Wright; Jan H Beumer; Edward Chu; Leonard J Appleman Journal: Cancer Chemother Pharmacol Date: 2021-06-23 Impact factor: 3.288