TY - JOUR
T1 - Epithelioid peritoneal mesothelioma
T2 - A hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework
AU - Bozzi, Fabio
AU - Brich, Silvia
AU - Dagrada, Gian Paolo
AU - Negri, Tiziana
AU - Conca, Elena
AU - Cortelazzi, Barbara
AU - Belfiore, Antonino
AU - Perrone, Federica
AU - Gualeni, Ambra Vittoria
AU - Gloghini, A.
AU - Cabras, Antonello
AU - Brenca, Monica
AU - Maestro, Roberta
AU - Zaffaroni, Nadia
AU - Casali, Paolo Giovanni
AU - Bertulli, Rossella
AU - Deraco, Marcello
AU - Pilotti, Silvana
PY - 2016
Y1 - 2016
N2 - The aim of this study was to reconsider the biological characteristics of epithelioid malignant peritoneal mesothelioma (E-MpM) in the light of new concepts about epithelial mesenchymal transition and mesenchymal epithelial reverse transition (EMT/MErT) and the role of epigenetic reprogramming in this context. To this end we profiled surgical specimens and derived cells cultures by a number of complementary approaches i.e. immunohistochemistry, immunofluorescence, in situ hybridization, biochemistry, pluripotent stem cell arrays, treatments with cytokines, growth factors and specific inhibitors. The analyses of the surgical specimens showed that i) EZH2 is expressed throughout the spectrum of MpM, ii) that E-MpM (including the high-grade undifferentiated form) are characterised by c-MYC and miRNA 17-5p expression, and iii) that progression to sarcomatoid MpM is dictated by EMT regulators. They also showed that E-MpM expressed c-MET and are enriched in E- and P-cadherins- and VEGFR2-expressing CSCs, thus strongly supporting a role for MErT reprogramming in endowing E-MpM tumour cells with stemness and plasticity, and hence with a drug resistant phenotype. The cell culture-based experiments confirmed the stemness traits and plasticity of E-MpM, and support the view that EZH2 is a druggable target in this tumor.
AB - The aim of this study was to reconsider the biological characteristics of epithelioid malignant peritoneal mesothelioma (E-MpM) in the light of new concepts about epithelial mesenchymal transition and mesenchymal epithelial reverse transition (EMT/MErT) and the role of epigenetic reprogramming in this context. To this end we profiled surgical specimens and derived cells cultures by a number of complementary approaches i.e. immunohistochemistry, immunofluorescence, in situ hybridization, biochemistry, pluripotent stem cell arrays, treatments with cytokines, growth factors and specific inhibitors. The analyses of the surgical specimens showed that i) EZH2 is expressed throughout the spectrum of MpM, ii) that E-MpM (including the high-grade undifferentiated form) are characterised by c-MYC and miRNA 17-5p expression, and iii) that progression to sarcomatoid MpM is dictated by EMT regulators. They also showed that E-MpM expressed c-MET and are enriched in E- and P-cadherins- and VEGFR2-expressing CSCs, thus strongly supporting a role for MErT reprogramming in endowing E-MpM tumour cells with stemness and plasticity, and hence with a drug resistant phenotype. The cell culture-based experiments confirmed the stemness traits and plasticity of E-MpM, and support the view that EZH2 is a druggable target in this tumor.
KW - Malignant peritoneal mesothelioma
KW - MErT
KW - MET
UR - http://www.scopus.com/inward/record.url?scp=84996773842&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84996773842&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.12262
DO - 10.18632/oncotarget.12262
M3 - Article
VL - 7
SP - 75503
EP - 75517
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 46
ER -