Research Papers:

Epithelioid peritoneal mesothelioma: a hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework

Fabio Bozzi, Silvia Brich, Gian Paolo Dagrada, Tiziana Negri, Elena Conca, Barbara Cortelazzi, Antonino Belfiore, Federica Perrone, Ambra Vittoria Gualeni, Annunziata Gloghini, Antonello Cabras, Monica Brenca, Roberta Maestro, Nadia Zaffaroni, Paolo Casali, Rossella Bertulli, Marcello Deraco and Silvana Pilotti _

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Oncotarget. 2016; 7:75503-75517. https://doi.org/10.18632/oncotarget.12262

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Fabio Bozzi1, Silvia Brich1,7, Gian Paolo Dagrada1, Tiziana Negri1, Elena Conca1, Barbara Cortelazzi1, Antonino Belfiore1, Federica Perrone2, Ambra Vittoria Gualeni2, Annunziata Gloghini2, Antonello Cabras2, Monica Brenca6, Roberta Maestro6, Nadia Zaffaroni3, Paolo Casali4, Rossella Bertulli4, Marcello Deraco5, Silvana Pilotti1

1Laboratory of Experimental Molecular Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

2Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

3Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

4Adult Mesenchymal Tumor Medical Oncology Unit, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

5Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Experimental Oncology 1, Centro di Riferimento Oncologico, CRO Aviano National Cancer Institute, Aviano, Italy

7MOSE-DEA University of Trieste, Trieste, Italy

Correspondence to:

Silvana Pilotti, email: [email protected]

Keywords: malignant peritoneal mesothelioma, MET, MErT

Received: April 05, 2016     Accepted: September 13, 2016     Published: September 26, 2016


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.

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