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

Our plain-English summary of Epithelioid peritoneal mesothelioma: a hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework, by F. Bozzi, S. Brich, G.P. Dagrada, et al (Oncotarget, 2016).

The study

• Authors: F. Bozzi, S. Brich, G.P. Dagrada, T. Negri, E. Conca, B. Cortelazzi, A. Belfiore, F. Perrone, A.V. Gualeni, A. Gloghini, A. Cabras, M. Brenca, R. Maestro, N. Zaffaroni, P. Casali, R. Bertulli, M. Deraco, S. Pilotti
• Journal: Oncotarget
• Published: 2016;7(46):75503-75517
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study from Milan, Italy, examined the biology of epithelioid malignant peritoneal mesothelioma, a cancer of the abdominal lining. The authors tested surgical tumour samples from 21 previously untreated patients: 17 epithelioid, 2 high-grade epithelioid and 2 sarcomatoid tumours. They also grew cells from three patients' tumours. The article did not report the patients' asbestos exposure. EZH2 was present across all tumour types. c-MYC, c-MET, VEGFR2 and E-cadherin were found in the epithelioid tumours. On tissue staining, the two sarcomatoid tumours lacked c-MYC, c-MET, VEGFR2 and E-cadherin and showed SLUG and TWIST, though a stem cell array detected E-cadherin in them. Many epithelioid tumour cells carried both E-cadherin and VEGFR2, which the authors called a hybrid phenotype. In cultured cells, bevacizumab and sunitinib increased SLUG. HGF lowered EZH2, while TGF-beta1 with IL-1 raised it. The EZH2 inhibitor GSK 126 reduced growth of one cell line. The authors concluded that this tumour is likely to respond poorly to traditional treatment but may respond to drugs that inhibit epigenetic regulators. These drug results came from laboratory cells, not treated patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of surgical tumour specimens and cell cultures derived from them (immunohistochemistry, immunofluorescence, in situ hybridization, biochemistry, stem cell arrays, drug and growth-factor treatments of cells)
• Who was studied: Surgical samples from 21 previously untreated patients with malignant peritoneal mesothelioma at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (17 epithelioid, 2 high-grade epithelioid, 2 sarcomatoid). Frozen material was available for 11 patients, and fresh material from 3 patients was used for cell cultures. Three omentum samples came from unrelated MpM patients. Dates are not given.
• Exposure: Not studied: the article does not report the patients' asbestos exposure. Laboratory exposures were bevacizumab, sunitinib, HGF, TGF-beta1/IL-1b and the EZH2 inhibitor GSK 126 applied to cultured tumour cells.
• Main results:
  • EZH2 was expressed in all MpM surgical specimens, to different extents.
  • c-MYC, c-MET, VEGFR2 and E-cadherin expression segregated with the epithelioid variant.
  • On immunohistochemistry, the two sarcomatoid specimens (cases #20 and #21) lacked E-cadherin, c-MYC, VEGFR2 and c-MET and were enriched in cells expressing SLUG and TWIST.
  • The pluripotent stem cell array detected E-cadherin in both epithelioid and sarcomatoid tumours, although tissue staining did not show it in the sarcomatoid tumours.
  • Two epithelioid tumours tested expressed high levels of miRNA 17-5p (in less than 25% of tumour cells); the sarcomatoid tumour tested showed no signal.
  • In epithelioid tumour tissue (case #1), some cells showed E-cadherin or VEGFR2 alone, but a considerable number showed both (the hybrid phenotype).
  • In the surgical samples, VEGFR2 showed very little or no activation.
  • In two short-term cell cultures (STC1 and STC2) treated for 24 hours with bevacizumab or sunitinib, both drugs increased SLUG.
  • In the stable cell line SSL1, HGF decreased EZH2 and TGF-beta1/IL1 increased it.
  • Treating SSL1 with the EZH2 inhibitor GSK 126 reduced growth and SLUG transcription.
• The authors' conclusion: The authors proposed that epithelioid peritoneal mesothelioma represents stemness-enriched tumour growth that is likely to respond poorly to traditional treatment but may respond to epigenetic regulator inhibitors.
• Limitations the authors state:
  • E-cadherin results differed between tissue staining and the stem cell array. The authors suggested this may be due to the two antibodies recognising different targets, but no information on those targets was available.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Epithelioid, Peritoneal Mesothelioma, Immunohistochemistry, STEM, Cytokine, Sarcomatoid.

Related studies

• Epithelial-mesenchymal transition in malignant mesothelioma — A. Fassina, R. Cappellesso, et al. (2012)
• Prognostic significance of epithelial-mesenchymal transition in malignant pleural mesothelioma — A. Schramm, I. Opitz, et al. (2010)
• Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells — X. He, L. Wang, et al. (2017)
• The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma — V. Ramundo, G. Zanirato, et al. (2021)
• Clinical significance of epithelial-mesenchymal transition-associated markers in malignant pleural mesothelioma — T. Iwanami, H. Uramoto, et al. (2014)
• The Role of Epithelial-Mesenchymal Transition in Malignant Pleural Mesothelioma: From Pathogenesis to Diagnosis and Treatment — D.E. Magouliotis, F. Minervini, et al. (2025)

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