Epithelial-mesenchymal transition in malignant mesothelioma

Our plain-English summary of Epithelial-mesenchymal transition in malignant mesothelioma, by A. Fassina, R. Cappellesso, V. Guzzardo, et al (Modern Pathology, 2012).

The study

• Authors: A. Fassina, R. Cappellesso, V. Guzzardo, L. Dalla Via, S. Piccolo, L. Ventura, M. Fassan
• Journal: Modern Pathology
• Published: 2012;25(1):86-99
• Cited by: 127 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Epithelial-mesenchymal transition is a physiopathological process by which epithelial cells acquire mesenchymal shape and properties. Malignant mesothelioma is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter being associated to worse prognosis, thus suggesting a role of epithelial-mesenchymal transition in this dual phenotype. We studied 109 malignant mesotheliomas (58 epithelioid, 26 sarcomatoid, and 25 biphasic) by immunohistochemistry and qRT-PCR analysis, and demonstrated a substantial switch from epithelial markers (E-cadherin, β-catenin, and cytokeratins 5/6) to mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin, Snail, Slug, Twist, ZEB1, ZEB2, S100A4, MMP2, and MMP9) through epithelioid to biphasic and sarcomatoid histotypes. In agreement with these findings, the ectopic expression of miR-205 (a repressor of ZEB1 and ZEB2 expression) in MeT-5A (mesothelial cell line), H2452 (an epithelioid malignant mesothelioma cell line) and MSTO-211H (a biphasic malignant mesothelioma cell line) not only induced a significant reduction of ZEB1 and ZEB2 and a consequent up-regulation of E-cadherin gene expression, but also inhibited migration and invasion. Moreover, miR-205 was significantly down-regulated in biphasic and sarcomatoid histotypes (qRT-PCR and in situ hybridization analyses). Collectively, our findings indicate that epithelial-mesenchymal transition has a significant part in the morphological features of malignant mesothelioma. In particular, miR-205 down-regulation correlated significantly with both a mesenchymal phenotype and a more aggressive behavior.

In plain English

This laboratory study examined 109 malignant mesotheliomas reported between 2002 and 2009 in the pathology archives of Padova University, Italy: 58 epithelioid, 26 biphasic and 25 sarcomatoid. It did not study asbestos or any other exposure. The authors measured markers of epithelial-mesenchymal transition, in which lining-type (epithelial) cells take on the properties of connective-tissue-type (mesenchymal) cells. Median survival was 6 months (95% confidence interval 6 to 13 months) with sarcomatoid tumors. This was significantly worse than with epithelioid or biphasic tumors, whose difference from each other was not statistically significant. Epithelial markers such as E-cadherin were positive in epithelioid tumors, weak in biphasic tumors and absent in sarcomatoid tumors. Several mesenchymal markers showed the reverse pattern. A small RNA molecule, miR-205, was higher in epithelioid than in biphasic or sarcomatoid tumors. In cell cultures, adding miR-205 reduced migration and invasion of the biphasic mesothelioma cell line. In an epithelioid mesothelioma cell line and a normal mesothelial cell line, the results were similar but not statistically significant. The authors concluded that the tumor patterns form a continuous spectrum determined by this transition, which correlated with a worse outcome.

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 pathology study of archived tumor samples (staining and gene-expression measurements, with a survival analysis), plus cell-culture experiments
• Who was studied: 109 malignant mesotheliomas (58 epithelioid, 26 biphasic, 25 sarcomatoid) reported between 2002 and 2009, from the archives of the Surgical Pathology and Cytopathology Unit at Padova University, Italy. Of these, 74 were pleural and 35 peritoneal; 76 patients were men and 33 women. The authors also studied three cell lines: one normal mesothelial line (MeT-5A) and two mesothelioma lines, epithelioid H2452 and biphasic MSTO-211H.
• Exposure: Not studied. The article reports no information on asbestos or any other exposure. It examined molecular markers in tumor tissue and cell lines.
• Main results:
  • Median survival for patients with sarcomatoid malignant mesothelioma was 6 months (95% CI 6 to 13 months).
  • Patients with sarcomatoid mesothelioma had a significantly worse prognosis than those with epithelioid or biphasic mesothelioma (P less than 0.001). The difference between the epithelioid and biphasic groups was not statistically significant (P = 0.146).
  • The epithelial markers E-cadherin and cytokeratins 5/6 were positive in epithelioid tumors, weak in biphasic tumors and absent in sarcomatoid tumors (P less than 0.001 for all markers).
  • The mesenchymal markers vimentin, S100A4 and ZEB1 stained strongly in all sarcomatoid samples, moderately in biphasic tumors, and weakly and focally in epithelioid tumors.
  • Survival time in epithelioid mesothelioma was associated with the staining level of E-cadherin (P = 0.042).
  • No differences in the findings were observed between pleural and peritoneal tumors.
  • In gene-expression tests on the tumors, SNAI1 and ZEB1 levels were not statistically different among the three tumor types.
  • miR-205 levels in tumor tissue were significantly higher in epithelioid than in biphasic or sarcomatoid samples (P less than 0.01 for both).
  • In 15 tumors (five of each type), a miR-205 test showed a strong and diffuse signal in epithelioid samples, a moderate signal in biphasic samples, and a weak and focal signal in sarcomatoid samples.
  • In the biphasic mesothelioma cell line MSTO-211H, adding miR-205 inhibited the cells' migration and invasion.
  • In the other two cell lines (MeT-5A, a normal mesothelial line, and H2452, an epithelioid mesothelioma line), the results were similar but did not reach statistical significance.
• The authors' conclusion: The authors concluded that the different microscopic patterns of malignant mesothelioma form a continuous spectrum determined by epithelial-mesenchymal transition. They concluded that this transition is initiated by activation of ZEB1 and ZEB2 and is correlated with a worse outcome.
• Limitations the authors state:
  • The authors evaluated only whether markers were lost or gained in their normal location. They did not consider other mechanisms of the transition, such as nuclear localization of beta-catenin and S100A4.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Epithelioid, Sarcomatoid, Prognosis, Biphasic Mesothelioma, Immunohistochemistry, Mesothelial Cells.

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• Prognostic significance of epithelial-mesenchymal transition in malignant pleural mesothelioma — A. Schramm, I. Opitz, et al. (2010)
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