Research Papers: Pathology:

Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy

Fabian D. Mairinger _, Jan Schmeller, Sabrina Borchert, Michael Wessolly, Elena Mairinger, Jens Kollmeier, Thomas Hager, Thomas Mairinger, Daniel C. Christoph, Robert F.H. Walter, Wilfried E.E. Eberhardt, Till Plönes, Jeremias Wohlschlaeger, Bharat Jasani, Kurt Werner Schmid and Agnes Bankfalvi

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Oncotarget. 2018; 9:22254-22268. https://doi.org/10.18632/oncotarget.24962

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Fabian D. Mairinger1,*, Jan Schmeller1,*, Sabrina Borchert1, Michael Wessolly1, Elena Mairinger1, Jens Kollmeier2, Thomas Hager1, Thomas Mairinger3, Daniel C. Christoph4,5, Robert F.H. Walter1,6, Wilfried E.E. Eberhardt4,6, Till Plönes7, Jeremias Wohlschlaeger1,8, Bharat Jasani9, Kurt Werner Schmid1 and Agnes Bankfalvi1

1Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

2Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany

3Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany

4Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

5Department of Internistic Oncology, Kliniken Essen Mitte, Essen, Germany

6Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

7Department of Thoracic Surgery and Thoracical Endoscopy, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

8Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany

9Department of Pathology, Targos Molecular Pathology GmbH, Kassel, Germany

*These authors have contributed equally to this work

Correspondence to:

Fabian D. Mairinger, email: [email protected]

Keywords: malignant pleural mesothelioma; metallothionein; overall survival; prognostic biomarker; platin-based chemotherapy; Pathology

Received: August 18, 2017     Accepted: March 11, 2018     Published: April 27, 2018


Background: Malignant pleural mesothelioma (MPM) is a biologically highly aggressive tumor arising from the pleura with a dismal prognosis. Cisplatin is the drug of choice for the treatment of MPM, and carboplatin seems to have comparable efficacy. Nevertheless, cisplatin treatment results in a response rate of merely 14% and a median survival of less than seven months. Due to their role in many cellular processes, methallothioneins (MTs) have been widely studied in various cancers. The known heavy metal detoxifying effect of MT-I and MT-II may be the reason for heavy metal drug resistance of various cancers including MPM.

Methods: 105 patients were retrospectively analyzed immunohistochemically for their MT expression levels. Survival analysis was done by Cox-regression, and statistical significance determined using likelihood ratio, Wald test and Score (logrank) tests.

Results: Cox-regression analyses were done in a linear and logarithmic scale revealing a significant association between expression of MT and shortened overall survival (OS) in a linear (p=0.0009) and logarithmic scale (p=0.0003). Reduced progression free survival (PFS) was also observed for MT expressing tumors (linear: p=0.0134, log: p=0.0152).

Conclusion: Since both, overall survival and progression-free survival are negatively correlated with detectable MT expression in MPM, our results indicate a possible resistance to platin-based chemotherapy associated with MT expression upregulation, found exclusively in progressive MPM samples. Initial cell culture studies suggest promoter DNA hypomethylation and expression of miRNA-566 a direct regulator of copper transporter SLC31A1 and a putative regulator of MT1A and MT2A gene expression, to be responsible for the drug resistance.

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