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, Agnes Bankfalvi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)22254-22268
Number of pages15
JournalOncotarget
Volume9
Issue number32
DOIs
Publication statusPublished - Apr 27 2018

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Metallothionein
Drug Therapy
Heavy Metals
Drug Resistance
Cisplatin
Disease-Free Survival
Survival
Neoplasms
Regression Analysis
Pleura
Carboplatin
Survival Analysis
MicroRNAs
Copper
Up-Regulation
Cell Culture Techniques
Malignant Mesothelioma
Gene Expression
DNA
Therapeutics

Keywords

  • Malignant pleural mesothelioma
  • Metallothionein
  • Overall survival
  • Platin-based chemotherapy
  • Prognostic biomarker

ASJC Scopus subject areas

  • Oncology

Cite this

Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy. / Mairinger, Fabian D.; Schmeller, Jan; Borchert, Sabrina; Wessolly, Michael; Mairinger, Elena; Kollmeier, Jens; Hager, Thomas; Mairinger, Thomas; Christoph, Daniel C.; Walter, Robert F.H.; Eberhardt, Wilfried E.E.; Plönes, Till; Wohlschlaeger, Jeremias; Jasani, Bharat; Schmid, Kurt Werner; Bankfalvi, Agnes.

In: Oncotarget, Vol. 9, No. 32, 27.04.2018, p. 22254-22268.

Research output: Contribution to journalArticle

Mairinger, FD, Schmeller, J, Borchert, S, Wessolly, M, Mairinger, E, Kollmeier, J, Hager, T, Mairinger, T, Christoph, DC, Walter, RFH, Eberhardt, WEE, Plönes, T, Wohlschlaeger, J, Jasani, B, Schmid, KW & Bankfalvi, A 2018, 'Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy', Oncotarget, vol. 9, no. 32, pp. 22254-22268. https://doi.org/10.18632/oncotarget.24962
Mairinger, Fabian D. ; Schmeller, Jan ; Borchert, Sabrina ; Wessolly, Michael ; Mairinger, Elena ; Kollmeier, Jens ; Hager, Thomas ; Mairinger, Thomas ; Christoph, Daniel C. ; Walter, Robert F.H. ; Eberhardt, Wilfried E.E. ; Plönes, Till ; Wohlschlaeger, Jeremias ; Jasani, Bharat ; Schmid, Kurt Werner ; Bankfalvi, Agnes. / Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy. In: Oncotarget. 2018 ; Vol. 9, No. 32. pp. 22254-22268.
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abstract = "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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T1 - Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy

AU - Mairinger, Fabian D.

AU - Schmeller, Jan

AU - Borchert, Sabrina

AU - Wessolly, Michael

AU - Mairinger, Elena

AU - Kollmeier, Jens

AU - Hager, Thomas

AU - Mairinger, Thomas

AU - Christoph, Daniel C.

AU - Walter, Robert F.H.

AU - Eberhardt, Wilfried E.E.

AU - Plönes, Till

AU - Wohlschlaeger, Jeremias

AU - Jasani, Bharat

AU - Schmid, Kurt Werner

AU - Bankfalvi, Agnes

PY - 2018/4/27

Y1 - 2018/4/27

N2 - 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.

AB - 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.

KW - Malignant pleural mesothelioma

KW - Metallothionein

KW - Overall survival

KW - Platin-based chemotherapy

KW - Prognostic biomarker

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