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 language | English |
|---|---|
| Pages (from-to) | 22254-22268 |
| Number of pages | 15 |
| Journal | Oncotarget |
| Volume | 9 |
| Issue number | 32 |
| DOIs | |
| Publication status | Published - Apr 27 2018 |
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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 journal › Article
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=85046093263&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046093263&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24962
DO - 10.18632/oncotarget.24962
M3 - Article
AN - SCOPUS:85046093263
VL - 9
SP - 22254
EP - 22268
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 32
ER -