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

Abstract

BackgroundMalignant 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.Methods105 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.ResultsCox-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).ConclusionSince 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.

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

“…Two subclasses—microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)—have been demonstrated to play important roles in cancer cell biology with tumor suppressor or oncogenic functions. Supported by extensive experimental evidence, ncRNAs possess potential clinical relevance as diagnostic biomarkers and molecular targets for many cancers including thoracic malignancies such as lung cancer and MPM [ 138 , 139 , 140 ]. Earlier MPM research on miRNAs and lncRNAs have been extensively reviewed elsewhere by Reid et al and Singh et al, respectively [ 141 , 142 ].…”

Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma

“…In a previous study, we found expression of metallothionein being predictive regarding response to cisplatin therapy in 105 MPM patients 21 . In the current study, we investigated the expression of metallothionein MT1A, MT1B and MT2A in selected MPM cell lines and the influence of cisplatin and siRNAs on MT-expression.…”

“…In the present study, we could proof earlier finding in clinical samples, indicating MTs crucial role in cellular response to cisplatin. Previous studies showed negative correlations of progression-free and overall survival and MT-expression 21 . In line with these findings, different cell lines showed different sensitivity against treatment with platinum compounds.…”

“…Against this background it might be suggested that MTs may cause drug resistance by binding cisplatin, oxidize and thus, inactivate it. In a previous study, we displayed a negative correlation between progression-free survival and expression of MT1/2 in 105 MPM patients 21 , maybe indicating cisplatin resistance is induced by MT-overexpression in tumor cells 21 . We also could suggest that miRNA expression of miR-566 is associated with MT1A and MT2A immunoexpression in clinical samples 21 .…”

“…Immunohistochemistry of cisplatin-treated and untreated, FFPE-embedded cells was performed according to standard protocols using an automated stainer (Ventana Discovery XT, Munich, Germany) and stained for MT1 and MT2 (monoclonal primary antibody MT1/MT2 clone 9, Agilent, Santa Clara, CA, USA). A semi quantitative scoring system, based on percentage of positive stained cells was used (score 0: no immunohistochemically signal, score 1: 1–5% MT-positive cells, score 2: 6–50% MT-positive cells, score 3: > 50% MT-positive cells) 21 .…”