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

ABSTRACT: 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.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.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).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.

SUBMITTER: Mairinger FD

PROVIDER: S-EPMC5976462 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Mairinger Fabian D FD Schmeller Jan J Borchert Sabrina S Wessolly Michael M Mairinger Elena E Kollmeier Jens J Hager Thomas T Mairinger Thomas T Christoph Daniel C DC Walter Robert F H RFH Eberhardt Wilfried E E WEE Plönes Till T Wohlschlaeger Jeremias J Jasani Bharat B Schmid Kurt Werner KW Bankfalvi Agnes A

Oncotarget 20180427 32

<h4>Background</h4>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 k ...[more]

PMID: 29854276

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Project description:Malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with dismal prognosis. Platinum-based chemotherapy is regularly used as part of multimodality therapy. The expression of metallothioneins (MT) has been identified as a reason for cisplatin resistance, which often leads to early therapy failure or relapse. Thus, knockdown of MT expression may improve response to cisplatin treatment. The MT gene- and protein expression of the MPM-cell lines MSTO-211H, NCI-H2052 and NCI-H2452 and the human fibroblast cell line MRC-5, as well as their sensitivity to cisplatin treatment have been evaluated. Knockdown of MT1A, 1B and 2A expression was induced by RNA interference. MT expression was measured using quantitative real-time PCR. An in vitro Assay based on enzyme activity was used to detect cell viability, necrosis and apoptosis before and after incubation with cisplatin. MT2A gene expression could be detected in all MPM cell lines, showing the highest expression in NCI-H2452 and NCI-H2052, whereas gene expression levels of MT1A and MT1B were low or absent. The immunohistochemically protein expression of MT-I/II reflect MT2A gene expression levels. Especially for MSTO-211H cell presenting low initial MT2A levels, a strong induction of MT2A expression could be observed during cisplatin treatment, indicating a cell line-specific and platin-dependent adaption mechanism. Additionally, a MT2A-dependent cellular evasion of apoptosis during cisplatin could be observed, leading to three different MT based phenotypes. MSTO-211H cells showed lower apoptosis rates at an increased expression level of MT2A after cisplatin treatment (from sixfold to fourfold). NCI-H2052 cells showed no changes in MT2A expression, while apoptosis rate is the highest (8-12-fold). NCI-H2452 cells showed neither changes in alteration rate of MT2A expression nor changes in apoptosis rates, indicating an MT2A-independent resistance mechanism. Knockdown of MT2A expression levels resulted in significantly induced apoptotic rates during cisplatin treatment with strongest induction of apoptosis in each of the MPM cell lines, but in different markedness. A therapeutic meaningful effect of MT2A knockdown and subsequent cisplatin treatment could be observed in MSTO-211H cells. The present study showed MT2A to be part of the underlying mechanism of cisplatin resistance in MPM. Especially in MSTO-211H cells we could demonstrate major effects by knockdown of MT2A expression, verifying our hypothesis of an MT driven resistance mechanism. We could prove the inhibition of MT2A as a powerful tool to boost response rates to cisplatin-based therapy in vitro. These data carry the potential to enhance the clinical outcome and management of MPM in the future.

Project description:We previously reported our technique for delivering intensity modulated radiation therapy (IMRT) to the entire pleura while attempting to spare the lung in patients with malignant pleural mesothelioma (MPM). Herein, we report a detailed pattern-of-failure analysis in patients with MPM who were unresectable or underwent pleurectomy/decortication (P/D), uniformly treated with hemithoracic pleural IMRT.Sixty-seven patients with MPM were treated with definitive or adjuvant hemithoracic pleural IMRT between November 2004 and May 2013. Pretreatment imaging, treatment plans, and posttreatment imaging were retrospectively reviewed to determine failure location(s). Failures were categorized as in-field (within the 90% isodose line), marginal (<90% and ?50% isodose lines), out-of-field (outside the 50% isodose line), or distant.The median follow-up was 24 months from diagnosis and the median time to in-field local failure from the end of RT was 10 months. Forty-three in-field local failures (64%) were found with a 1- and 2-year actuarial failure rate of 56% and 74%, respectively. For patients who underwent P/D versus those who received a partial pleurectomy or were deemed unresectable, the median time to in-field local failure was 14 months versus 6 months, respectively, with 1- and 2-year actuarial in-field local failure rates of 43% and 60% versus 66% and 83%, respectively (P=.03). There were 13 marginal failures (19%). Five of the marginal failures (38%) were located within the costomediastinal recess. Marginal failures decreased with increasing institutional experience (P=.04). Twenty-five patients (37%) had out-of-field failures. Distant failures occurred in 32 patients (48%).After hemithoracic pleural IMRT, local failure remains the dominant form of failure pattern. Patients treated with adjuvant hemithoracic pleural IMRT after P/D experience a significantly longer time to local and distant failure than patients treated with definitive pleural IMRT. Increasing experience and improvement in target delineation minimize the incidence of avoidable marginal failures.

Dataset Information

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

Publications

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

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