Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study

Our plain-English summary of Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study, by A. Mathilakathu, S. Borchert, M. Wessolly, et al (Translational Lung Cancer Research, 2021).

The study

• Authors: A. Mathilakathu, S. Borchert, M. Wessolly, E. Mairinger, H. Beckert, J. Steinborn, T. Hager, D.C. Christoph, J. Kollmeier, J. Wohlschlaeger, T. Mairinger, K.W. Schmid, R.F.H. Walter, L. Brcic, F.D. Mairinger
• Journal: Translational Lung Cancer Research
• Published: 2021;10(7):3030-3042
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare malignant tumor associated with asbestos exposure, with infaust prognosis and overall survival below 20 months in treated patients. Platinum is still the backbone of the chemotherapy protocols, and the reasons for the rather poor efficacy of platinum compounds in MPM remain largely unknown. Therefore, we aimed to analyze differences in key signaling pathways and biological mechanisms in therapy-naïve samples and samples after chemotherapy in order to evaluate the effect of platinum-based chemotherapy.

Methods: The study cohort comprised 24 MPM tumor specimens, 12 from therapy-naïve and 12 from patients after platinum-based therapy. Tumor samples were screened using the NanoString nCounter platform for digital gene expression analysis with an appurtenant custom-designed panel comprising a total of 366 mRNAs covering the most important tumor signaling pathways. Significant pathway associations were identified by gene set enrichment analysis using the WEB-based GEne SeT AnaLysis Toolkit (WebGestalt).

Results: We have found reduced activity of TNF (normalized enrichment score: 2.03), IL-17 (normalized enrichment score: 1.93), MAPK (normalized enrichment score: 1.51), and relaxin signaling pathways (normalized enrichment score: 1.42) in the samples obtained after platinum-based therapy. In contrast, AMPK (normalized enrichment score: -1.58), mTOR (normalized enrichment score: -1.50), Wnt (normalized enrichment score: -1.38), and longevity regulating pathway (normalized enrichment score: -1.31) showed significantly elevated expression in the same samples.

Conclusions: We could identify deregulated signaling pathways due to a directed cellular response to platinum-induced cell stress. Our results are paving the ground for a better understanding of cellular responses and escape mechanisms, carrying a high potential for improved clinical management of patients with MPM.

2021 Translational Lung Cancer Research. All rights reserved.

In plain English

This retrospective, exploratory laboratory study examined tumor tissue from 24 patients with malignant pleural mesothelioma of the epithelioid subtype, treated at the West German Cancer Centre or the West German Lung Centre between 2005 and 2009. Twelve samples were taken before any treatment and twelve after platinum-based chemotherapy. These were not paired samples from the same patients. The authors measured the expression of 366 messenger RNAs (357 target genes and 9 reference genes) and used these results to analyze biological pathways. Compared with untreated samples, samples taken after chemotherapy showed higher activity in the AMPK, mTOR, Wnt and longevity regulating pathways, and lower activity in the TNF, IL-17, MAPK and relaxin signaling pathways. Some individual genes, such as H2AFX, were higher after therapy, while DUSP6, MYC, IL8 and ANGPT2 were lower. Lower expression of 19 genes was associated with longer overall survival. The study did not measure asbestos exposure. The authors concluded that the changes reflected the tumor cells' response to stress caused by platinum. They stated that the study was retrospective, used a small cohort and should be read as a pilot study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective, exploratory gene-expression (mRNA) study of archived tumor tissue. A custom NanoString panel of 366 mRNAs (357 target genes and 9 potential reference genes) was used, and pathways were analyzed by gene set enrichment analysis. Samples taken before treatment were compared with samples taken after platinum-based chemotherapy.
• Who was studied: 24 formalin-fixed tumor specimens from patients with malignant pleural mesothelioma, all of the epithelioid subtype, treated at the West German Cancer Centre or the West German Lung Centre (Germany) between 2005 and 2009. Twelve were therapy-naïve and twelve were taken after platinum-based therapy. 22 patients were male and 2 female. Mean/median age at diagnosis was 65/63.5 years (range 51 to 80). 23 had died by the end of follow-up (August 31, 2014).
• Exposure: Platinum-based chemotherapy: samples taken after this treatment were compared with samples taken before any therapy. Asbestos exposure was not studied or measured.
• Main results:
  • Pathways enriched in samples taken after platinum therapy included AMPK signaling (normalized enrichment score -1.58), mTOR signaling (-1.50), Wnt signaling (-1.38) and the longevity regulating pathway (-1.31). The negative scores marked enrichment after therapy.
  • Pathways associated with therapy-naïve samples (lower activity after platinum therapy) included TNF signaling (normalized enrichment score 2.03), IL-17 signaling (1.93), MAPK signaling (1.51) and relaxin signaling (1.42).
  • Samples taken after therapy showed higher expression of H2AFX (P=0.005), PCNA (P=0.024), XRCC1 (P=0.029), DUOX2 (P=0.034) and NELL2 (P=0.034) than treatment-naïve samples.
  • In samples taken after therapy, expression of DUSP6 (P=0.010), MYC (P=0.020), IL8 (P=0.045) and ANGPT2 (P=0.050) was lower.
  • Expression levels of 22 genes were associated with overall survival in the cohort. Lower expression of 19 of these genes was associated with longer overall survival.
  • For the whole cohort of 24 patients, mean/median overall survival was 19.4/16.3 months and mean/median progression-free survival was 9.7/6.3 months.
• The authors' conclusion: The authors concluded that they had identified deregulated signaling pathways resulting from a directed cellular response to platinum-induced (oxidative) cell stress. They named MAPK, relaxin, TNF and Wnt signaling, energy metabolism regulation via AMPK and mTOR, and cytokine-mediated tumor immunogenicity as playing roles.
• Limitations the authors state:
  • The study was retrospective and used a rather small cohort.
  • Paired samples from the same patients before and after therapy were not analyzed.
  • The authors stated that the results should be interpreted as a pilot study meant to generate further hypotheses.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Prognosis, Overall Survival, Chemotherapy.

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