Metabolic rewiring and redox alterations in malignant pleural mesothelioma

Our plain-English summary of Metabolic rewiring and redox alterations in malignant pleural mesothelioma, by L. Urso, I. Cavallari, E. Sharova, et al (British Journal of Cancer, 2020).

The study

• Authors: L. Urso, I. Cavallari, E. Sharova, F. Ciccarese, G. Pasello, V. Ciminale
• Journal: British Journal of Cancer
• Published: 2020;122(1):52-61
• Type of article: Review
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in 18F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.

In plain English

This article was a review, not a new study. The authors summarised published research on how malignant pleural mesothelioma (MPM) cells use energy and handle reactive oxygen species (ROS), reactive forms of oxygen that can damage cells. They described earlier work suggesting that inhaled asbestos fibres raise ROS levels directly, through iron on the fibres, and indirectly, through chronic inflammation. They described this environment as able to foster cancerous change in mesothelial cells. They wrote that amphiboles are more carcinogenic than chrysotile because of higher iron content and greater rigidity. The review described MPM tumours as commonly highly glycolytic (heavily dependent on breaking down glucose) and positive on 18F-FDG PET scans. It also discussed how BAP1 mutations and MTAP loss alter tumour metabolism. The authors cautioned that some cited signalling studies were short-term experiments on MPM cell lines that died after asbestos treatment, which argues against a direct carcinogenic effect of asbestos on MPM cells. They concluded that drugs raising ROS to levels that kill MPM cells appear particularly attractive, and that findings need validation in large cohort studies.

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: Narrative review of published research (laboratory, animal and patient studies) on metabolism and redox (ROS) changes in malignant pleural mesothelioma
• Who was studied: No new participants; the review discussed previously published studies of MPM cell lines, mesothelial cells, animal models (mice, rats) and MPM patients
• Exposure: Asbestos fibres in general. The review named the amphiboles crocidolite, amosite, tremolite, anthophyllite and actinolite, and the serpentine chrysotile. Many of the experiments it cited used crocidolite, and one used chrysotile. It also discussed the asbestos-like silicate erionite and the silicate palygorskite.
• Main results:
  • The review described asbestos fibres as raising ROS levels in two ways: directly, through iron-driven reactions, and indirectly, through frustrated phagocytosis (immune cells unable to clear long fibres) and chronic inflammation.
  • The authors stated that amphiboles are more carcinogenic than chrysotile because of their higher iron content and rigidity. They added that iron content alone does not predict how carcinogenic a fibre is.
  • The review described MPM lesions as commonly highly glycolytic and positive on 18F-FDG PET scans.
  • Citing earlier work, the review reported that BAP1 loss-of-function mutations are present in families predisposed to mesothelioma and in 60% of patients with sporadic mesothelioma. It described BAP1 loss as a contributor to the metabolic rewiring of MPM cells.
  • The review described a subset of MPM with deletion of the MTAP gene. In these tumours the substance MTA accumulates and inhibits the enzyme PRMT5, and the review stated that MTAP-defective cells are selectively vulnerable to drugs that inhibit PRMT5.
  • The authors suggested that high levels of antioxidant systems in MPM may explain tumour resistance to ROS-generating therapies such as cisplatin/pemetrexed, epirubicin and radiotherapy.
  • The review cited a study in which pegylated arginine deiminase (ADI PEG20) produced a modest but significant increase in progression-free survival in patients with ASS1-deficient advanced MPM.
• The authors' conclusion: The authors concluded that drug approaches pushing ROS to levels that kill cells appear particularly attractive for selectively targeting MPM cells. They also concluded that metabolic features such as glycolysis, BAP1 loss and MTAP loss may offer treatment targets and markers for selecting patients.
• Limitations the authors state:
  • The authors cautioned that some of the cited signalling studies were short-term experiments on MPM cell lines that died after asbestos treatment, which argues against a direct carcinogenic effect of asbestos on MPM cells.
  • The authors stated that the mechanisms by which loss of BAP1 function promotes the glycolytic (Warburg) effect are not completely understood.
  • The authors stated that further studies are needed to understand pemetrexed resistance in MPM and to identify predictive biomarkers.
  • The authors stated that the findings need validation in large cohort studies.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelial Cells, Prognosis, Occupational Exposure, Reactive Oxygen Species (ROS), Silicate, Macrophage, Inflammation.

Related studies

• Asbestos-derived reactive oxygen species activate TGF-beta1 — D.A. Pociask, P.J. Sime, et al. (2004)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma — M. Nasu, M. Emi, et al. (2015)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• The spectrum of tumors harboring BAP1 gene alterations — Y. Laitman, J. Newberg, et al. (2021)
• Morphological difference between pleural mesothelioma cells in effusion smears with either BAP1 loss or 9p21 homozygous deletion and reactive mesothelial cells without the gene alterations — S. Matsumoto, M. Hamasaki, et al. (2019)

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