Malignant mesothelioma as an oxidative stress-induced cancer: An update

Our plain-English summary of Malignant mesothelioma as an oxidative stress-induced cancer: An update, by S.H. Chew, S. Toyokuni (Free Radical Biology & Medicine, 2015).

The study

• Authors: S.H. Chew, S. Toyokuni
• Journal: Free Radical Biology & Medicine
• Published: 2015;86:166-78
• Type of article: Review
• Cited by: 66 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. On fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasomes in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and TGF-β pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP1 as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still ~8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by β-catenin, has been recognized as a hopeful target for therapy, especially in sarcomatoid subtype. Recent research outcomes related to microRNAs and cancer stem cells also offer additional novel targets for the treatment of MM. Iron reduction as chemoprevention of mesothelioma is helpful at least in an animal preclinical study. Integrated approaches to fiber-induced oxidative stress would be necessary to overcome this currently fatal disease.

Copyright © 2015 Elsevier Inc. All rights reserved.

In plain English

This was a review article summarizing published research on malignant mesothelioma and the role of iron and oxidative stress (damage caused by reactive forms of oxygen) in how asbestos causes it. It covered human, cell-culture and animal studies, including the authors' own rat experiments. The review described evidence that asbestos fibers generate free radicals that damage DNA. This happened through iron on the fibers or, for iron-free chrysotile, through iron from hemoglobin released when fibers break red blood cells. Among common genetic changes, loss of p16INK4a/p14ARF was reported in 50–70% of tumor tissues and primary cells. In one cited study, BAP1 changes were found in 42% of 53 pleural mesothelioma samples. In the authors' earlier rat work, tremolite was strongly carcinogenic and anthophyllite weakly so. The iron-removing drug deferasirox did not prevent mesothelioma in rats but increased the share with the epithelioid subtype. Repeated blood removal (phlebotomy) showed no difference, which the authors said might reflect technical difficulties in rodents. The review discussed blood biomarkers. The authors concluded that molecules central to iron overload, inflammation and oxidative stress might offer treatment and prevention targets.

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: Review article (narrative review of published research)
• Who was studied: No study population of its own. The review covered published human, cell-culture and animal (mainly rat) research on malignant mesothelioma, including the authors' own laboratory studies.
• Exposure: Asbestos fibers: the amphiboles (crocidolite, amosite, tremolite, anthophyllite, actinolite) and the serpentine chrysotile. Crocidolite, amosite and chrysotile were the main commercial types. Carbon nanotubes were also discussed.
• Main results:
  • The authors' earlier work, as described in the review, found that intraperitoneal injection of chrysotile, crocidolite and amosite fibers all caused iron deposition and oxidative DNA base modification.
  • In the authors' earlier rat studies, adding the iron chelator nitrilotriacetate (NTA) to asbestos accelerated mesothelioma development.
  • In the authors' earlier animal experiments, the carcinogenicity of tremolite was strong and that of anthophyllite was weak.
  • In a rat model where fibers were put in direct contact with mesothelial cells, the authors' earlier data showed a stronger carcinogenic potential for chrysotile than for the amphiboles.
  • Cited studies reported homozygous deletion of p16INK4a/p14ARF in 50–70% of human mesothelioma tissues and primary cells, and in up to 90% of stable cell lines.
  • A cited study (Bott and colleagues) of 53 malignant pleural mesothelioma samples reported BAP1 loss, mutation, or both in 42% of tumors, and somatic inactivating BAP1 mutations in 23%.
  • In the authors' earlier rat study, deferasirox did not prevent mesothelioma after asbestos administration. It significantly increased the fraction of rats with the epithelioid subtype, and the treated group survived better.
  • In the same rat study, phlebotomy showed no difference from the untreated group. The authors said this might be attributed to technical difficulties with repeated phlebotomy in rodents.
  • Cited studies of the blood marker fibulin-3 conflicted. One reported 100% sensitivity and 94% specificity; another found 22% sensitivity at 95% specificity.
• The authors' conclusion: The authors concluded that standard chemotherapy is insufficient and that new targets should be used in combination. Because asbestos-induced mesothelioma is associated with iron overload and chronic inflammation leading to oxidative stress, they concluded that molecules central to these processes might be another option for treatment and prevention.
• Limitations the authors state:
  • The authors noted that the lack of effect of phlebotomy in their rat study might be due to technical difficulties with repeated phlebotomy in rodents.
  • The authors stated that many aspects of the disease remain unclear and that the prognosis of patients has barely improved.
  • The authors noted that their findings on CTGF as a possible blood marker, based on a rat model, have not yet been validated.

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: Malignant Mesothelioma, Oxidative Stress, Mesothelial Cells, Chrysotile, Chronic Inflammation, Macrophage, Carcinogenesis, Homozygous Deletion.

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