Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention

Our plain-English summary of Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention, by S. Toyokuni (Free Radical Biology & Medicine, 2019).

The study

• Author: S. Toyokuni
• Journal: Free Radical Biology & Medicine
• Published: 2019;133:206-215
• Type of article: Review
• Cited by: 73 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cancer is the primary cause of human mortality in most countries. This tendency has increased as various medical therapeutics have advanced, which suggests that we cannot escape carcinogenesis, although the final outcome may be modified by exposomes and statistics. Cancer is classified by its cellular differentiation. Mesothelial cells are distinct in that they line somatic cavities, facilitating the smooth movement of organs, but are not exposed to the external environment. Malignant mesothelioma, or simply mesothelioma, develops either in the pleural, peritoneal or pericardial cavities, or in the tunica vaginalis testes. Mesothelioma has been a relatively rare cancer but is socially important due to its association with asbestos exposure, caused by modern industrial development. The major pathogenic mechanisms include oxidative stress either via catalytic reactions against the asbestos surface or frustrated phagocytosis of macrophages, and specific adsorption of hemoglobin and histones by asbestos fibers in the presence of phagocytic activity of mesothelial cells. Multiwall carbon nanotubes of ~50 nm-diameter, additionally adsorbing transferrin, are similarly carcinogenic to mesothelial cells in rodents and were thus classified as Group 2B carcinogens. Genetic alterations found in human and rat mesothelioma notably contain changes found in other excess iron-induced carcinogenesis models. Phlebotomy and iron chelation therapies have been successful in the prevention of mesothelioma in rats. Alternatively, loading of oxidative stress by non-thermal plasma to mesothelioma cells causes ferroptosis. Therefore, carcinogenesis by foreign fibrous inorganic materials may overlap the uncovered molecular mechanisms of birth of life and its evolution.

Copyright © 2018. Published by Elsevier Inc.

In plain English

This article is a narrative review by a single author at Nagoya University, Japan, on how asbestos causes mesothelioma. It reported no new study of its own. Instead it summarized earlier work, much of it rat experiments from the author's own laboratory. The review described findings that chrysotile, crocidolite and amosite fibers all bind hemoglobin, histones and actin on their surface, and that fibers in the lung collect iron for decades. It reported that rats developed peritoneal mesothelioma about one and a half years after 10 mg of asbestos was injected into the abdomen. It also reported that multiwall carbon nanotubes about 50 nm wide caused mesothelioma in rodents, while no human cases have been reported. In the earlier rat experiments, the iron-removing drug deferasirox did not change survival, but weekly blood removal (phlebotomy) significantly extended survival. The author concluded that local iron overload drives asbestos-induced mesothelioma and that there are many possible routes to prevention. The author noted that some of the suggested prevention strategies are supported only by preclinical evidence and others are still hypothetical.

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 by a single author, summarizing published work, much of it from the author's own laboratory
• Who was studied: No study population of its own. The review covers published human data and rodent experiments, including the author's laboratory's rat model in which asbestos was injected into the abdomen of wild-type rats.
• Exposure: Asbestos (chrysotile, crocidolite, amosite; also tremolite and anthophyllite in rats) and multiwall carbon nanotubes
• Main results:
  • Reviewed finding from the author's laboratory: the main proteins that stick to asbestos fiber surfaces were hemoglobin, histones and actin, common to all three asbestos types
  • The review stated that asbestos fibers in the lung collect iron from their surroundings over decades
  • Reviewed rat work: wild-type rats developed peritoneal mesothelioma about 1.5 years after an intraperitoneal injection of 10 mg of asbestos
  • Reviewed rat work: tremolite was highly carcinogenic in wild-type rats after intraperitoneal injection, while anthophyllite had low carcinogenicity
  • Reviewed work: multiwall carbon nanotubes about 50 nm in diameter were carcinogenic in rodents (p53+/- mice and wild-type rats)
  • The author stated there is no report so far of carbon nanotube-induced mesothelioma in humans
  • Reviewed rat work: the iron chelator deferasirox did not change survival after 10 mg asbestos injection, but significantly increased the share of less aggressive (epithelioid) tumor subtypes
  • Reviewed rat work: weekly phlebotomy significantly extended survival and decreased the share of more aggressive tumor subtypes
  • Reviewed laboratory work: mesothelioma cells were susceptible to non-thermal plasma, through a process that depended on iron
• The authors' conclusion: The author concluded that the molecular mechanisms of asbestos-induced mesothelioma have been made clear: local iron overload causes iron addiction and ferroptosis resistance in mesothelial cells. The author also concluded that there are many possibilities for prevention and therapy.
• Limitations the authors state:
  • The author noted that some of the proposed prevention strategies are supported by preclinical evidence while others are still hypothetical
  • Causes of mesothelioma other than asbestos were not covered, apart from familial (genetic) factors and fibrous nanomaterials
  • Effects of these fibers on lung cancer were not discussed because of space limits
  • For deferasirox, the author noted possible kidney toxicity and high cost for human use

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: Carcinogenesis, Mesothelioma, Mesothelial Cells, Malignant Mesothelioma, Pericardial, Tunica Vaginalis, Asbestos Exposure, Oxidative Stress.

Related studies

• The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy — S. Toyokuni (2016)
• Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin — F. Ito, K. Kato, et al. (2021)
• Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis — L. Jiang, S.H. Chew, et al. (2016)
• Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia — Z. Li, L. Jiang, et al. (2019)
• Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice — S. Funahashi, Y. Okazaki, et al. (2018)
• Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis — S. Toyokuni (2014)

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