Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis

Our plain-English summary of Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis, by S. Toyokuni (Redox Report, 2014).

The study

• Author: S. Toyokuni
• Journal: Redox Report
• Published: 2014;19(1):1-7
• Type of article: Review
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated because of the long incubation period for MM.

In plain English

This single-author review from Nagoya University, Japan, argued that local iron overload is a major mechanism behind asbestos-induced malignant mesothelioma. It mainly described earlier rat experiments by the author's research group. In those experiments, asbestos injected into the abdominal (peritoneal) cavity caused mesothelioma. Chrysotile acted fastest, with 50% of rats affected about 400 days after a 10 mg dose, compared with about 600 days for crocidolite and amosite. Nitrilotriacetic acid, a chemical that promotes iron-driven reactions, significantly promoted tumor development for all three fibers. Homozygous deletion (complete loss) of the Cdkn2a/2b tumor-suppressor genes was found in 93% of these rat tumors. Lifetime treatment with the iron-removing drug deferasirox increased the share of the less aggressive epithelioid tumor type, and survival rose marginally only in female rats. Repeated blood removal (phlebotomy) for one year produced no significant change. The author concluded that local iron deposits should be the target for prevention. The author also noted that injection into the body cavity differs from real human exposure and that the side effects of any prevention must be considered.

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, drawing mainly on the author's research group's earlier laboratory and rat experiments
• Who was studied: No new population was studied. The review covers published work, mostly rat experiments by the author's group at Nagoya University, Japan.
• Exposure: Intraperitoneal injection in rats of chrysotile, crocidolite and amosite asbestos, in some experiments followed by nitrilotriacetic acid. Also discussed: ferric saccharate (an iron compound) and iron reduction by deferasirox or phlebotomy.
• Main results:
  • In rats given 10 mg of chrysotile intraperitoneally, 50% developed malignant mesothelioma at about 400 days.
  • For crocidolite and amosite, it took about 600 days for 50% of the rats to develop malignant mesothelioma.
  • For all three asbestos types, repeated nitrilotriacetic acid after asbestos injection significantly promoted mesothelial carcinogenesis in rats.
  • Homozygous deletion of Cdkn2a/2b was found in 93% of the rat malignant mesotheliomas induced by the three asbestos fibers.
  • Homozygous deletion of Cdkn2a/2b was found in 80% of the sarcomatoid subtype of rat mesothelioma induced by intraperitoneal ferric saccharate.
  • A 1989 study by the author's group found that iron deposits from intraperitoneal ferric saccharate caused peritoneal mesothelioma in rats, with an extremely long incubation time, a low incidence and a male preference.
  • In rats given asbestos, lifetime deferasirox treatment significantly increased the fraction of the epithelioid subtype, and survival was marginally increased only in female rats.
  • Repeated phlebotomy for 1 year in rats produced no significant alteration.
• The authors' conclusion: The author concluded that local iron overload associated with asbestos is critically important for both the initiation and the promotion of malignant mesothelioma, and that local iron deposits should be the target for prevention.
• Limitations the authors state:
  • Injecting asbestos into the body cavity of animals differs from real human exposure.
  • The proposed process of asbestos attaching to chromosomes in dividing mesothelial cells has not been well analyzed in living animals.
  • Repeated phlebotomy is technically difficult in rats, and the phlebotomy result requires further investigation.
  • Side effects of an iron-reducing preventive intervention must be considered, because asbestos-induced carcinogenesis takes several decades.

Topics

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

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Carcinogenic, Malignant Mesothelioma, Mesothelial Cells, Asbestos Exposure, Prognosis, Mesothelioma, Pathology.

Related studies

• Iron overload signature in chrysotile-induced malignant mesothelioma — L. Jiang, S. Akatsuka, et al. (2012)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model — D. Minami, N. Takigawa, et al. (2015)
• Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention — S. Toyokuni (2019)
• Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis — L. Jiang, S.H. Chew, et al. (2016)
• SV40-induced expression of calretinin protects mesothelial cells from asbestos cytotoxicity and may be a key factor contributing to mesothelioma pathogenesis — T. Henzi, W.V. Blum, et al. (2009)

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