Decoding the molecular enigma behind asbestos and fibrous nanomaterial-induced carcinogenesis

Our plain-English summary of Decoding the molecular enigma behind asbestos and fibrous nanomaterial-induced carcinogenesis, by S. Toyokuni, Y. Kong (Journal of Occupational Health, 2025).

The study

• Authors: S. Toyokuni, Y. Kong
• Journal: Journal of Occupational Health
• Published: 2025;67(1)
• Type of article: Review
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: The natural fibrous mineral, asbestos, has been useful in industry for many centuries. In the 1960s, epidemiology recognized the association between asbestos exposure and mesothelioma, and in 1987 the International Agency for Research on Cancer designated all kinds of asbestos as Group 1 carcinogens. However, various scientific enigmas remained regarding the molecular mechanisms of asbestos-induced mesothelial carcinogenesis. This review article was undertaken to reveal and summarize recent discoveries to resolve those enigmas.

Methods: We collected recent important findings from our own laboratory and others to explain why mesothelial cells are the target for asbestos-induced carcinogenesis and what are the key molecular mechanisms.

Results: The long incubation period of 30-40 years for mesothelial carcinogenesis after asbestos exposure allows the asbestos fibers to go through the pulmonary parenchyma from the central to peripheral portions and ultimately reach the parietal mesothelium by piercing visceral pleura. Asbestos fibers have affinity for hemoglobin and histones, thus accumulating iron on the surface while traveling through the lung. Mesothelial cells are phagocytic cells, engulfing iron-coated asbestos fibers. Accordingly, homozygous deletion of the p16INK4a tumor suppressor gene, a signature of excess iron-induced carcinogenesis, is acquired through oxidative DNA damage. Recently, exosome-dependent iron transfer from asbestos-fed macrophages to mesothelial cells was reported. Similar molecular mechanisms are observed with multiwalled carbon nanotubes of ~50-nm diameter.

Conclusions: Physical dimensions, biopersistence, and affinity to iron/histones are essential for fibrous material to be carcinogenic to mesothelial cells. Therefore, local iron reduction may be a strategy to prevent mesothelial carcinogenesis.

© The Author(s) [2025]. Published by Oxford University Press on behalf of the Japan Society for Occupational Health.

In plain English

This invited mini-review, which generated no new data, summarized findings from the authors' own laboratory and others on how asbestos may cause mesothelioma. The authors described inhaled fibers moving over decades from the central to the outer lung, collecting iron through an affinity for hemoglobin and histones, piercing the visceral pleura, and being engulfed by mesothelial cells of the parietal pleura. They noted that crocidolite and amosite contain about 30% iron, while chrysotile does not but coats its surface with iron from hemoglobin. The review described homozygous deletion of the p16INK4a tumor suppressor gene as the major genetic change in asbestos-induced mesothelioma. It reported the same change in the authors' rat chrysotile experiments and in their studies of multiwalled carbon nanotubes about 50 nm wide, for which no human cancer cases have been reported. It also described animal studies in which iron removal, by the drug deferasirox or by phlebotomy, gave prolonged survival and reduced tumor mass. The authors concluded that iron removal may be a strategy to prevent mesothelial carcinogenesis.

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: Invited mini-review summarizing laboratory and animal findings from the authors' laboratory and others; no new data
• Who was studied: Not a study of people. The review covered published laboratory findings, including rat experiments using intraperitoneal injection, from the authors' laboratory at Nagoya University, Japan, and from others.
• Exposure: Asbestos fibers (crocidolite, amosite and chrysotile) and multiwalled carbon nanotubes
• Main results:
  • The review described asbestos fibers moving from the central lung toward the outer lung because of the negative pressure of the pleural cavity, a process the authors stated takes decades.
  • The review described asbestos fibers as having an affinity for hemoglobin and histone, so that they adsorb iron on their way to the outer lung.
  • Crocidolite and amosite contain about 30% iron, while chrysotile does not. According to the review, chrysotile causes hemolysis and covers its surface with iron from hemoglobin.
  • The review described homozygous deletion of the p16INK4a tumor suppressor gene as the major genetic change in asbestos-induced mesothelioma, in humans and in animal models.
  • In the authors' rat experiments, mesothelioma developed in about 1.5 years after intraperitoneal injection, and the target gene in chrysotile-induced mesothelioma was the same.
  • In the authors' studies of multiwalled carbon nanotubes, nanotubes about 50 nm in diameter showed the highest carcinogenicity, with the same p16INK4a deletion. No human cases of cancer caused by these nanotubes have been reported.
  • The review described a proposed mechanism: macrophages that engulf crocidolite fibers secrete exosomes containing iron-loaded ferritin, and nearby mesothelial cells take these up.
  • In the authors' preclinical animal studies of iron removal, using the iron chelator deferasirox or phlebotomy, the authors reported significant results such as prolonged survival and reduced tumor mass.
  • In an animal experiment, the authors found that BRCA1 haploinsufficiency promoted chrysotile-induced mesothelial carcinogenesis in male rats.
• The authors' conclusion: The authors concluded that the physical dimensions of a fiber are critical for mesothelial carcinogenesis, in which excess iron leads to oxidative damage and p16INK4a deletion. Given the long incubation period, they concluded that iron removal may be an appropriate strategy to prevent mesothelial carcinogenesis.

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, Epidemiology, Asbestos Exposure, Mesothelioma, Mesothelial Cells, Parenchyma, Mesothelium, Visceral Pleura.

Related studies

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• A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials — V.C. Sanchez, P. Weston, et al. (2011)
• Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention — S. Toyokuni (2019)
• Biopersistence and potential adverse health impacts of fibrous nanomaterials: what have we learned from asbestos? — V.C. Sanchez, J.R. Pietruska, et al. (2009)
• In vitro genotoxicity data of nanomaterials compared to carcinogenic potency of inorganic substances after inhalational exposure — M. Roller (2011)
• Engineered nanomaterial-induced lysosomal membrane permeabilization and anti-cathepsin agents — M. Bunderson-Schelvan, A. Holian, et al. (2017)

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