How asbestos and other fibers cause mesothelioma

Our plain-English summary of How asbestos and other fibers cause mesothelioma, by G. Gaudino, J. Xue, H. Yang (Translational Lung Cancer Research, 2020).

The study

• Authors: G. Gaudino, J. Xue, H. Yang
• Journal: Translational Lung Cancer Research
• Published: 2020;9(Suppl 1):S39-S46
• Type of article: Review
• Cited by: 64 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma has long been associated with the exposure to asbestos, which was largely used in manufacturing activities. Toxicology studies in vitro and in vivo demonstrated that asbestos fibers were carcinogenic, and epidemiology studies revealed that asbestos exposure was paralleled by the increase in the incidence of mesothelioma and related mortality rates. More recently, the role of chronic inflammation and the molecular mechanisms involved in carcinogenesis by mineral fibers were elucidated following the discovery of the roles of HMGB1 and inflammasome. A change of paradigm was the discovery of a prevalence of mesotheliomas attributable to inherited mutations of cancer susceptibility genes. The discovery of BAP1 as a predisposition gene for the development of familial mesothelioma and other cancers implemented genome studies in patients with mesothelioma and routine clinical surveys in individuals at risk to identify germline mutations associated with cancers included in the BAP1 syndrome. A further progress in the approach to asbestos-related malignancy was the adoption of combined genetics and environmental analyses according to the model of gene-environment (GxE) interactions. This review aims at updating on the most recently discovered mechanisms of tumorigenesis and the pivotal role of GxE interactions.

2020 Translational Lung Cancer Research. All rights reserved.

In plain English

This article is a review, not a new study. The authors, from the University of Hawai'i Cancer Center, summarized published research on how asbestos and other mineral fibers cause mesothelioma. They described earlier work showing that fiber dimensions, durability and dose govern cancer-causing potency. This included a cited meta-analysis that linked exposure to fibers longer than 10 μm, and even 20 μm, to a significantly higher risk of asbestos-related disease. They wrote that chrysotile, which persists in the body for a shorter time than amphiboles and erionite, has lower carcinogenic potential, but that with prolonged chrysotile exposure mesothelial cells are equally transformed. They outlined a mechanism in which fiber-damaged mesothelial cells release a protein called HMGB1, which drives chronic inflammation that lets some cells survive and accumulate mutations. They noted that only about 5% of miners and shipyard or manufacturing workers with prolonged asbestos exposure developed mesothelioma. They also reviewed studies linking inherited BAP1 mutations to familial mesothelioma and other cancers. The authors concluded that genetic factors play critical roles in susceptibility and that further studies are needed.

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 summarizing published laboratory, animal, genetic and epidemiological research. No new data were collected.
• Who was studied: Not applicable. The review covers previously published studies of human mesothelial cells, mesothelioma tumors, mice, exposed workers, Cappadocian villagers in Turkey, and families with inherited BAP1 mutations. The article does not describe how the studies were selected.
• Exposure: Asbestos as defined in regulations (five amphiboles: crocidolite, actinolite, tremolite, anthophyllite and amosite; and one serpentine: chrysotile). Also unregulated, naturally occurring fibers such as erionite and palygorskite.
• Main results:
  • Cited earlier work: long, thin fibers are associated with higher potency for cytotoxicity and mutagenesis. A meta-analysis cited by the review found significantly higher risk of asbestos-related disease in individuals exposed to fibers longer than 10 μm and even 20 μm.
  • The review states that chrysotile has shorter biopersistence and lower carcinogenic potential than amphiboles and erionite. It adds that when chrysotile exposure is prolonged, mesothelial cells are equally transformed (citing an earlier study).
  • The review describes naturally occurring erionite fibers, to which residents of some Cappadocian villages in Turkey and of North Dakota are exposed, as more carcinogenic than regulated asbestos.
  • Mechanism described from earlier studies: mesothelial cells exposed to crocidolite, chrysotile or erionite mostly die by programmed necrosis and release HMGB1. This sustains chronic inflammation through macrophages and the inflammasome. TNF-α activates NF-κB, promoting survival of exposed mesothelial cells, which then accumulate mutations.
  • Citing epidemiological evidence, the review states that only about 5% of miners and shipyard or manufacturing workers with prolonged asbestos exposure developed mesothelioma.
  • Cited studies identified germline BAP1 mutations in two unrelated US families with high mesothelioma incidence and no occupational asbestos exposure. These mutations were associated with autosomal dominant transmission of mesothelioma and uveal melanoma.
  • Cited animal studies: mice carrying one mutated copy of Bap1 developed mesothelioma when exposed to ten-times lower doses of asbestos fibers, doses that barely caused any mesothelioma in wild-type mice.
  • Cited genetic findings: p16 was missing in up to 80% of primary pleural mesotheliomas, and NF2 is inactivated in about 40% of malignant mesothelioma.
• The authors' conclusion: The authors concluded that not everyone exposed to asbestos or erionite develops mesothelioma and that genetic factors play critical roles in susceptibility. They identified BAP1 as a predisposition gene and chronic inflammation mediated by HMGB1 and the inflammasome as key mechanisms. They wrote that further studies are required to identify the full set of predisposing genes.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Carcinogenic, Epidemiology, Asbestos Exposure, Chronic Inflammation, Carcinogenesis, Mineral Fiber, Discovery.

Related studies

• Mortality from cancer and other causes in the Balangero cohort of chrysotile asbestos miners — E. Pira, C. Pelucchi, et al. (2009)
• Mortality from cancer and other causes among Italian chrysotile asbestos miners — E. Pira, C. Romano, et al. (2017)
• Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases — S.X. Huang, M.C. Jaurand, et al. (2011)
• Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey — A.U. Dogan, Y.I. Baris, et al. (2006)
• Multiple mechanisms for the carcinogenic effects of asbestos and other mineral fibers — J.C. Barrett, P.W. Lamb, et al. (1989)
• Ingested mineral fibers. Do they penetrate tissue or cause cancer? — P. Gross, R.A. Harley, et al. (1974)

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