Iron overload signature in chrysotile-induced malignant mesothelioma

Our plain-English summary of Iron overload signature in chrysotile-induced malignant mesothelioma, by L. Jiang, S. Akatsuka, H. Nagai, et al (The Journal of Pathology, 2012).

The study

• Authors: L. Jiang, S. Akatsuka, H. Nagai, S.H. Chew, H. Ohara, Y. Okazaki, Y. Yamashita, Y. Yoshikawa, H. Yasui, K. Ikuta, K. Sasaki, Y. Kohgo, S. Hirano, Y. Shinohara, N. Kohyama, T. Takahashi, S. Toyokuni
• Journal: The Journal of Pathology
• Published: 2012;228(3):366-77
• Cited by: 88 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure.

Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In plain English

This was an animal experiment in Japan. The authors injected 10 mg of standard (UICC) chrysotile, crocidolite or amosite asbestos into the abdominal (peritoneal) cavity of hybrid rats. Some rats also received weekly injections of nitrilotriacetate (NTA), a chemical used to boost iron-driven chemical reactions. Untreated rats and rats given a type of carbon nanotube served as controls. Malignant mesothelioma of the peritoneum developed in 94 of 97 asbestos-injected rats (96.9%) within 800 days. Rats given chrysotile had significantly shorter survival than rats given crocidolite or amosite. They also more often had the sarcomatoid tumour type, though that difference was not statistically significant. NTA significantly sped up tumour development with all three fibers. Asbestos-treated rats had more iron in abdominal organs and higher blood ferritin than controls. Loss of both copies of the CDKN2A/2B genes was found in 25 of 27 tumours tested. The authors concluded that chrysotile is a strong carcinogen that acts through local iron overload when it reaches mesothelial cells. They noted that injection into the abdomen differs from human exposure.

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: Animal experiment (rats given asbestos by intraperitoneal injection, followed until death or sacrifice), with a short-term (sub-acute) sub-study and genetic analysis of the tumours
• Who was studied: 141 F1 hybrid rats (female Fischer 344 crossed with male Brown-Norway) in five groups: untreated control (38), chrysotile (28), crocidolite (41), amosite (28), and tangled multi-walled carbon nanotube (6). The experiments were approved at Kyoto University and Nagoya University, Japan.
• Exposure: A total of 10 mg of UICC standard asbestos (chrysotile A, crocidolite or amosite) per rat, given as three intraperitoneal injections starting at 6 weeks of age. Some asbestos-treated rats also received 80 mg/kg nitrilotriacetate (NTA) by intraperitoneal injection once a week for 16 weeks.
• Main results:
  • Malignant mesothelioma developed in 96.9% (94/97) of asbestos-injected rats within 800 days after injection
  • No mesothelioma was seen in 2 of 41 rats in the crocidolite group and 1 of 28 rats in the amosite group
  • At the same weight of fiber, chrysotile caused significantly shorter survival of rats through mesothelioma than crocidolite or amosite
  • Sarcomatoid mesothelioma was more frequent in the chrysotile group, but the difference was not statistically significant (p = 0.111 versus amosite)
  • Repeated weekly NTA significantly accelerated mesothelioma development in the chrysotile, crocidolite and amosite groups
  • Rats with asbestos-induced mesothelioma had prominent iron deposits in the spleen, liver and kidney, including surface mesothelial cells. Iron deposits were minimal in age-matched controls.
  • Serum ferritin 420 days after asbestos injection was significantly higher in 11 chrysotile-treated, 11 crocidolite-treated and 15 amosite-treated rats than in controls
  • Homozygous deletion of CDKN2A/2B was found in 25 of 27 tumours analysed: 88.9% of chrysotile- or crocidolite-induced and 100% of amosite-induced mesotheliomas
  • Genetic (aCGH) profiles did not separate the three asbestos types
• The authors' conclusion: The authors concluded that chrysotile is a strong carcinogen that acts through inducing local iron overload when it reaches mesothelial cells. They suggested that removing local excess iron might be a strategy to prevent mesothelioma in people already exposed to asbestos.
• Limitations the authors state:
  • Injecting asbestos into the abdominal cavity differs from human environmental exposure; the experiments tested fibers in direct contact with mesothelial cells.
  • Chrysotile contained a higher fraction of long fibers, and the authors could not rule out that this affected its carcinogenicity.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile, Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Chrysotile, Malignant Mesothelioma, Crocidolite, Amosite, Peritoneal Cavity, Mesothelioma, Sarcomatoid, Histology.

Related studies

• Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis — S. Toyokuni (2014)
• Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats — Y. Okazaki, S.H. Chew, et al. (2020)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• CD146 and insulin-like growth factor 2 mRNA-binding protein 3 predict prognosis of asbestos-induced rat mesothelioma — Y. Okazaki, H. Nagai, et al. (2013)
• Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis — D. Aierken, Y. Okazaki, et al. (2014)
• Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma — L. Jiang, Y. Yamashita, et al. (2014)

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