No conflicts of interest were declared.
Iron overload signature in chrysotile-induced malignant mesothelioma†
Article first published online: 2 AUG 2012
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 228, Issue 3, pages 366–377, November 2012
How to Cite
Jiang, L., Akatsuka, S., Nagai, H., Chew, S.-H., Ohara, H., Okazaki, Y., Yamashita, Y., Yoshikawa, Y., Yasui, H., Ikuta, K., Sasaki, K., Kohgo, Y., Hirano, S., Shinohara, Y., Kohyama, N., Takahashi, T. and Toyokuni, S. (2012), Iron overload signature in chrysotile-induced malignant mesothelioma. J. Pathol., 228: 366–377. doi: 10.1002/path.4075
- Issue published online: 12 OCT 2012
- Article first published online: 2 AUG 2012
- Manuscript Accepted: 11 JUL 2012
- Manuscript Revised: 28 JUN 2012
- Manuscript Received: 3 APR 2012
- malignant mesothelioma;
- array-based comparative genomic hybridization;
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.