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Iron overload signature in chrysotile‐induced malignant mesothelioma
Author(s) -
Jiang Li,
Akatsuka Shinya,
Nagai Hirotaka,
Chew ShanHwu,
Ohara Hiroki,
Okazaki Yasumasa,
Yamashita Yoriko,
Yoshikawa Yutaka,
Yasui Hiroyuki,
Ikuta Katsuya,
Sasaki Katsunori,
Kohgo Yutaka,
Hirano Seishiro,
Shinohara Yasushi,
Kohyama Norihiko,
Takahashi Takashi,
Toyokuni Shinya
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4075
Subject(s) - chrysotile , mesothelioma , carcinogen , carcinogenesis , cancer research , asbestos , pathology , mesothelial cell , biology , medicine , chemistry , cancer , genetics , materials science , metallurgy
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.