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Iron overload signature in chrysotile-induced malignant mesothelioma

Authors

  • Li Jiang,

    1. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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  • Shinya Akatsuka,

    1. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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  • Hirotaka Nagai,

    1. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
    2. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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  • Shan-Hwu Chew,

    1. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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  • Hiroki Ohara,

    1. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
    2. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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  • Yasumasa Okazaki,

    1. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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  • Yoriko Yamashita,

    1. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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  • Yutaka Yoshikawa,

    1. Division of Analytical and Physical Chemistry, Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan
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  • Hiroyuki Yasui,

    1. Division of Analytical and Physical Chemistry, Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan
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  • Katsuya Ikuta,

    1. Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
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  • Katsunori Sasaki,

    1. Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
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  • Yutaka Kohgo,

    1. Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
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  • Seishiro Hirano,

    1. Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan
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  • Yasushi Shinohara,

    1. Work Environment Research Group, National Institute of Occupational Health and Safety, 6-21-1 Nagao, Tama-ku, Kawasaki 214-8585, Japan
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  • Norihiko Kohyama,

    1. National Science Laboratory, Faculty of Economics, Toyo University, 5-28-20, Hakusan, Bunkyo-ku, Tokyo 112-8606, Japan
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  • Takashi Takahashi,

    1. Department of Tumor Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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  • Shinya Toyokuni

    Corresponding author
    • Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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  • No conflicts of interest were declared.

Shinya Toyokuni, Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: toyokuni@med.nagoya-u.ac.jp

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.

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