title: Iron overload signature in chrysotile-induced malignant mesothelioma.
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.
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nagai
authors.forename: Shan-Hwu
authors.initials: SH
authors.lastname: Chew
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohara
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
authors.forename: Seishiro
authors.initials: S
authors.lastname: Hirano
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kohyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D000818:Animals; D017632:Asbestos, Serpentine / Q000009:adverse effects* / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D056915:DNA Copy Number Variations / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009571:Nitrilotriacetic Acid / Q000494:pharmacology; D010534:Peritoneal Neoplasms / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017632:Asbestos, Serpentine; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D007501:Iron; D009571:Nitrilotriacetic Acid; D014157:Transcription Factors; C088334:Distal-less homeobox proteins; C097341:helix-loop-helix protein, eHAND