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: Li Jiang, Shinya Akatsuka, Hirotaka Nagai, Shan-Hwu Chew, Hiroki Ohara, Yasumasa Okazaki, Yoriko Yamashita, Yutaka Yoshikawa, Hiroyuki Yasui, Katsuya Ikuta, Katsunori Sasaki, Yutaka Kohgo, Seishiro Hirano, Yasushi Shinohara, Norihiko Kohyama, Takashi Takahashi, Shinya Toyokuni
• Journal: The Journal of pathology (J Pathol) Vol. 228 Issue 3 Pg. 366-77 (Nov 2012) ISSN: 1096-9896 [Electronic] England
• PMID: 22864872 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Asbestos, Serpentine
• Basic Helix-Loop-Helix Transcription Factors
• Biomarkers, Tumor
• DNA, Neoplasm
• Distal-less homeobox proteins
• Homeodomain Proteins
• Transcription Factors
• helix-loop-helix protein, eHAND
• Iron
• Nitrilotriacetic Acid

Topics

• Animals
• Asbestos, Serpentine (adverse effects, pharmacology)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Biomarkers, Tumor (metabolism)
• Cell Transformation, Neoplastic (drug effects)
• DNA Copy Number Variations (drug effects)
• DNA, Neoplasm (drug effects)
• Disease Models, Animal
• Homeodomain Proteins (metabolism)
• Iron (metabolism)
• Iron Overload (metabolism)
• Lung Neoplasms (chemically induced, metabolism, pathology)
• Male
• Mesothelioma (chemically induced, metabolism, pathology)
• Mesothelioma, Malignant
• Nitrilotriacetic Acid (pharmacology)
• Peritoneal Neoplasms (chemically induced, metabolism, pathology)
• Rats
• Rats, Inbred BN
• Rats, Inbred F344
• Signal Transduction (drug effects)
• Transcription Factors (metabolism)