Abstract 3588: Common and different effects induced in primary human mesothelial cells and mice exposed to chrysotile or crocidolite asbestos.

Abstract

Abstract Crocidolite is considered the most oncogenic asbestos type. Chrysotile accounts for >90% of asbestos used worldwide, however its capacity to induce MM is still debated. We linked crocidolite carcinogenesis to the release of High-Mobility Group Box-1 protein (HMGB1) and activation of downstream genes (TNF-α and NF-κB). We compared the carcinogenicity of crocidolite and chrysotile in primary human mesothelial cells (HM). Microarray analyses of HM exposed to crocidolite or chrysotile identified 57 genes that were significantly induced or repressed. Forty-eight hours after exposure we observed induction of HMGB1 and NF-κB targeted genes and E-cadherin and SFRP4 down-regulation. In vitro, both crocidolite and chrysotile induced HMGB1 and TNF-α secretion, induced β-catenin nuclear translocation and caused HM death and epithelial-mesenchymal transition in surviving cells. Five weeks from exposure these effects were sustained in HM exposed to crocidolite; the expression of these genes had returned to normal in HM exposed to chrysotile. Soon after injection, serum HMGB1 levels were elevated in mice injected with either crocidolite or chrysotile, and remained elevated 10 weeks post-injection only in mice injected with crocidolite. Our results show that chrysotile induces the same intracellular signaling elicited by crocidolite, however these effects are transient. Accordingly, HM exposure to chrysotile in the presence of TNF-α or in co-culture with macrophages, induced foci formation with a lower transforming efficiency compared to crocidolite. Citation Format: Fang Qi, Gordon Okimoto, Sandro Jube, Harvey I. Pass, Rozalia Laczko, Richard M. DeMay, Ghazal Khan, Maarit Tiirikainen, Haining Yang, Giovanni Gaudino, Michele Carbone. Common and different effects induced in primary human mesothelial cells and mice exposed to chrysotile or crocidolite asbestos. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3588. doi:10.1158/1538-7445.AM2013-3588