Author of

• 10984

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  P1.22 - Poster Session 1 - Epidemiology, Etiology (ID 166)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Prevention & Epidemiology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10996

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    P1.22-012 - Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling. (ID 3478)

    09:30 - 09:30  |  Author(s): M. Carbone
    • Abstract

    Background
    Background: Malignant mesothelioma is strongly associated with asbestos exposure. Among asbestos fibers, crocidolite is considered the most and chrysotile the least oncogenic. Chrysotile accounts for >90% of asbestos used worldwide but its capacity to induce malignant mesothelioma is still controversial.

    Methods
    Methods: Human mesothelial cells were exposed to crocidolite or chrysotile for a period of 48hr or 5 weeks, either in the presence of TNF–α or human macrophages in a co-culture system mimicking the process of recruitment and activation of inflammatory cells to sites of fiber deposition, which leads to the carcinogenesis of mesothelioma. Functional studies, as well as whole-genome wide expression profiling were performed to compare the molecular mechanisms and the carcinogenic potential of chrysotile and crocidolite.

    Results
    Results: We found that chrysotile and crocidolite exposures have similar effects on human mesothelial cells. Morphological and molecular alterations suggestive of epithelial-mesenchymal transition, such as E–cadherin down-regulation and β–catenin phosphorylation followed by nuclear translocation, were induced by chrysotile and crocidolite. Gene expression profiling data detected High-Mobility Group Box-1 protein (HMGB1) as a key regulator of the transcriptional alterations induced by both chrysotile and crocidolite. Crocidolite and chrysotile induced differential expression of 57 out of 28,869 genes interrogated by oligo-nucleotide microarrays and 13 were HMGB1 targeted genes. Crocidolite-induced gene alterations were sustained, while chrysotile effects returned to background levels in five weeks. Similarly, HMGB1 release in vivo progressively increased for 10 or more weeks following crocidolite exposure, while returned to background levels eight weeks from chrysotile exposure.

    Conclusion
    Conclusion: Our results show that chrysotile has the capacity to induce, in HM, molecular changes associated to MM development similar to those induced by crocidolite, but these changes are short lasting. The data suggest that HMGB1 and TNF–α are key mediators of these processes for both crocidolite and chrysotile. However a continuous administration of chrysotile was required for inducing sustained HMGB1 levels. These data support the hypothesis that the different bio-persistence of the two asbestos fibers influences their biological activities.