Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways

Abstract

Fifteen years have passed since we published findings in the AJRCMB demonstrating that induction of early response fos/jun proto-oncogenes in rodent tracheal and mesothelial cells correlates with fibrous geometry and pathogenicity of asbestos. Our study was the first to suggest that the aberrant induction of signaling responses by crocidolite asbestos and erionite, a fibrous zeolite mineral associated with the development of malignant mesotheliomas (MMs) in areas of Turkey, led to altered gene expression. New data questioned the widely held belief at that time that the carcinogenic effects of asbestos in the development of lung cancer and MM were due to genotoxic or mutagenic effects. Later studies by our group revealed that proto-oncogene expression and several of the signaling pathways activated by asbestos were redox dependent, explaining why antioxidants and antioxidant enzymes were elevated in lung and pleura after exposure to asbestos and how they alleviated many of the phenotypic and functional effects of asbestos in vitro or after inhalation. Since these original studies, our efforts have expanded to understand the interface between asbestos-induced redox-dependent signal transduction cascades, the relationship between these pathways and cell fate, and the role of asbestos and cell interactions in development of asbestos-associated diseases. Of considerable significance is the fact that the signal transduction pathways activated by asbestos are also important in survival and chemoresistance of MMs and lung cancers. An understanding of the pathogenic features of asbestos fibers and dysregulation of signaling pathways allows strategies for the prevention and therapy of asbestos-related diseases.

Figure 1.

Asbestos has pleiotropic effects on cell signaling pathways. Either through direct interactions with receptors or via the genesis of reactive oxygen species (ROS), asbestos activates cell signaling pathways that regulate gene expression and cell fate. Direct interaction with the epidermal growth factor receptor (EGFR) activates the Ras-Raf-extracellular signal–regulated kinase (ERK) pathway, which controls expression and transcriptional activity of the Fos family members of the activator protein-1 (AP-1) transcription factor. Asbestos also regulates c-Jun through activation of ERK5. Through AP-1, ERK1/2 and ERK5 govern outcomes that include cell proliferation, cell migration, and aspects of neoplastic transformation. Activation of the phosphoinositol-3 kinase (PI3K)/AKT pathway promotes cell survival through NF-κB. Recent work also indicates that asbestos fibers or ROS activate signaling through the TNF receptor. The diverse phenotypic outcomes of asbestos exposure depend on fiber type, fiber dose, and the signaling pathways resident in specific cell types. Moreover, the physical properties of asbestos tend to promote robust and persistent activation of signaling through ERK and other redox-responsive kinase cascades.