ASBESTOS AND THE PATHOGENESIS OF HUMAN CANCERS

Exposure to asbestos, a collection of fibrous silicates, is linked to pulmonary fibrosis, lung cancer and mesothelioma. The pathologic properties of specific asbestos subtypes are dictated by chemical composition, fiber geometry, and surface chemistry, all of which influence dose-dependent cellular responses that range from induction of cell proliferation to cell death. Many of the acute responses to asbestos are ameliorated by antioxidants or antioxidant enzymes, indicating that induction of oxidative stress is a prominent mechanism in the pathogenesis of asbestos-related disease. Reactive oxygen species (ROS) may be generated directly at the fiber surface, and through activation of pathways that induce the production of ROS from multiple intracellular sources. Studies with lung epithelial and mesothelial cells in vitro and in animal models have identified redox-responsive signaling pathways that mediate cellular responses to asbestos, and deregulation of these signaling pathways is known to play a critical role in many human cancers, including mesothelioma. For example, crocidolite asbestos fibers activate signaling through the epidermal growth factor receptor (EGFR) to the mitogen-activated protein kinase (MAPK) network to influence gene expression programs that control cell fate decisions, including cell proliferation. Recent studies also show that asbestos fibers induce inflammatory responses that promote the expression of immune system modulators (i.e. cytokines) that may encourage tumor growth, indicating chronic inflammation is a critical component of the pathogenesis of asbestos-related disease. Current models suggest that asbestos induces disease through induction of cycles of cell death and compensatory proliferation, coupled with chronic inflammation, that together lead to tissue remodeling and, in some instances, malignant transformation. More thorough chemical and physical characterization of mineral fibers is needed in order to understand which properties of asbestos are responsible for activating individual signaling pathways that mediate specific cellular responses, and how these responses over time contribute to disease.