Mechanisms of Action of Asbestos Fibers

The potential of asbestos fibers to cause cancer has been linked to their geometry, size, and chemical composition. Long (more than 5 mm), thin (diameter less than 3 mm) fibers are a health concern89 and have been found to cause mesothe-lioma and fibrosis after intrapleural or intraperitoneal administration to rodents.90 In addition to size, the chemical composition of fibers plays an important role in determining the durability, biopersistence, and biodegradability of asbestos types. The greater durability of amphiboles compared to chrysotile appears to be one of the principal reasons for their greater carcinogenic potential. Amphibole fibers persist at sites of tumor development and may serve as stimuli for neo-plastic growth of cells.91,92 The persistence of the amphibole fibers at the site of tumor formation is important to both tumor induction and promotion because the mean latency period between initial exposure to asbestos and the development of mesothelioma is around 30 to 40 years.67,93

An important unresolved issue is whether asbestos fiber carcinogenicity is through direct effects of asbestos on mesothelial cells or through indirect mechanisms involving oxidative stress.94,95 A ramification of interaction of long (more than 5 mm) fibers with cells is frustrated phagocytosis and a prolonged oxidative burst.96 The increased durability and high iron content of the amphiboles, crocidolite, and amosite also may contribute to their higher carcinogenic potential through oxidants catalyzed by iron and/or surface reactions occurring on the fiber. The cytotoxicity of crocido-lite fibers in human lung carcinoma cells is directly linked to iron mobilization and is followed by increased ferritin synthesis, a perpetual feedback system for uptake of iron by cells.97,98 Studies on animal models and cell cultures have confirmed that asbestos fibers generate ROS and reactive nitrogen species (RNS).67,95,99 These effects may be potentiated by the inflammation associated with fiber exposures.100

A complex profile of somatic genetic changes has been revealed in human malignant mesotheliomas. These changes implicate a multistep process of tumorigenesis. The occurrence of multiple, recurrent cytogenetic deletions suggests that loss and/or inactivation of tumor suppressor genes are critical to the development and progression of mesothelioma. Deletions of specific regions in the short (p) arms of chromosomes 1, 3, and 9 and long (q) arms of 6, 13, 15, and 22 are repeatedly observed, and loss of a copy of chromosome 22 is the single most consistent numerical change.101

Asbestos fibers in vitro cause the production of DNA damage either via production of ROS or by direct damage to chromosomes after phagocytosis of fibers.90,102 The consequences of such DNA damage could be the loss of tumor suppressor genes, activation of proto-oncogenes, or unregulated generation of growth factors through paracrine/autocrine mechanisms.103 Asbestos also causes alterations in cell signaling pathways linked to abnormal growth control in pulmonary epithelial cells, mesothelial cells, endothelial cells, and fibroblasts.3,104 Asbestos also activates redox-sensitive transcription factors such as NF-Kp105 and AP-1,106 which leads to increased cell survival, inflammation, and, paradoxically, the upregulation of antioxidant enzymes such as manganese superoxide dismutase.100 This enzyme is also overexpressed in asbestos-related mesotheliomas,107,108 rendering them highly resistant to oxidative stress in comparison to normal mesothelial cells.

Carcinogenesis was classically thought to be a proliferation-driven process. However, it is now recognized that neoplastic growth is an imbalance between apoptosis and proliferation. In support of this concept, a dynamic balance between apoptosis and cell proliferation is observed in mesothelial cells exposed to crocidolite asbestos.109 Studies in vitro indicate that asbestos can induce apoptosis in mesothelial cells through formation of ROS110,111 and by mitochondrial pathways.94,112

Studies in our group have found that the EGFR is an important initial target of asbestos fibers at the cell membrane (Figure 18.1). This growth factor is required for proliferation of human mesothelial cells113 and is produced in an autocrine fashion in mesotheliomas.114 Autophosphoryla-tion of the EGFR occurs in mesothelial cells after in vitro exposures to asbestos. Moreover, aggregation and phos-phorylation of the EGFR by long fibers initiates cell signaling cascades linked to asbestos-induced injury and mitogene-sis.115,116 Increased expression of EGFR in rat pleural mesothe-lial cells correlates with the carcinogenicity of mineral fibers.117

We have also shown that the EGFR is causally linked to activation of the MAPK cascade and increased expression of the proto-oncogenes c-fos and c-jun (see Figure 18.1).116,118 Expression of both fos and jun family members (components of the transcription factor AP-1 complex) is required for transition through the G1 phase and entry into the S phase of the cell cycle.119 Most recently, ERK 1/2-induced activation by asbestos has been linked to the induction of fra-1, an important component of the AP-1 complex that is causally related to anchorage-independent growth in mesothelioma.107 Microarray analyses have shown increased expression of fra-1 in rat and human mesotheliomas.120 Other growth factors and their receptors also are important in malignant mesothe-lioma including transforming growth factor-alpha (TGF-a), which binds to the EGFR,121 insulin growth factor II,122 and PDGF.123 Increased levels of hepatocyte growth factor (HGF)

Figure 18.1. Schematic showing some of the major cell signaling events thought to be involved in asbestos-induced carcinogenesis.

Figure 18.1. Schematic showing some of the major cell signaling events thought to be involved in asbestos-induced carcinogenesis.

TABLE 18.3. Summary of important environmental/occupational carcinogens and their modes of action

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