Mesothelioma and Asbestos
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Pathophysiology of Mesothelioma
The Mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.
Pleural Contamination with asbestos or other mineral fibres, has been shown to induce carcinogenesis. Malignant mesothelioma (MM) development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibres. It has been suggested that in humans, transport of fibres to the pleura is critical to the pathogenesis of MM. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localised lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats.
Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of MM occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibres remain unclear despite the demonstration of its oncogenic capabilities. However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibres has not yet been achieved.
Studies involving intrapleural or intraperitoneal inoculation of rats and mice with different types of asbestos fibre established that long, thin fibres caused a higher incidence of mesothelioma than did short fibres and that cells phagocytose and accumulate longer fibres more effectively than shorter fibres. Similarly, incubation of Syrian hamster cells with fibreglass which had an average length of 9.5µm resulted in cell transformation with an efficiency identical to crocidolite. Grinding these fibres to approximately 2.2µm reduced the transforming ability 10- to 20-fold while further reduction to <1µm completely eliminated the transforming ability of the fibreglass particles.
Analysis of the interactions between asbestos fibres and DNA has shown that phagocytosed fibres are able to make contact with chromosomes, often adhering to the chromatin fibres or becoming entangled within the chromosome. Most commonly observed are chromosomal translocations or deletions, in addition to trisomies and polysomies of chromosomes 5, 7, 11, 12 and 20, and monosomies of chromosomes 1, 3, 4, 9, 14, 15, 18, 19 and 22. Whilst none of the cytogenetic abnormalities have been found to be specific for MM, Tiainen et al. (1989) reported a statistically significant inverse correlation between the number of copies of chromosome 7 p-arms and the survival rate for MM. This latter finding may provide a useful tool in the prognosis of MM.
Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by four possible mechanisms:
- Inactivation of genes responsible for the regulation of normal cell growth
- The activation of oncogenes during the transfection process
- Activation of proto-oncogenes in the host genome due to incorporation of foreign DNA containing a promoter region
- Activation of DNA repair enzymes which may be prone to error.
Asbestos may also possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer (LAK) cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-b (TGF-b) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.