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.
Pathophysiology of mesothelioma shows a deposition of asbestos fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber 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 fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.
Pleural contamination with asbestos or other mineral fibers, has been shown to induce carcinogenesis. Malignant mesothelioma (MM) development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibers. It has been suggested that in humans, transport of fibers 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
localized lesions of accumulated asbestos fibers in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed and cellular changes within the lesion culminated in a morphologically malignant
tumor.
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 fibers 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 fibers has not yet been achieved. In general, asbestos fibers are thought to exert their carcinogenic effects via direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.
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Studies involving intrapleural or intraperitoneal inoculation of rats and mice with different types of asbestos fiber established that long, thin fibers caused a higher incidence of mesothelioma than did short fibers and that cells phagocytose and accumulate longer fibers more effectively than shorter
fibers. Similarly, incubation of Syrian hamster cells with fiberglass which had an average length of 9.5µm resulted in cell transformation with an efficiency identical to
crocidolite. Grinding these fibers to approximately 2.2µm reduced the transforming ability 10- to 20-fold while further reduction to <1µm completely eliminated the transforming ability of the fiberglass particles.
Analysis of the interactions between asbestos fibers and DNA has shown that phagocytosed fibers are able to make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. This contact between the asbestos fiber and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. 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:
i) inactivation of genes responsible for the regulation of normal cell growth, ii) the activation of oncogenes during the transfection process, iii) activation of
proto-oncogenes in the host genome due to incorporation of foreign DNA containing a promoter region, and iv) activation of DNA repair enzymes which may be prone to error.
Asbestos fibers have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which
favor the development of
mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos
carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant
deficiencies.
Asbestos may also possess immunosuppressive properties. For example, chrysotile fibers 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
fibers.
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