The term pathogenesis refers to the incidental development of a disease due to a series of changes in the structure and/or functions of cells via chemical, microbial or physical agents, and can include infection, inflammation and tissue breakdown leading to malignancy.
The pathogenesis of mesothelioma in humans is predicated on the transport of asbestos fibers to the pleura of the lungs – the fluid-filled sac that surrounds the lungs. These fibers induce an immune system response, by macrophages and other specialized cells, to the lesions that occur as a result of asbestos-fiber irritation of tissues. These lesions continue to attract, and aggregate, specialized cells, causing cellular changes within the lesion that terminate in a malignant tumor.
Evidence gathered from animal experiments indicates that asbestos acts as a complete carcinogen, though the molecular mechanisms of malignancy are not entirely clear. However, research indicates that asbestos fibers act directly on chromosomes, or structural proteins within the cell wall, to effect complex changes, with chromosome 22 showing the most distinct changes. These changes can lead to either deletion of tumor suppressing genes or the prevention of apoptosis (programmed cell death) or activation of oncogenes, via the interposition of foreign DNA, which asbestos appears to facilitate.
Some of the malignancy pathways that have been suggested are:
- Oxygen-free radicals like hydroxyls released by macrophages which interact with chromosomal material.
- Growth factors triggering mesothelial cell proliferation
- Immunosuppressive factors integral to asbestos which may reduce the production of lymphocytes
Four-fifths of the malignant mesotheliomas in humans result from higher than normal exposure to asbestos either through occupational or regional exposure, though recent studies suggest a genetic factor that predisposes some individuals in Turkey to mesothelioma. In addition, natural serpentine rock formations around the world predicate higher-than-normal occurrences of mesothelioma.
Of the estimated two billion mesothelial cells which form the linings
of body cavities like the pleura, peritoneum, pericardium, and tunica
(which protects the internal reproductive organs in both sexes), all are
affected by four principal processes which can lead to malignancy. These
are: irritation, mitotic disruption, DNA damage via iron-rich oxygen radicals,
and the phosphorylation of the mitogen-activated protein (MAP) kinases
which are involved in cell differentiation and apoptosis.
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Of the two basic fiber types of asbestos, the larger are the most carcinogenic,
due to their greater persistence in the body and their higher iron content,
which promote higher production of reactive oxygen radicals. However,
less than 10 percent of individuals exposed to asbestos at higher doses
over long periods of time actually develop malignant
pleural mesothelioma, or MPM, leading researchers to search for other
etiologies, specifically a genetic component, a viral component (SV40)
implicated in various other cancers (and formerly used in the Salk polio
vaccine), and a potential link with hyaluronic acid, which is a definitive
diagnostic cell stain for differentiating mesothelioma from adenocarcinomas.
The predictive pathway for mesothelial pathogenesis remains a subject of intense scrutiny and considerable dispute among scientists, with only one definitive cause recognized; genetics may play as large role in the development of mesothelioma as it does in other cancers, where a gene known as p53 has been tentatively identified as the flashpoint for mutations leading to cancer.
Related: Multimodality treatment of mesothelioma