Biology and Pathophysiology of Mesothelioma
Mesothelia consists of a single layer of flattened cells that form the epithelial lining of the serous lining of the body (these include the peritoneal [stomach: see image left], pericardial [heart] and pleural [lung: see image above]) cavities. Deposits of asbestos fibres deep in the base of the lungs may result in these fibres penetrating through into the pleural membranes where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. It has been proposed that the development of peritoneal mesothelioma results from asbestos fibres either being coughed up and swallowed, or by fibres from the lungs being transported to the abdomen and associated organs via the lymphatic system.
Since the 1960s it has been known that contamination of the pleural membranes with asbestos or other mineral fibres induces carcinogenesis. Here, long in asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers). However, the development of mesothelioma 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 mesothelioma. 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. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumour.
How Asbestos Causes Cancer
Experimental evidence suggests that asbestos acts as what's known as a complete carcinogen. In short, asbestos fibres 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.
Studies performed in 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 will actually internalize (phagocytose) longer fibres more effectively than shorter fibres. Once in the cell asbestos can interact directly with the chromosomes in the cell's nucleus and may become entangled within a chromosome. This direct interaction can interfere with the DNA's normal function inducing abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms. Often, in mesothelioma genes responsible for preventing tumours are switched off (suppressed) and the most common genes affected are: Neurofibromatosis type 2, P16INK4A and P14ARF.
Asbestos has also been shown to aid the entry of foreign DNA into healthy cells. This foreign DNA can insert itself into the human genome, causing mutations by one of the following mechanisms:
- Activation of oncogenes (genes directly responsible for causing cells to turn cancerous).
- Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region (these are normally dormant genes which are 'switched on' due to this change).
- Prevention of apoptosis (all cells are normally programmed to die, and they die because of a process called apoptosis which is switched off in cancer cells).
- Inactivation of tumor suppressor genes (these are genes that normally act to prevent cells from becoming cancerous).
- Activation of DNA repair enzymes (these enzymes are responsible for the 'emergency repair' of damaged DNA and their action is often prone to error, causing mutations).
Asbestos has also been shown to alter both the function and secretory properties of macrophages which are white blood cells responsible for the destruction and elimination of foreign cells. In addition after they phagocytose (internalize) asbestos macrophages generate increased amounts of hydroxyl radicals which by themselves are 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 defences.
As well as directly causing cancer asbestos may also promote the spread of cancerous cells by acting as an immunosuppressant. Chrysolite (white asbestos) fibres have been shown to suppress the development of new lymphocytes (white blood cells) and also to suppress the destructive power of killer T-cells (the primary defence against foreign bodies). Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens (cell transforming factors) such as platelet-derived growth factor and transforming growth factor-γ which induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.
The image on the left shows a section of mesothelioma stained in a manner that reveals the cancerous cells as dark brown blobs. This is an image of a highly-aggressive form of mesothelioma which is spreading rapidly through the normal tissue.
Epidemiology
Though the overall incidence of this disease has increased during the past 20 years, it remains a very rare disease with an incidence of approximately 1 per 1000000. For comparison, populations with high levels of smoking can have a lung cancer incidence of over 1 in 1000 (a thousand times higher). Incidence of malignant mesothelioma currently ranges from about 7 to 40 per 1,000,000 in industrialized Western nations, depending on the amount of asbestos exposure of the populations during the past several decades. Current estimates indicate that the overall incidence in the USA peaked in 2004 at a level of 15 per 1,000,000 though the incidence is expected to increase for some time yet in other parts of the world.