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
cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are
more potent carcinogens than "feathery fibers" (chrysotile or white asbestos
fibers).[4] However, there is now evidence that smaller particles may be more
dangerous than the larger fibers.[1][2] They remain suspended in the air where
they can be inhaled, and may penetrate more easily and deeper into the lungs.
"We probably will find out a lot more about the health aspects of asbestos from
[the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of
pulmonary and critical-care medicine at North Shore-Long Island Jewish Health
System. Dr. Fein has treated several patients for "World Trade Center syndrome"
or respiratory ailments from brief exposures of only a day or two near the
collapsed buildings.[3]
Mesothelioma 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
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.
Experimental evidence suggests that asbestos acts as a complete carcinogen with
the development of mesothelioma 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. In general,
asbestos fibres are thought to act through direct physical interactions with the
cells of the mesothelium in conjunction with indirect effects following
interaction with inflammatory cells such as macrophages.
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. This contact
between the asbestos fibre and the chromosomes or structural proteins of the
spindle apparatus can induce complex abnormalities. The most common abnormality
is monosomy of chromosome 22. Other frequent abnormalities include structural
rearrangement of 1p, 3p, 9p and 6q chromosome arms.
Common gene abnormalities in mesothelioma cell lines include deletion of the
tumor suppressor genes:
* Neurofibromatosis type 2 at 22q12
* P16INK4A
* P14ARF
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 several possible mechanisms:
* Inactivation of tumor suppressor genes
* Activation of oncogenes
* Activation of proto-oncogenes due to incorporation of foreign DNA containing a
promoter region
* Activation of DNA repair enzymes, which may be prone to error
* Activation of telomerase
* Prevention of apoptosis
Asbestos fibres have been shown to alter the function and secretory properties
of macrophages, ultimately creating conditions which favour 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 defences.
Asbestos also may 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 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-β
(TGF-β) which in turn, may induce the chronic stimulation and proliferation
of mesothelial cells after injury by asbestos fibres
.
