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Asbestos exposure is documented in only 50-80% of patients with MPM, though crystals of the amphibole (straight, rod-like) crocidolite were found on the pleura of most patients with mesothelioma (Suzuki and Yuen 2002). Inhaled asbestos fibers brake through alveoli and eventually concentrate in “milky spots” of the parietal pleura (Boutin, Dumortier et al. 1996) which are most prevalent in intercostals spaces of costovertebral gutters. Milky spots or anthracotic “black spots” are subserosal collections of macrophages and lymphocytes located on lymphatic capillaries. These cell collections are traversed by specialized post-capillary venules, suggesting resemblance to lymph nodes. Mesothelial cells covering milky spots have stem cell properties, they are cuboid, their connections to surrounding cells incomplete, leaving open access routes to the subserosal connective tissue. It is likely that macrophages activated by indigestible asbestos fibers produce cytokines which induce the proliferation of mesothelial cells covering milky spots while reactive oxygen produced by the same macrophages contributes to DNA damage. Moreover, effusion fluid originates in milky spots and is absorbed through milky spots. Mesothelioma cells metastasize to milky spots where they gain access to subserosal connective tissue through the gaps between mesothelial cells.
Malignant transformation of mesothelial cells might be assisted by the Simian Virus 40 (SV40), a small, 5,243 bp circular ds DNA virus, which drives cells into replication by its small t-antigens’ ability to bind Rb and large T-antigens’ ability to blocks their death through its binding to p53. SV40 was found in most mesotheliomas in the USA (Carbone, Pass et al. 2003) and is likely contributing to the malignant transformation leading to mesothelioma by driving mesothelial proliferation and possibly by upregulating the expression of VEGF receptor (Catalano, Romano et al. 2002).
Once transformed, mesothelioma cells metastasize into other milky spots of the parietal pleura (explaining why mesothelioma appears to develop initially in a multifocal fashion), and to sites where the subserosal connective tissue matrix of the parietal or visceral pleura was made accessible by inflammation or mechanical erosion. Once adhering to the connective tissue matrix, mesothelioma induces brisk angiogenesis and desmoplasia. The growth of mesothelioma is further driven by growth factors emanating from irritated pleural cells and macrophages (PDGF, IL-6, IL-8, TGF-?,VEGF, VEGF-C etc). Mesothelioma is locally invasive (MMP, tenascin C), metastasizes to regional lymph nodes and in the late stages of the disease distantly.
Source: http://www.umm.edu/thoracic/approach_mesoth.htm
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