Mesotheliomas - Pleural Mesothelioma, Asbestos Fibers

Experimental Evidence for the Role of Asbestos

Animal experiments have confirmed the oncogenicity of asbestos. A singleexplanation for the pathogenesis of mesothelioma. Normal human mesothelial cells can phagocytose asbestos fibers and are 10 times more sensitive than normal human bronchial epithelial cells to asbestos cytotoxicity in vitro.153 Mesothelial cells are 100 times more sensitive than fibroblasts.

Following in vitro exposure to asbestos, mesothelial cells display chromosomal aberrations indicative of clonal origin.153 Occurrence of DNA strand breaks has been found after exposure of cells to asbestos in vitro.131,159 Such effects could further lead to activation of oncogenes and/or loss of suppressor genes.23 Indeed, karyotypic analyses of human mesotheliomas have revealed frequent abnormalities, particularly involving chromosomes 1, 2, 3, 6, 7, 9, 11, 17, and 22.23,109,183,200 One of the most common nonrandom changes is deletion of the short arm of chromosome 3 between the region of p14 to 21.200

This finding is of interest, especially since deletions and loss of heterozygosity of the short arm of chromosome 3 have been reported also in lung cancer, particularly the small cell type in the region of p14 to 23,302 suggesting evidence for a suppressor gene important in respiratory carcinogenesis.

A significant correlation exists between chromosomal aberrations and pulmonary asbestos fiber burden in patients with mesothelioma.268 An inverse correlation between survival and the number of copies of chromosome 7 short arms has been reported.268 These cytogenetic changes may also be important in explaining the likely constitutional susceptibility to mesothelioma (see below).

Exposure of normal human mesothelial cells to asbestos fibers in vitro has as yet been unsuccessful in producing mesothelioma.153,183 Malignant transformation was achieved in one experiment by first transfecting cells with a plasmid containing the simian virus SV40, resulting in immortalization, followed by transfection with the EJ-ras gene, resulting in tumorigenicity.208 Exposure to asbestos failed to produce tumorigenicity, however. It may be extremely difficult to realize in vitro all the different conditions and interactions which may operate in vivo.

The existence of transforming genes has been detected in human mesothelioma, but their exact nature remains to be identified.23,149 They do not seem to be related to the ras gene family, which was found activated in 50% of asbestos-induced Syrian hamster tumor cell lines,23 or to the myc, myb, neu, or fos oncogenes.101 Loss of heterozygosity for the p53 gene located on the short arm of chromosome 17 has recently been observed in three of four mesothelioma cell lines.72

In another study of 20 cell lines from 17 patients with malignant mesothelioma, p53 abnormalities were found in three lines only.180 Wilms' tumor suppressor gene (WT-1) transcripts were found to be expressed in normal human mesothelial cells and in 7 of 7 human mesothelioma cell lines.297 Recently, changes in another suppressor gene, p16, were described, with homozygous deletions in 85% of mesothelioma cell lines and 22% of primary tumor specimens.65

Asbestos fibers can also transfect cells by binding to exogenous nucleic acids, such as plasmid DNA, which then becomes associated with chromosomal DNA, thereby altering gene expression.14 Knowledge of the role of growth factors in the genesis and proliferation of mesothelioma is rapidly expanding. The role of plateletderived growth factors (PDGF) has been emphasized.108 Mesothelioma cells express messenger RNAs (mRNAs) for both PDGF-A and -B chains at higher levels than normal human mesothelial cells, whereas the reverse is true for transforming growth factor-‰ (TGF-‰), suggesting that PDGF may be an autocrine growth factor for mesothelioma.

108 The corresponding genes for PDGF-A and PDGF-B (which is almost identical to the c-sis gene) are located on chromosomes 7p21 to p22 and 22q13.1, respectively, and although visible abnormalities of these chromosomes are not constant in mesothelioma, alterations at a molecular level cannot be excluded.108,278 Human mesothelioma cell lines, compared with normal human mesothelial cells, have shown strongly increased expression of the c-sis oncogene (PDGF-B) and to a lesser degree of the gene for PDGF-A.278

Normal mesothelial cell lines seem to express PDGF-‡ receptor genes, whereas mesothelioma cell lines express predominantly PDGF-‰ receptor genes.279 These findings could conceivably provide also a role for the thrombocytosis commonly observed in mesothelioma patients, in view of its negative prognostic influence.62,63,225 No increased expression of epidermal intrapleural or intraperitoneal injection of various asbestos fibers (chrysotile or amphibole) produce mesotheliomas in rats, hamsters, and mice, often after a relatively long delay of 7 months or more.261

Intratracheal instillation or inhalation is less often successful.25,290 Physical characteristics, rather than chemical properties, are incriminated, since many durable fibers of similar size and shape but of different nature (glass, aluminum oxide, talc, attapulgite) can also produce mesothelioma in animals.167,251 The most oncogenic fibers are the long, thin ones, with a length > 8 microns and a diameter < 0.25 micron, the so-called Stanton hypothesis, whereas shorter fibers may be inactivated by phagocytosis.117,251 These long, thin fibers may penetrate deep in the lung parenchyma,117,221,251 eventually reaching the subpleural and pleural structures and penetrating into cells without killing them, thereby implementing a complex oncogenic process.

The effect of gravity on inhaled fibers may explain the predominance of pleural mesothelioma in the lower thorax and on the right side.138 The pathogenesis of peritoneal mesothelioma is more obscure. Although the disease has not been produced in animals by feeding experiments, ingestion of asbestos fibers is likely to occur through the action of the tracheobronchial mucociliary apparatus, and these fibers may penetrate the gastrointestinal mucosa.138 Alternatively, retrograde spread to the peritoneal cavity from the pleura may take place.85 In fact, autopsy studies have revealed that asbestos fibers are found in many organs besides the lungs, including the spleen, thyroid, pancreas, heart, adrenals, kidneys, liver, prostate, and even brain.17

The possibility that asbestos exposure increases the risk of other cancers besides mesothelioma and lung cancer has been reviewed.85 The evidence is strong for laryngeal cancer (relative risk 1.4), suggestive but not conclusive for esophageal cancer, possible for renal cancer, and inconclusive for gastrointestinal, pancreatic, and ovarian cancers (where misdiagnosis of mesothelioma is difficult to exclude). There appears also to be no overall association with lymphomas, except possibly with large cell lymphomas of the oral cavity and gastrointestinal tract (see below).