OF MALIGNANT MESOTHELIOMA
Rochelle Cutrone, Maurizio Bocchetta, and Michele Carbone
Loyola University, USA
Mesothelial cells are undifferentiated cells, forming the serosal lining of the pleural, peritoneal and pericardial cavities. They are the adult remnants of the coelomic mesoderm, and are able to differentiate into epithelial-like or fibroblast-like cells. They can be identified using their immunophenotype and ultramicroscopic characteristics. Mesothelial cells have a level of wild-type p53 that is 4 to 5 times higher than seen in other cells. This allows for easy detection of p53 using immunostaining, since wild-type p53 accumulates to adequate levels to be detected.
Mesotheliomas are malignant tumors, arising from the transformation of mesothelial cells. The aggressiveness of this tumor, and its ability to resist all current therapies, is responsible for the poor prognosis and a typical survival of about one year from the time of diagnosis.1 Until the second half of the twentieth century, this tumor was relatively unknown. The rise in mesotheliomas cases has increased to more than 2,000 cases per year in the United States. About 80% of mesotheliomas are associated with asbestos exposure, however, only 5% of asbestos workers develop this tumor.1,7 Mesotheliomas generally develop in adults after more than a 20 year latency period from exposure, and are rarely seen in children. Additional factors or genetic susceptibility may increase the carcinogenic effects of asbestos since there is a low percentage of people that develop mesotheliomas from asbestos exposure and 20% of mesotheliomas have no known asbestos exposure. The exact mechanism by which asbestos causes malignant cell transformation is not known and it is under investigation. 1, 3
Asbestos is a name given to a family of naturally occurring silicate minerals, each differing in their carcinogenicity.5 Asbestos is also responsible for lung cancer in smoking, asbestosis, pleural plaques, and pleural effusions. The two main groups of asbestos are serpentine, consisting of crysotile, and amphibole, which includes crocidolite, amosite, anthophyllite, and tremolite.3-7 While the role of amphibole asbestos in the pathogenesis of mesotheliomas is well demonstrated, the effects of crysotile asbestos lacks clarity.5-7 Disagreement on the carcinogenicity of crysotile asbestos is in part due to circumstances of Canadian crysotile asbestos being contaminated with 1% of tremolite, and to the finding that crysotile miners have more amphibole asbestos than crysotile asbestos in their lungs.4-6 This is because crysotile can be partially digested and removed from the lungs, whereas amphibole asbestos is more resistant to cellular enzymatic digestion and accumulates in the lungs.4 This makes it difficult to determine to what extent a person is exposed to a certain type of asbestos, and ultimately which type of asbestos causes mesothelioma.
Along with the lung macrophages and mononuclear phagocytes, mesothelial cells are also highly phagocytic cells. Exposure of these cells to asbestos fibers initiates a response by the cells to phagocytize the fibers, which causes cell death. Complete removal of short fibers from the lungs is possible, whereas the longer fibers seen with amphibole asbestos cannot be solubilized and removed from the lungs. Asbestos can possibly favor tumor development by the involvement of inflammatory cells or by influencing the normal activity of genes that regulate the cell cycle. In response to asbestos exposure, macrophages produce reactive oxygen radicals and lymphokines that interfere with the immune system and cause DNA damage.8,9,11,12 DNA mutations that are produced by the hydroxyl radicals and superoxide anions, include double strand breaks and deletions.1,3,4,8 It has been found that stimulation of the autophosphorylation of the epidermal growth factor by crocidolite asbestos, stimulates the extracellular-regulated kinase cascade, increasing AP-1 activity. Either cell mitosis or cell apoptosis will occur depending on whether or not the DNA damage can be repaired.3,4
Lanphear and Buncher reviewed 21 articles and reported that out of 1690 mesotheliomas, 99% of them occurred 15 years or more after exposure to asbestos, 96% has a latent period of at least 20 years, and that none occurred less than 10 years from exposure.21 It is possible that asbestos induces genetic alterations that accumulate over time, eventually leading to malignant transformation of the cell. In order for this to occur, the same cell or cell lineage accumulates damage over a 30 year or more period. Since asbestos has proven to be toxic to mesothelial cells, the idea of a damaged cell or daughter cell surviving for 30 years or more in the presence of asbestos while accumulating genetic damage seems unlikely.2,3 However, if a key regulatory gene, such as the p16 (a CDK inhibitor often deleted in mesothelioma) is affected, this would allow a dividing cell to accumulate additional mutations relatively rapidly.1 Most of these mutations may be incompatible with the survival of the cell, but some may lead to the malignant phenotype. If the mutations were to accumulate rapidly before asbestos induces apoptosis, this scenario would seem more likely. Once the cell has reached its malignant transformed phenotype, there would be rapid cell growth and the tumor would become clinically detectable which would account for the clinical observation that malignant mesotheliomas are aggressive and fast growing, developing 20-50 years after asbestos exposure.
Recent studies have linked mesotheliomas with the Simian virus 40 (SV40).20 SV40 is DNA tumor virus that was first introduced to the human population between 1954-1963 through the poliovaccine, contaminated with both anntenuated and killed SV40, and the adenovaccine.14,19,20 An estimated 96 million adults and children in the United States were immunized with the potentially SV40 contaminated poliovaccine. About one third of those vaccines contained infectious SV40.1,13,14,19,20 Through its double stranded, circular genome, this virus is capable of encoding two transforming proteins, large tumor antigen (Tag) and small tumor antigen (tag), and three capsid proteins, (VP1-3). In the absence of cell lysis, Tag is capable of inducing cellular transformation. Tag has the ability to bind and inactivate the products of several tumor suppressor genes, including cellular p53 and the Rb family of proteins, induce IL-1 and its receptor, and introduce chromosomal changes through its mutagenic effects.15-17 Tag is the replicase of SV40. SV40 tag can inhibit protein phosphatase 2A (PP2A), enhancing Tag functions, and therefore, contributing to the malignancy.18
SV40 has different modes of action in different cell types.10 The permissive monkey cells allow for SV40 replication and eventual cell lysis, where the virus is considered nonpermissive in rodent cells, allowing for only viral integration into the host cell genome. Human cells are considered to be semipermissive to SV40, allowing for both viral replication and viral integration into the cell genome. Recent studies show that human mesothelial cells are more efficiently infected and transformed with SV40 than the human fibroblast and epithelial cell.10 The role of SV40 in the pathogenesis of mesothelioma has been reviewed at a recent international consensus meeting.24
Back in the 1970's, Dr. Y.I. Baris reported a high incidence of mesothelioma in three villages in the Cappadocia region of Turkey. The search for asbestos began immediately, since it was the only known factor involved in causing mesothelioma at that time However, the widespread finding of asbestos could not account for this particular high incidence of mesothelioma. Another type of mineral fiber, known as erionite, was detected in the lungs of their villagers, which brought about the concept that this may be the causative factor of mesotheliomas.22,24 Erionite is a fibrous zeolite commonly found in the stone houses in the villages Karain and Tuzkoy in Turkey. When erionite was injected intrapleurally into animals, 100% of them developed mesotheliomas as compared to less than 10% of animals developing mesotheliomas following intrapleural injection of asbestos. This makes erionite the most carcinogenic of the two. Since only half of the individuals exposed to erionite developed mesothelioma, it became apparent that additional factors rendered some individuals more susceptible. The mechanism of erionite being a contributing factor in mesotheliomas in individuals genetically predisposed, is presently being investigated in our lab in collaboration with our colleagues in Turkey: Dr. Y. I. Baris, Dr. S. Emri, and Dr. A. U. Dogan. Recent studies revealed that some families in Cappadocia are genetically predisposed to mesotheliomas. In conclusion, Mesothelioma is a cancer in which genetics, viruses, and environmental carcinogens such as asbestos and erionite may interact to cause malignancy.
References
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This research was supported by a generous donation by Eli Lilly and by NIH R01 CA92657
