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Evolving Aspects of Mesothelioma Carcinogenesis: SV40 and Genetic Predisposition

2006; Elsevier BV; Volume: 1; Issue: 2 Linguagem: Inglês

10.1016/s1556-0864(15)31534-3

ISSN

1556-1380

Autores

Michele Carbone, Harvey I. Pass,

Tópico(s)

Polyomavirus and related diseases

Resumo

Malignant mesothelioma is characterized by a long latency from the time of exposure to asbestos to the onset of disease, which suggests that multiple somatic genetic events are required for tumorigenic conversion of a normal mesothelial cell. Epidemiological studies have established that exposure to asbestos fibers is the primary cause of malignant mesothelioma1Price B Analysis of current trends in United States mesothelioma incidence.Am J Epidemiol. 1997; 145: 211-218Crossref PubMed Scopus (250) Google Scholar, 2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, and recent investigations have implicated simian virus 40 (SV40) and genetic predisposition in the etiology of some malignant mesothelioma. SV40 is a DNA tumor virus that is endogenous in rhesus monkeys and is now widespread among the human population. The modes by which the virus was transferred from monkey to human are uncertain, but it is possible that the bulk of this transfer may have occurred from 1954 to 1963 through SV40-contaminated polio vaccines administered worldwide.3Gazdar AF Butel JS Carbone M SV40 and human tumours: Myth, association or causality?.Nat Rev Cancer. 2002; 2: 957-964Crossref PubMed Scopus (182) Google Scholar SV40 can be excreted via human feces, breast milk, and semen4Carbone M Pass HI Miele L Bocchetta M New developments about the association of SV40 with human mesothelioma.Oncogene. 2003; 22: 5173-5180Crossref PubMed Scopus (87) Google Scholar, and Butel et al.5Butel JS Arrington AS Wong C Lednicky JA Finegold MJ Molecular evidence of simian virus 40 infections in children.J Infect Dis. 1999; 180: 884-887Crossref PubMed Scopus (64) Google Scholar and Butel and Lednicky 6Butel JS Lednicky JA Cell and molecular biology of simian virus 40: Implications for human infections and disease.J Natl Cancer Inst. 1999; 91: 119-134Crossref PubMed Scopus (299) Google Scholar have reported that 5.9% of 377 Texas children born between 1980 and 1995 had SV40-neutralizing antibodies. SV40 produces two oncogenic proteins, the large and small t antigens.2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 4Carbone M Pass HI Miele L Bocchetta M New developments about the association of SV40 with human mesothelioma.Oncogene. 2003; 22: 5173-5180Crossref PubMed Scopus (87) Google Scholar The large T antigen (Tag) is capable of inducing structural and numerical chromosomal alterations. Tag also induces insulin-like growth factor expression and inhibits p53 and the pRb family, and it induces c-met activity to stimulate cell proliferation.3Gazdar AF Butel JS Carbone M SV40 and human tumours: Myth, association or causality?.Nat Rev Cancer. 2002; 2: 957-964Crossref PubMed Scopus (182) Google Scholar, 4Carbone M Pass HI Miele L Bocchetta M New developments about the association of SV40 with human mesothelioma.Oncogene. 2003; 22: 5173-5180Crossref PubMed Scopus (87) Google Scholar The small t antigen (tag) inhibits cellular phosphatase 2A, stimulates MAP kinase and AP-1 activity, and works with Tag to bind and inhibit p53 and pRb.3Gazdar AF Butel JS Carbone M SV40 and human tumours: Myth, association or causality?.Nat Rev Cancer. 2002; 2: 957-964Crossref PubMed Scopus (182) Google Scholar The combined activity of both the large Tag and the small tag induce Notch-1 and telomerase activity, which are required for malignant transformation and immortalization.7Bocchetta M Miele L Pass HI Carbone M Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells.Oncogene. 2003; 22: 81-89Crossref PubMed Scopus (95) Google Scholar, 8Foddis R De Rienzo A Broccoli D et al.SV40 infection induces telomerase activity in human mesothelial cells.Oncogene. 2002; 21: 1434-1442Crossref PubMed Scopus (102) Google Scholar Analysis of human mesotheliomas for the virus revealed that SV40 sequences were present in 29 of 48 human mesothelioma samples (60%). Sequence analysis confirmed that the virus detected was SV40.9Carbone M Pass HI Rizzo P et al.Simian virus 40-like DNA sequences in human pleural mesothelioma.Oncogene. 1994; 9: 1781-1790PubMed Google Scholar Polymerase chain reaction analysis, mRNA in situ hybridization, microdissection, and immunostaining techniques used in several studies have also shown that SV40 sequences and antigens are found in tumor cells but not in the normal adjacent tissue.2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 4Carbone M Pass HI Miele L Bocchetta M New developments about the association of SV40 with human mesothelioma.Oncogene. 2003; 22: 5173-5180Crossref PubMed Scopus (87) Google Scholar Although more than 60 laboratories have found SV40 in human mesotheliomas and other tumors, the virus was not detected in Finnish, Austrian, and Turkish mesothelioma specimens,2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 3Gazdar AF Butel JS Carbone M SV40 and human tumours: Myth, association or causality?.Nat Rev Cancer. 2002; 2: 957-964Crossref PubMed Scopus (182) Google Scholar, 4Carbone M Pass HI Miele L Bocchetta M New developments about the association of SV40 with human mesothelioma.Oncogene. 2003; 22: 5173-5180Crossref PubMed Scopus (87) Google Scholar which suggests that the presence of SV40 in human tumors may be influenced by geographic factors. One of these factors may be related to polio vaccine distribution, because SV40-contaminated polio vaccines were not administered in Finland, Austria, and Turkey.2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 3Gazdar AF Butel JS Carbone M SV40 and human tumours: Myth, association or causality?.Nat Rev Cancer. 2002; 2: 957-964Crossref PubMed Scopus (182) Google Scholar Three independent panels have reviewed and confirmed the association of SV40 with human tumors, especially mesothelioma.10Klein G Powers A Croce C Association of SV40 with human tumors.Oncogene. 2002; 21: 1141-1149Crossref PubMed Scopus (109) Google Scholar, 11Wong M Pagano JS Schiller JT Tevethia SS Raab-Traub N Gruber J New associations of human papillomavirus, Simian virus 40, and Epstein-Barr virus with human cancer.J Natl Cancer Inst. 2002; 94: 1832-1836Crossref PubMed Scopus (64) Google Scholar, 12Cutrone R Lednicky J Dunn G Rizzo P Bocchetta M Chumakov K Minor P Carbone M Some oral poliovirus vaccines were contaminated with infectious SV40 after 1961.Cancer Res. 2005; 22: 10273-10279Crossref Scopus (90) Google Scholar Human mesothelial cells are unusually susceptible to SV40 infection compared with fibroblasts.3Gazdar AF Butel JS Carbone M SV40 and human tumours: Myth, association or causality?.Nat Rev Cancer. 2002; 2: 957-964Crossref PubMed Scopus (182) Google Scholar, 4Carbone M Pass HI Miele L Bocchetta M New developments about the association of SV40 with human mesothelioma.Oncogene. 2003; 22: 5173-5180Crossref PubMed Scopus (87) Google Scholar, 5Butel JS Arrington AS Wong C Lednicky JA Finegold MJ Molecular evidence of simian virus 40 infections in children.J Infect Dis. 1999; 180: 884-887Crossref PubMed Scopus (64) Google Scholar In mesothelial cells, Tag binds p53 and inhibits its tumor suppressor activity. At the same time, the interaction inhibits the ability of the virus to replicate, which ultimately leads to prolonged exposure of the cell to the mutagenic effects of Tag. This may be responsible for the high rate of transformation observed in SV40-infected mesothelial cells and may explain the ability of SV40 to preferentially induce mesotheliomas in hamsters and its presence in most human mesotheliomas.5Butel JS Arrington AS Wong C Lednicky JA Finegold MJ Molecular evidence of simian virus 40 infections in children.J Infect Dis. 1999; 180: 884-887Crossref PubMed Scopus (64) Google Scholar Overall, substantial evidence supports a role for SV40 in mesothelioma pathogenesis. SV40 is present in human mesotheliomas, where it is specifically found in the tumor cells and not in the normal surrounding tissues. Within these tumor cells, SV40 binds and inactivates essential tumor suppressor gene products, including p53 and pRb, and stimulates met, Notch-1, and telomerase activity. Moreover, SV40 causes promoter methylation and, thus, inactivation of the tumor suppressor RASSF1A, which causes a more aggressive tumor phenotype.13Baris YI Sahin AA Ozesmi M et al.An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia.Thorax. 1978; 33: 181-192Crossref PubMed Scopus (197) Google Scholar In animals, SV40 is a potent carcinogen, causing mesotheliomas in 100% of hamsters after intrapleural injection. Several arguments about the precise role of SV40 in the pathogenesis of all mesotheliomas remain. First, the possible impact of SV40 on overall mesothelioma incidence has not been determined. This has been limited by the fact that studies comparing mesothelioma incidence in SV40-infected cohorts versus non-infected cohorts are unreliable, because it seems impossible to identify infected and uninfected cohorts.12Cutrone R Lednicky J Dunn G Rizzo P Bocchetta M Chumakov K Minor P Carbone M Some oral poliovirus vaccines were contaminated with infectious SV40 after 1961.Cancer Res. 2005; 22: 10273-10279Crossref Scopus (90) Google Scholar Second, most mesotheliomas develop in people who have been exposed to asbestos, some of whom are SV40-negative. It may be difficult to separate the effect of SV40 and asbestos in individuals exposed to both carcinogens. Third, SV40-infected mesothelial cells should express viral antigens that would be an easy target for the immune system. Why they would not be eliminated before tumor development is unclear, but the immunosuppressive effects of asbestos may play a role. Fourth, SV40 was not found in mesotheliomas in certain countries,3Gazdar AF Butel JS Carbone M SV40 and human tumours: Myth, association or causality?.Nat Rev Cancer. 2002; 2: 957-964Crossref PubMed Scopus (182) Google Scholar and it is not found in all American mesotheliomas, which indicates that, like asbestos, it is not always necessary for mesothelioma development. It is unlikely that SV40 acts alone in mesothelioma development, as most cancers are multifactorial and most mesotheliomas occur in asbestos-exposed individuals. Instead, it seems more likely that asbestos and SV40 may act as co-carcinogens in the development of some mesotheliomas. SV40 and asbestos have been shown to act as co-carcinogens in vitro4Carbone M Pass HI Miele L Bocchetta M New developments about the association of SV40 with human mesothelioma.Oncogene. 2003; 22: 5173-5180Crossref PubMed Scopus (87) Google Scholar and more recently in animal experiments (Carbone et al., unpublished observations). The possibility that SV40 and asbestos may also act as co-carcinogens in humans is important because SV40 is frequently found in mesothelioma patients with a history of asbestos exposure. Additional co-factors, such as radiation exposure or genetics, may also act in conjunction with SV40, asbestos, or both. Future studies may be able to target Tag as an immunogen to treat mesothelioma with immunotherapy. Intriguing epidemiologic data imply that genetic predisposition may play an important role in determining individual susceptibility to mineral fiber carcinogenesis and to the development of mesothelioma. In villages built with stones mined from the nearby natural caves in Cappadocia, a region in Central Anatolia, Turkey, at least 50% of deaths are caused by malignant mesothelioma.13Baris YI Sahin AA Ozesmi M et al.An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia.Thorax. 1978; 33: 181-192Crossref PubMed Scopus (197) Google Scholar, 14Artvinli M Baris YI Malignant mesotheliomas in a small village in the Anatolian region of Turkey: An epidemiologic study.J Natl Cancer Inst. 1979; 63: 17-22PubMed Google Scholar, 15Baris YI Artvinli M Sahin AA Environmental mesothelioma in Turkey.Ann NY Acad Sci. 1979; 330: 423-432Crossref PubMed Scopus (113) Google Scholar, 16Baris YI Saracci R Simonato L Skidmore JW Artvinli M Malignant mesothelioma and radiological chest abnormalities in two villages in Central Turkey: An epidemiological and environmental investigation.Lancet. 1981; 1: 984-987Abstract PubMed Scopus (106) Google Scholar, 17Baris I Simonato L Artvinli M et al.Epidemiological and environmental evidence of the health effects of exposure to erionite fibres: A four-year study in the Cappadocian region of Turkey.Int J Cancer. 1987; 39: 10-17Crossref PubMed Scopus (206) Google Scholar When Baris et al.13Baris YI Sahin AA Ozesmi M et al.An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia.Thorax. 1978; 33: 181-192Crossref PubMed Scopus (197) Google Scholar discovered a very high incidence of mesothelioma in the village of Karain, scientists looked for asbestos, and some asbestos was found;18Rohl AN Langer AM Moncure G Selikoff IJ Fischbein A Endemic pleural disease associated with exposure to mixed fibrous dust in Turkey.Science. 1982; 216: 518-520Crossref PubMed Scopus (85) Google Scholar however, additional studies demonstrated that asbestos is omnipresent in Cappadocia because it is a natural component of that volcanic terrain and because asbestos-tremolite–based stucco has been widely used in building construction in all Cappadocian villages.14Artvinli M Baris YI Malignant mesotheliomas in a small village in the Anatolian region of Turkey: An epidemiologic study.J Natl Cancer Inst. 1979; 63: 17-22PubMed Google Scholar, 15Baris YI Artvinli M Sahin AA Environmental mesothelioma in Turkey.Ann NY Acad Sci. 1979; 330: 423-432Crossref PubMed Scopus (113) Google Scholar, 16Baris YI Saracci R Simonato L Skidmore JW Artvinli M Malignant mesothelioma and radiological chest abnormalities in two villages in Central Turkey: An epidemiological and environmental investigation.Lancet. 1981; 1: 984-987Abstract PubMed Scopus (106) Google Scholar, 17Baris I Simonato L Artvinli M et al.Epidemiological and environmental evidence of the health effects of exposure to erionite fibres: A four-year study in the Cappadocian region of Turkey.Int J Cancer. 1987; 39: 10-17Crossref PubMed Scopus (206) Google Scholar, 19Baris B Demir AU Shehu V Karakoca Y Kisacik G Baris YI Environmental fibrous zeolite (erionite) exposure and malignant tumors other than mesothelioma.J Environ Pathol Toxicol Oncol. 1996; 15: 183-189PubMed Google Scholar Hence, asbestos could not account for the uniquely high incidence of mesotheliomas in these three villages.14Artvinli M Baris YI Malignant mesotheliomas in a small village in the Anatolian region of Turkey: An epidemiologic study.J Natl Cancer Inst. 1979; 63: 17-22PubMed Google Scholar, 15Baris YI Artvinli M Sahin AA Environmental mesothelioma in Turkey.Ann NY Acad Sci. 1979; 330: 423-432Crossref PubMed Scopus (113) Google Scholar, 16Baris YI Saracci R Simonato L Skidmore JW Artvinli M Malignant mesothelioma and radiological chest abnormalities in two villages in Central Turkey: An epidemiological and environmental investigation.Lancet. 1981; 1: 984-987Abstract PubMed Scopus (106) Google Scholar, 17Baris I Simonato L Artvinli M et al.Epidemiological and environmental evidence of the health effects of exposure to erionite fibres: A four-year study in the Cappadocian region of Turkey.Int J Cancer. 1987; 39: 10-17Crossref PubMed Scopus (206) Google Scholar, 19Baris B Demir AU Shehu V Karakoca Y Kisacik G Baris YI Environmental fibrous zeolite (erionite) exposure and malignant tumors other than mesothelioma.J Environ Pathol Toxicol Oncol. 1996; 15: 183-189PubMed Google Scholar Another type of mineral fiber, erionite, which had been detected in the lungs of several villagers, was suspected as causative agent.14Artvinli M Baris YI Malignant mesotheliomas in a small village in the Anatolian region of Turkey: An epidemiologic study.J Natl Cancer Inst. 1979; 63: 17-22PubMed Google Scholar, 15Baris YI Artvinli M Sahin AA Environmental mesothelioma in Turkey.Ann NY Acad Sci. 1979; 330: 423-432Crossref PubMed Scopus (113) Google Scholar, 16Baris YI Saracci R Simonato L Skidmore JW Artvinli M Malignant mesothelioma and radiological chest abnormalities in two villages in Central Turkey: An epidemiological and environmental investigation.Lancet. 1981; 1: 984-987Abstract PubMed Scopus (106) Google Scholar, 17Baris I Simonato L Artvinli M et al.Epidemiological and environmental evidence of the health effects of exposure to erionite fibres: A four-year study in the Cappadocian region of Turkey.Int J Cancer. 1987; 39: 10-17Crossref PubMed Scopus (206) Google Scholar, 19Baris B Demir AU Shehu V Karakoca Y Kisacik G Baris YI Environmental fibrous zeolite (erionite) exposure and malignant tumors other than mesothelioma.J Environ Pathol Toxicol Oncol. 1996; 15: 183-189PubMed Google Scholar Erionite is a type of fibrous zeolite commonly found in the stones of the houses of Karain, Sarihidir, and Tuzkoy,2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 17Baris I Simonato L Artvinli M et al.Epidemiological and environmental evidence of the health effects of exposure to erionite fibres: A four-year study in the Cappadocian region of Turkey.Int J Cancer. 1987; 39: 10-17Crossref PubMed Scopus (206) Google Scholar, 19Baris B Demir AU Shehu V Karakoca Y Kisacik G Baris YI Environmental fibrous zeolite (erionite) exposure and malignant tumors other than mesothelioma.J Environ Pathol Toxicol Oncol. 1996; 15: 183-189PubMed Google Scholar, 20Baris YI Asbestos and erionite related chest diseases. Semih Ofset Matbaacilik Ltd. Co, Ankara, Turkey1987Google Scholar which, when injected intrapleurally into animals, caused mesothelioma.21Wagner JC Skidmore JW Hill RJ Griffiths DM Erionite exposure and mesotheliomas in rats.Br J Cancer. 1985; 51: 727-730Crossref PubMed Scopus (181) Google Scholar Erionite, therefore, seemed much more potent than asbestos in causing mesothelioma because more than half of the villagers died of this disease,17Baris I Simonato L Artvinli M et al.Epidemiological and environmental evidence of the health effects of exposure to erionite fibres: A four-year study in the Cappadocian region of Turkey.Int J Cancer. 1987; 39: 10-17Crossref PubMed Scopus (206) Google Scholar, 19Baris B Demir AU Shehu V Karakoca Y Kisacik G Baris YI Environmental fibrous zeolite (erionite) exposure and malignant tumors other than mesothelioma.J Environ Pathol Toxicol Oncol. 1996; 15: 183-189PubMed Google Scholar, 22Emri S Demir A Dogan M et al.Lung diseases due to environmental exposures to erionite and asbestos in Turkey.Toxicol Lett. 2002; 127: 251-257Crossref PubMed Scopus (87) Google Scholar and erionite is thought to be one of the most potent human carcinogens.20Baris YI Asbestos and erionite related chest diseases. Semih Ofset Matbaacilik Ltd. Co, Ankara, Turkey1987Google Scholar Studies tried to link erionite to other human tumors, but there were no significant differences in the incidence of any other tumor types in these two villages compared with the rest of Turkey.2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar Why such a potent carcinogen would specifically cause mesothelioma was unknown, and why approximately 50% of villagers seemed to experience no consequence from exposure to such a potent carcinogen was also unknown. However, closer observation revealed that mesotheliomas only occurred in certain homes and not in others (homes in these areas are inhabited by multiple generations and passed down), even though all homes contained similar amounts of erionite according to recent mineralogical analysis.2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 23Roushdy-Hammady I Siegel J Emri S Testa JR Carbone M Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey.Lancet. 2001; 357: 444-445Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Furthermore, in the nearby village of Karlik, where homes are built from the same materials and contain the same types of erionite fibers, only one mesothelioma had been known to occur, which was in a woman who had migrated from Karain.2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 23Roushdy-Hammady I Siegel J Emri S Testa JR Carbone M Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey.Lancet. 2001; 357: 444-445Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Further analysis of pedigrees of families who lived in homes in which mesotheliomas occurred showed that these mesotheliomas seemed to be inherited in an autosomal dominant pattern. Approximately 50% of descendents of affected parents developed mesotheliomas. When members of unaffected families married into affected families, 50% of their descendents also developed mesotheliomas.2Carbone M Kratzke RA Testa JR The pathogenesis of mesothelioma.Semin Oncol. 2002; 29: 2-17Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 23Roushdy-Hammady I Siegel J Emri S Testa JR Carbone M Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey.Lancet. 2001; 357: 444-445Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Whether genetics alone or in conjunction with erionite are responsible for these mesotheliomas remains unknown, but clearly genetics is a key factor because mesotheliomas do not develop in non-affected families regardless of environmental exposure. The study of these villages is part of an international American Cancer Society Grant funded for the purpose of possibly detecting a specific tumor suppressor gene for mesothelioma.

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