A Novel SV40 TAg Transgenic Model of Asbestos-Induced Mesothelioma: Malignant Transformation Is Dose Dependent

Abstract

Although it has been clear for >40 years that mesothelioma can be caused by asbestos, not all patients with this disease have a history of asbestos exposure. Other factors, including non-asbestos fibers and ionizing radiation, are known to cause malignant transformation of mesothelial cells. In addition, it is likely that genetics will play some role in susceptibility. Recently, it has been suggested that SV40 viral oncogenes could contribute to the carcinogenicity of asbestos. To better understand the role of SV40, we used the mesothelin promoter to construct MexTAg mice that express SV40 large T antigen (TAg) in the mesothelial compartment. We generated four MexTAg lines that carry high, intermediate, and low copy numbers of the transgene. All of these mice show a relatively low level of spontaneous tumor development. High-copy, 299h mice rapidly developed mesotheliomas when exposed to asbestos, and these tumors were faster growing and more invasive than those developing in wild-type and single-copy (266s) mice. In addition, we found a direct relationship between transgene copy number and survival after exposure to asbestos. A single copy of TAg was sufficient to immortalize mesothelial cells in vitro, but these cells did not show evidence of malignant transformation. In contrast, cell lines developed from mesothelial cells of animals carrying multiple copies of TAg were growth factor independent and could be cloned at limiting dilution in soft agar. These data provide the first in vivo demonstration of co-carcinogenicity between SV40 and asbestos. (Cancer Res 2006; 66(22): 10786-94)

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

“…However, recent studies showed that animals infected with SV40 or transfected with SV40 large T-antigen (TAg) were extremely susceptible to asbestos carcinogenesis, and this is currently used as an in vivo model of SV40 as a co-carcinogen for mesothelioma development [47,48]. A molecular epidemiological study has also indicated a co-carcinogen role of SV40 and studies addressing this question are awaited [49].…”

High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma

“…The serum against JCV was kindly provided by E.O. Major (Laboratory of Molecular Medicine and Neuroscience, National Institute of (21) 27 (15) Statistical analysis was performed by the χ 2 test with Yates' correction. No statistically significant differences of SV40 seroprevalence were found between the cohorts of pregnant women and healthy blood donors (P = 0.43) and between the cohorts of subjects exposed to asbestos fibers and healthy blood donors (P = 0.19).…”

“…Indeed, many reports have detected SV40 sequences at high prevalence and the expression of its large tumor antigen (Tag) oncoprotein in MPM. A transforming synergistic action between asbestos fibers and SV40 has been proved in human, hamster, and murine mesothelial cells and in animal models (14)(15)(16).…”

Eighth International Mesothelioma Interest Group

“…These mice had a higher risk of developing mesothelioma when exposed to asbestos, and the transgenes that contained a higher copy number were at the highest risk (Robinson et al, 2006). Pietruska and Kane (2007) (USA) found that SV40 may contribute to mesothelioma progression by circumventing stress-induced senescence in cells exposed to asbestos in part through p53 inactivation.…”