Abstract
BackgroundSimian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, however gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. The commercially-available human uroepithelial cell lines were either SV40-immortalized (HUC) or SV40-immortalized and then 3-MC-transformed (HUC-TC).ResultsTo characterize the SV40 - 3MC interaction, we compared human gene expression in these cell lines using a human cancer array and confirmed selected changes by RT-PCR. Many viral Large T Antigen (Tag) expression-related changes occurred in HUC-TC, and it is concluded that SV40 and 3-MC may act synergistically to transform cells. Changes noted in IFP 9-27, 2'-5' OAS, IF 56, MxA and MxAB were typical of those that occur in response to viral exposure and are part of the innate immune response. Because interferon is crucial to innate immune host defenses and many gene changes were interferon-related, we explored cellular growth responses to exogenous IFN-γ and found that treatment impeded growth in tumor, but not immortalized HUC on days 4 - 7. Cellular metabolism however, was inhibited in both cell types. We conclude that IFN-γ metabolic responses were functional in both cell lines, but IFN-γ anti-proliferative responses functioned only in tumor cells.ConclusionsSynergism of SV40 with 3-MC or other environmental carcinogens may be of concern as SV40 is now endemic in 2-5.9% of the U.S. population. In addition, SV40-immortalization is a generally-accepted method used in many research materials, but the possibility of off-target effects in studies carried out using these cells has not been considered. We hope that our work will stimulate further study of this important phenomenon.
Highlights
Simian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored
Discussions and investigations regarding the molecular identity of the SV40 isolates, revealed the sequences found in cancers were ‘wild type’, not laboratory strains [5], ruling out artifacts
Retrospective studies on human cohorts inadvertently exposed to SV40 via poliovirus vaccine increased the level of concern
Summary
Simian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. 60% of the population in the U.S and abroad was exposed to SV40 This caused little alarm, but the virus was later found to induce mesotheliomas in hamsters [3,4] and afterwards was found in a high percentage of certain types of human cancers, especially mesotheliomas, but not in surrounding tissues [reviewed in [2]]. Retrospective studies on human cohorts inadvertently exposed to SV40 via poliovirus vaccine increased the level of concern. A three-fold elevation in the incidence of mesothelioma was reported in infants and children in an exposed cohort [2], and other studies reviewed therein indicated an elevated risk of brain tumors. A vaccine against SV40 [8] is being developed
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