SV40 and human mesothelioma

Abstract

Simian virus 40 (SV40) is a DNA tumor virus capable of infecting and transforming human mesothelial (HM) cells in vitro. Hamsters injected intracardially to expose most tissue types to SV40 preferentially develop mesotheliomas. In humans, asbestos is the main cause of mesothelioma, and asbestos and SV40 are co-carcinogens in transforming HM cells in tissue culture and in causing mesothelioma in hamsters. Laser microdissection experiments conducted in the laboratory of Adi Gazdar demonstrated that SV40 was present specifically in the malignant mesothelioma cells and not in nearby stromal cells. Further experiments demonstrated that SV40 remains episomal in HM cells and astrocytes because of the production of a long antisense RNA that represses viral capsid protein production. Thus, the potent SV40 oncoprotein, T-antigen (Tag), is expressed, but because the capsid proteins are not produced, the cells are not lysed and, instead, become transformed. Together this evidence suggests that SV40 may contribute to the development of mesotheliomas in humans. However, epidemiological evidence to support this hypothesis is lacking. This chapter also summarizes the introduction of SV40, a monkey virus, into the human population as an unrecognized contaminant of early poliovaccines. In addition to mesotheliomas, SV40 now is linked with brain cancers, osteosarcomas, and lymphomas in humans. Explanations are provided for the apparent geographic variations in SV40 prevalence and for controversies about the role of SV40 in human cancer.

Keywords: Simian virus 40 (SV40); asbestos; cancer; mesothelioma.

Figure 1

Laser microdissection experiments conducted in Dr. Adi Gazdar laboratory on pleura/lung biopsies. Mesothelioma tissue and lung tissue were present on the same slide, and were microdissected and analyzed in parallel. SV40 DNA was specifically detected in mesothelioma microdissected tissue (red) and not in nearby lung tissue (yellow) (83).

Figure 2

Adi Gazdar showed this slide to illustrate his thought process regarding the presence and significance of SV40 detection in human mesotheliomas and in other malignancies.

Figure 3

Two separate mRNAs (arrows) are produced from the Ori region of replication, one going counter-clockwise in the so called early region that is spliced to produce the large (Tag) and the small t antigen (tag), and an mRNA going in the opposite, clockwise direction, known as late region, which is spliced to produce the different SV40 VP capsid proteins. In mesothelial cells and in astrocytes, but not in fibroblasts, the late region mRNA—which codes for Tag and tag, does not detach from the SV40 DNA template when it reaches the Poly A site, and instead continues to run along the circular genome, resulting in the formation of an antisense RNA that pairs with the mRNA coding for the capsid proteins, forming double-stranded mRNA that is degraded (97).