Virus Oncogenesis of Malignant Pleural Mesothelioma

Simian Vacuolating Virus 40 (SV40) was isolated in 1960 from polio vaccines contaminated during the manufacturing process. SV40 is able to induce tumors in animals and is causally associated with human malignant mesothelioma, lymphoma, and bone and brain tumors. SV40 is a co-factor for malignant mesothelioma development in hamsters and mice exposed to asbestos, based on different mechanisms. In addition, SV40 cooperates with asbestos and possibly other mineral fibers, leading to in vitro transformation of primary human mesothelial cells (HM). SV40 induces transformation of HM, rather than cell lysis as occurs in other human cell types, due to the transcription of antisense RNA repressing late viral gene expression. The mechanism of SV40 carcinogenesis relies on the activity of the two SV40 early proteins, large T antigen (Tag) and small t antigen (tag). In SV40-infected mesothelial cells, Tag binds p53 and the resulting complex associates with retinoblastoma protein (Rb), p300, p400 and CREB-binding protein (CBP). This larger complex establishes a potent transcriptional regulator, able to induce IGF-1, Met and Notch-1 expression and the associated downstream signaling pathways. The induction of calretinin expression is also a part of Tag activity in host cells. The interaction of Tag with other binding partners suggests additional mechanisms of interference with cell cycle or survival of the host infected cells.

Keywords: Co-carcinogenesis, large T antigen, mesothelial cells, oncogenes, simian Virus 40, transformation.