Virus Oncogenesis of Malignant Pleural Mesothelioma
Pp. 145-154 (10)
Giovanni Gaudino, Fang Qi, Haining Yang and Michele Carbone
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.
Co-carcinogenesis, large T antigen, mesothelial cells, oncogenes,
simian Virus 40, transformation.
University of Hawai Cancer Center, 701 Ilalo St 96813, Honolulu, HI, United States.