Evolving Aspects of Mesothelioma Carcinogenesis: SV40 and Genetic Predisposition

Abstract

M alignant mesothelioma is characterized by a long latency from the time of exposure to asbestos to the onset of disease, which suggests that multiple somatic genetic events are required for tumorigenic conversion of a normal mesothelial cell. Epidemiological studies have established that exposure to asbestos fibers is the primary cause of malignant mesothelioma 1,2 , and recent investigations have implicated simian virus 40 (SV40) and genetic predisposition in the etiology of some malignant mesothelioma. SV40SV40 is a DNA tumor virus that is endogenous in rhesus monkeys and is now widespread among the human population. The modes by which the virus was transferred from monkey to human are uncertain, but it is possible that the bulk of this transfer may have occurred from 1954 to 1963 through SV40-contaminated polio vaccines administered worldwide. 3 SV40 can be excreted via human feces, breast milk, and semen 4 , and Butel et al. 5 and Butel and Lednicky 6 have reported that 5.9% of 377 Texas children born between 1980 and 1995 had SV40-neutralizing antibodies. SV40 produces two oncogenic proteins, the large and small t antigens. 2,4 The large T antigen (Tag) is capable of inducing structural and numerical chromosomal alterations. Tag also induces insulin-like growth factor expression and inhibits p53 and the pRb family, and it induces c-met activity to stimulate cell proliferation. 3,4 The small t antigen (tag) inhibits cellular phosphatase 2A, stimulates MAP kinase and AP-1 activity, and works with Tag to bind and inhibit p53 and pRb. 3 The combined activity of both the large Tag and the small tag induce Notch-1 and telomerase activity, which are required for malignant transformation and immortalization. 7,8 Analysis of human mesotheliomas for the virus revealed that SV40 sequences were present in 29 of 48 human mesothelioma samples (60%). Sequence analysis confirmed that the virus detected was SV40. 9 Polymerase chain reaction analysis, mRNA in situ hybridization, microdissection, and immunostaining techniques used in several studies have also shown that SV40 sequences and antigens are found in tumor cells but not in the normal adjacent tissue. 2,4 Although more than 60 laboratories have found SV40 in human mesotheliomas and other tumors, the virus was not detected in Finnish, Austrian, and Turkish mesothelioma specimens, 2-4 which suggests that the presence of SV40 in human tumors may be influenced by geographic factors. One of these factors may be related to polio vaccine distribution, because SV40-contaminated polio vaccines were not administered in Finland, Austria, and Turkey. 2,3 Three independent panels have reviewed and confirmed the association of SV40 with human tumors, especially mesothelioma. 10 -12 Human mesothelial cells are unusually susceptible to SV40 infection compared with fibroblasts. [3][4][5] In mesothelial cells, Tag binds p53 and inhibits its tumor suppressor activity. At the same time, the interaction inhibits the ability of the virus to replicate, which ultimately leads to prolonge...

In Arrayed Ranks: Array Technology in the Study of Mesothelioma

“…116 Another controversial serum marker for mesothelioma concerns SV40. 117,118 Links between asbestos exposure and SV40 in human malignant mesothelioma have been demonstrated, 114,119,120 but other studies have been unable to identify such a link. [121][122][123] A recent study in prediagnostic serum samples was unable to detect the SV40 T antigen, nor was it able to detect SV40 virus DNA.…”