Mesothelioma, a malignancy associated with asbestos, has been recently linked to simian virus 40 (SV40). We found that infection of human mesothelial cells by SV40 is very different from the semipermissive infection thought to be characteristic of human cells. Mesothelial cells are uniformly infected but not lysed by SV40, a mechanism related to p53, and undergo cell transformation at an extremely high rate. Exposure of mesothelial cells to asbestos complemented SV40 mutants in transformation. Our data provide a mechanistic explanation for the ability of SV40 to transform mesothelial cells preferentially and indicate that asbestos and SV40 may be cocarcinogens. M alignant mesothelioma (MM) is a tumor of the serosal lining the pleural, pericardial, and peritoneal cavities that causes about 2,500 deaths per year in the United States (1). MM arises from the malignant transformation of mesothelial cells, which are undifferentiated cells representing the adult remnants of the surface coelomic mesoderm (1). Although MM has been associated with past exposure to asbestos fibers, the mechanisms through which asbestos causes mesothelial cell transformation are unclear. The capacity of asbestos to induce autophosphorylation of the epidermal growth factor receptor, which leads to activation protein-1 activity in human mesothelial cells (HM; ref.2); the production of reactive oxygen species by cells exposed to asbestos (3); and the local and systemic immunosuppressive effects of asbestos (4) may all contribute to carcinogenesis (1). Other factors act alone or synergistically with asbestos in causing MM, because only 5-10% of individuals exposed to high levels of asbestos develop MM, and 10-20% of MM occurs in individuals with no known exposure (1).Recently, simian virus 40 (SV40) has been associated with human mesothelioma and brain and bone tumors (reviewed in refs. 1 and 5-7). SV40 (5-8) is a DNA tumor virus encoding two transforming proteins (the large tumor antigen, or Tag; and the small tumor antigen, or tag), and three capsid proteins (VP1-3). Tag is the replicase of SV40. Expression of Tag in the absence of cell lysis leads to cellular transformation through several mechanisms, including Tag-mediated inhibition of cellular p53 and Rb family proteins, induction of insulin-like growth factor-I and its receptor, and the direct mutagenic effect of Tag. SV40 tag enhances Tag functions by inhibiting protein phosphatase 2A, contributing to malignancy (1, 9). SV40 infects cells from different species, and the cell type determines the outcome of SV40 infection (5-8). Permissive monkey cells support SV40 replication, which results in cell lysis. In nonpermissive rodent cells SV40 DNA cannot be replicated, and cells are not lysed and can be transformed. Human cells are termed semipermissive because only a fraction of cells express SV40 Tag after infection, these infected cells are lysed, and cell transformation is a very rare event.SV40 is highly oncogenic in rodents (5-7). We found that intracardial injection of SV40 induced MM...
