SV40, growth factors, and mesothelioma: another piece of the puzzle.

Abstract

The initiation and development of malignant mesothelioma, a tumor derived from mesothelial cells which line the pleural and peritoneal cavities, are under intense investigation as this unique tumor has been associated historically with occupational exposures to asbestos (1, 2), and is increasing in several countries (3). More importantly, the prognosis of patients with mesothelioma is grim, most surviving less than a year after initial diagnosis (1, 2). Thus, effective therapeutic strategies are desperately needed. In the past few years, simian virus 40 (SV40), a DNA virus, has been linked to the etiology of mesothelioma in multiinstitutional studies showing that 50% of human mesotheliomas in the United States contain SV40 large T antigen (T-Ag) DNA sequences (reviewed in Refs. 4, 5). The link between mesothelioma and SV40 appears to be related to the contamination of polio vaccine stocks with SV40 sequences, but it is unclear how the virus is spread in humans (4). In Finland, where the polio vaccine shows no SV40 contamination, the frequency of mesothelioma is significantly lower (10 5 compared with 1.4 10 5 ) and associated with environmental asbestos exposure rather than concomitant exposure to SV40 sequences (6). A causal link between SV40 and mesothelioma has also been strengthened by studies showing that SV40 sequences are selectively expressed in mesothelioma cells, and not in adjacent parenchymal cells or lung carcinomas (7, 8). Moreover, mechanistic work demonstrates that human mesothelial cells are uniquely susceptible to SV40 infection and malignant transformation (9). In these experiments, infection of normal human mesothelial cells by SV40 led to an extremely high rate of morphologic transformation (at least 1,000 times higher than other cell types infected with this virus), and immortality. In addition, SV40 acts synergistically with asbestos to cause malignant transformation of human mesothelial cells (9). SV40-associated mesothelial cell transformation has been attributed to the ability of SV40 T-Ag to inactivate the tumor suppressors, p53 (10) and p-retinoblastoma (Rb) family proteins (11). Inactivation of pRb and p53 by the SV40 T-Ag also has an indirect effect on p16 and p21 cyclin D–dependent kinases that appear to be depleted in mesothelioma cells as a result of loss of heterozygosity (LOH), and through a reduction in p53-dependent transcription, respectively (12, 13). As a result of the T-Ag activity, cyclin-dependent kinase subunits are rearranged (14). The SV40 small t-antigen (t-Ag) also modulates cell proliferation by enhancing the activity of telomerase (15), Extracellular Signal-Regulated Kinases (ERKs) and Activator Protein-1 (AP-1) (16). This appears to be a function of a t-Ag– mediated decrease in Protein Phosphatase 2A (PP2A). Yet other events involved in immortalization of cells and tumor development by SV40 are clearly involved, because mesotheliomas have long latency periods in man, averaging from 25 to 40 yr (1). Growth factors may be critical stimuli of mesothelial cell proliferation, increasing not only the susceptibility of cells to DNA-damaging agents and genetic instability, but also the expansion of transformed cell populations. In addition, elaboration of growth factors may be essential to creation of a favorable environment for tumor development. Normal human and rodent mesothelial cells proliferate in response to a number of growth factors, including epidermal growth factor (EGF) (17, 18), tumor necrosis factor (TNF)(17, 19), platelet-derived growth factor (PDGF) (18), hepatocyte growth factor (HGF) (20), and keratinocyte growth factor (KGF) (20). In vivo , rodent pleural mesothelial cells exhibit increases in DNA synthesis several days after inhalation (21) or intratracheal instillation of amphibole types of asbestos (20, 22). These early proliferative events may be mediated in part via increased levels of HGF and KGF in pleural lavage fluid (20), as opposed to direct effects of fibers on mesothelial cells, as few fibers have been detected at the pleural surface in this short time frame of exposure. Although HGF is produced in general by mesenchymal cells, recent work by Cacciotti and colleagues (23) shows that the HGF receptor, Met, a proto-oncogene product whose activation leads to cell growth and altered morphogenesis, is activated in SV40positive mesothelioma cells. Moreover, when normal human mesothelial cells are transfected with full-length SV40 DNA, Met receptor activation is induced and associated with S-phase entry, fibroblastoid morphology, and the assembly of viral particles that infect adjacent mesothelial cells, inducing an HGF-dependent Met activation. This work ( Received in original form December 24, 2001 )