Our initial finding that SV40 small t antigen was required to induce DNA replication and to transform resting cells (J. Virology 1992 and 1994) and to inactivate p300 (EMBO J. 1996) led to our discovery that SV40 induced mesotheliomas and osteosarcomas in hamsters (Am. J. Pathol 1993, Virology 1992). These results prompted experiments in which we demonstrated the presence of SV40 in human mesotheliomas (Oncogene 1994) and osteosarcomas (Oncogene 1996). We demonstrated that SV40 inhibited p53 (Nature Medicine 1997) and Rb (Nature Medicine 1997) in human mesothelioma, and that the same strains of SV40 found in mesothelioma were present in the poliovaccines used in the 50s (Cancer Res. 1999, Virology 2001). We discovered the mechanisms that make mesothelial cells susceptible to SV40, and we found that asbestos and SV40 may be co-carcinogens (PNAS 2000). We investigated the molecular pathways induced by SV40 that cause a unusual high rate of human mesothelial cell transformation. We found that SV40 induces telomerase activity (Oncogene 2002), and Notch-1 (Oncogene 2003), and in collaboration with Adi Gazdar (University of Texas), that SV40 inactivates RASSF1A (Oncogene 2002). More recently we uncovered the viral and cellular mechanisms that make mesothelial cells susceptible only to SV40 and not to other polyomaviruses (Carbone et al., Cancer Res. Adv. In brief, In press) and a chemical inhibitor of the SV40Tag-p53 interaction (Carbone et al., Virology in press). Our findings have now been reviewed positively by 3 independent panels: George Klein et al., Oncogene 2002; Institute of Medicine (IOM), Vaccine Safety Review Committee, October 2002; May Wong et al., JNCI 2002. Presently, there are more than 70 papers from 60 different laboratories that have confirmed the association of SV40 with human mesothelioma, bone and brain tumors (reviewed in Adi Gazdar et al., Nature Cancer Review, 2002). This project (SV40 and human mesothelioma) is funded by the NIH/NCI and by a generous donation of the Riviera Country Club in Illinois.

We also discovered that mesothelioma is genetically transmitted in some families in Turkey (The Lancet 2001). We hope that by studying these families we will be able to identify a gene/s that when altered causes a high incidence of mesothelioma in individuals exposed to carcinogenic fibers or tumor viruses. This project (genetic predisposition to mesothelioma) is funded by the American Cancer Society and by the Cancer Research Foundation of America.

Our studies suggest that viruses, environmental carcinogens, and genetics can interact to cause human cancer. Our research is most relevant to the fields of SV40 and mesothelioma. However, our work has general relevance to cancer research. In the long term, we hope that our work will help to elucidate the biological effects of SV40 when present in human tissues, and the pathogenesis of mesothelioma. We want to understand how viruses, environmental carcinogens, and genetics interact in causing human cancer. Our hope, of course, is that our research will help to prevent and treat mesothelioma and other cancers. The diagnostic pathology expertise of Dr. Carbone in mesothelioma has proven a great resource for our research by providing new ideas and specimens to study.