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We study how viruses (SV40), mineral fibers (asbestos, erionite, etc.) and genetics interact in human malignancies (Carbone M., et al., Cancer Res 2004).

We found that SV40, a DNA tumor virus that contaminated human polio vaccines (Rizzo P et al. Cancer Res. 1999; Cutrone R. et al., Cancer Res. 2005), preferentially causes mesothelioma in hamsters (Cicala C et al. Am J. Pathol 1993), is present in some human mesotheliomas (Carbone M et al., Oncogene 1994, 1996, 1997; Gazdar A et al., Nat Rev Cancer 2002), and that human mesothelial cells are unusually susceptible to SV40-mediated malignant transformation (Bocchetta M et al. Proc Natl Aca Sci USA 2000). We elucidated some of the mechanisms of SV40 mediated transformation in human mesothelial cells (Carbone M et al., Nature Med 1997, Foddis R et al., Oncogene 2002; Bocchetta M et al., Oncogene 2003) and we are presently studying the mechanisms that allow SV40 to establish a latent infection in these cells. These studies have been funded initially by the NIH, and are presently funded through two separate NCI RO-1s.

The finding that SV40 preferentially transformed human mesothelial cells and caused mesothelioma in animals prompted our investigations on asbestos and erionite carcinogenesis. These mineral fibers are causally linked to the increased incidence of mesothelioma in the past 50 years from almost no cases to the current 2-3,00 cases/year in the US. The mechanisms of asbestos carcinogenesis have remained obscure for many years: on one hand asbestos causes mesothelial cell lysis, on the other hand it is clearly linked to the development of mesothelioma. How could an agent that causes mesothelial cell lysis cause mesothelioma? We found that asbestos induces mesothelial cells and nearby macrophages to release TNF-alpha and to express the TNF-alpha receptor. In mesothelial cells, TNF-alpha induced NF-kB activity making these cells resistant to asbestos cytotoxicity (Yang H. et al. Proc Natl Aca Sci USA 2006). A clinical trial is in the works to test the possible preventive medical effects of drugs that inhibits the NF-kB pathway, in a high-risk mesothelioma population in Turkey. These studies are funded by a recently awarded NCI-PO-1, M. Carbone PI, B Mossman, JR Testa, HI Pass, co-investigators.

We investigated our hypothesis that SV40 and asbestos may interact in mesothelioma pathogenesis. We discovered that SV40 and asbestos are co-carcinogens in causing mesothelioma in hamsters and in transforming human and hamster mesothelial cells in tissue culture and we have elucidated some of the mechanisms of co-carcinogenesis (Krocznyska B. et al., Proc Natl Aca Sci USA In Press). This is the first time that mineral fibers and viruses are shown to interact in carcinogenesis. Our findings open a new research field to study the interactions among viruses and fibers in human carcinogenesis, and provide new targets to develop novel preventive and therapeutic approaches.

In parallel studies we discovered that a mesothelioma epidemic in three villages in Cappadocia Turkey is caused by genetic predisposition to the mineral fiber erionite (Roushdy-Hammady et al. The Lancet 2001; Dogan et al. Cancer Res. 2006). In collaboration with Drs. U. Dogan at Ankara University and Dr. I. Steele at U. Chicago, we determined the chemical and crystal structure of the erionite in Cappadocia and compared to the erionite in the USA and found that they are apparently identical. These findings underscore the potential risk of erionite exposure in the Western World. These studies have been funded through grants from The American Cancer Society, The Cancer Research Foundation of America, the Illinois Riviera Country Club, the Association for Research on Asbestos, Mesothelioma and Cancer, and the Butitta Mesothelioma Foundation. In collaboration with Dr. N. Cox at the University of Chicago and Drs. Y. I. Baris, S. Emri and M. Tuncer in Ankara, Turkey, we are now attempting to isolate the mesothelioma susceptibility gene. These studies are supported by our PO-1.

We have also participated in studies that led to the isolation of a new serum marker, osteopontin, that appears useful to identify patients with early mesothelioma (Pass HI et al., N. Engl J Med 2005). We are testing prospectively the reliability of this and other markers in the high-risk mesothelioma population in Cappadocia Turkey. It is hoped that if we can validate prospectively the usefulness of these serological markers we will be able to monitor cohorts of workers exposed to asbestos for early sign of mesothelioma and for early treatment that is linked to a better survival.