Simian virus 40 (SV40 is a DNA virus which specifically induces mesotheliomas, ependymomas, sarcomas and osteosarcomas in rodents. These same tumor types contain SV40 sequences in humans, but the role of SV40 in human carcinogenesis is unknown. We are investigating if SV40 contributes to the development of human mesothelioma, a very aggressive tumor of the pleura whose incidence continues to increase. Mesothelioma is strongly associated with asbestos exposure, but only 5-10 percent of workers exposed to high levels of asbestos develop this tumor, and about 20 percent of mesotheliomas patients have not been exposed to asbestos. It would be very important to find the co-factor/s that render some workers more susceptible to asbestos or that cause mesothelioma in individuals who have not been exposed to asbestos. We propose to investigate the mechanisms that make mesothelial cells very susceptible to SV40-mediated transformation, and their possible relevance to human malignant mesothelioma. During the previous grant period, we established the possible biological significance of SV40 when present in some human mesotheliomas, and the utility of an in vitro SV40-human mesothelial cell system for studying this association. We propose to build on these studies to identify: 1) the natural history of SV40 infection in humans, 2) the mechanisms that cause the frequent immortalization of mesothelial cells following infection with SV40, 3) the mechanisms which may account for the presence of the more rapidly replicating non-archetypal SV40 in mesotheliomas, compared to the less rapidly replicating archetypal SV40 in ependymomas and bone tumors, and whether these mechanisms are related to oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092657-03
Application #
6732027
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Wong, May
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$359,792
Indirect Cost
Name
Loyola University Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Qi, Fang; Carbone, Michele; Yang, Haining et al. (2011) Simian virus 40 transformation, malignant mesothelioma and brain tumors. Expert Rev Respir Med 5:683-97
Nasu, Masaki; Carbone, Michele; Gaudino, Giovanni et al. (2011) Ranpirnase Interferes with NF-?B Pathway and MMP9 Activity, Inhibiting Malignant Mesothelioma Cell Invasiveness and Xenograft Growth. Genes Cancer 2:576-84
Zhang, Lei; Qi, Fang; Gaudino, Giovanni et al. (2010) Tissue Tropism of SV40 Transformation of Human Cells: Role of the Viral Regulatory Region and of Cellular Oncogenes. Genes Cancer 1:1008-20
Carbone, Michele; Pannuti, Antonio; Zhang, Lei et al. (2008) A novel mechanism of late gene silencing drives SV40 transformation of human mesothelial cells. Cancer Res 68:9488-96
Rivera, Zeyana; Strianese, Oriana; Bertino, Pietro et al. (2008) The relationship between simian virus 40 and mesothelioma. Curr Opin Pulm Med 14:316-21
Bocchetta, Maurizio; Eliasz, Sandra; De Marco, Melissa Arakelian et al. (2008) The SV40 large T antigen-p53 complexes bind and activate the insulin-like growth factor-I promoter stimulating cell growth. Cancer Res 68:1022-9
Carbone, Michele; Strianese, Oriana; Theos, Kimberly et al. (2007) Mesothelioma. Hawaii Med J 66:48-50
Yang, Haining; Bocchetta, Maurizio; Kroczynska, Barbara et al. (2006) TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc Natl Acad Sci U S A 103:10397-402
Kroczynska, Barbara; Cutrone, Rochelle; Bocchetta, Maurizio et al. (2006) Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters. Proc Natl Acad Sci U S A 103:14128-33
Elmishad, A G; Bocchetta, M; Pass, H I et al. (2006) Polio vaccines, SV40 and human tumours, an update on false positive and false negative results. Dev Biol (Basel) 123:109-17; discussion 119-32

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