A novel SV40 TAG transgenic model of asbestos-induced mesothelioma : Malignant transformation is dose dependent

Although it has been clear for >40 years that mesothelioma can be caused by asbestos, not all patients with this disease have a history of asbestos exposure. Other factors, including non-asbestos fibers and ionizing radiation, are known to cause malignant transformation of mesothelial cells. In a...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006-11, Vol.66 (22), p.10786-10794
Main Authors: ROBINSON, Cleo, VAN BRUGGEN, Ivonne, SEGAL, Amanda, DUNHAM, Melissa, SHERWOOD, Amanda, KOENTGEN, Frank, ROBINSON, Bruce W. S, LAKE, Richard A
Format: Article
Language:English
Subjects:
Animals
Antigens, Polyomavirus Transforming - genetics
Antineoplastic agents
Asbestos - poisoning
Biological and medical sciences
Cell Line, Transformed
Cell Transformation, Neoplastic
Dose-Response Relationship, Drug
Medical sciences
Mesothelioma - etiology
Mesothelioma - genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pharmacology. Drug treatments
Simian virus 40
Tumors
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Summary:Although it has been clear for >40 years that mesothelioma can be caused by asbestos, not all patients with this disease have a history of asbestos exposure. Other factors, including non-asbestos fibers and ionizing radiation, are known to cause malignant transformation of mesothelial cells. In addition, it is likely that genetics will play some role in susceptibility. Recently, it has been suggested that SV40 viral oncogenes could contribute to the carcinogenicity of asbestos. To better understand the role of SV40, we used the mesothelin promoter to construct MexTAg mice that express SV40 large T antigen (TAg) in the mesothelial compartment. We generated four MexTAg lines that carry high, intermediate, and low copy numbers of the transgene. All of these mice show a relatively low level of spontaneous tumor development. High-copy, 299h mice rapidly developed mesotheliomas when exposed to asbestos, and these tumors were faster growing and more invasive than those developing in wild-type and single-copy (266s) mice. In addition, we found a direct relationship between transgene copy number and survival after exposure to asbestos. A single copy of TAg was sufficient to immortalize mesothelial cells in vitro, but these cells did not show evidence of malignant transformation. In contrast, cell lines developed from mesothelial cells of animals carrying multiple copies of TAg were growth factor independent and could be cloned at limiting dilution in soft agar. These data provide the first in vivo demonstration of co-carcinogenicity between SV40 and asbestos.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-4668