A novel SV40 TAg transgenic model of asbestos-induced mesothelioma: malignant transformation is dose dependent

Cancer Research. 2006 Nov 15;66(22):10786-94.Click here to read [Link]

Cleo Robinson¹, Ivonne van Bruggen¹, Amanda Segal², Melissa Dunham¹, Amanda Sherwood¹, Frank Koentgen³, Bruce W.S. Robinson¹ and Richard A. Lake¹

¹ School of Medicine and Pharmacology and Western Australian Institute for Medical Research, University of Western Australia; ² Path Centre, Sir Charles Gairdner Hospital; and ³ Ozgene Pty Ltd, Perth, Australia

Requests for reprints: Richard A. Lake, School of Medicine and Pharmacology and Western Australian Institute for Medical Research, University of Western Australia, 4th Floor, G-block, Sir Charles Gairdner Hospital, Nedlands, Perth, 6009, Australia. Phone: 61-89-346-3127; Fax: 61-89-346-2816; E-mail: rlake@cyllene.uwa.edu.au.

Abstract

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.