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Asbest en virus samen schadelijker

09-11-2006 00:00

Het sv-40 virus maakt muizen en hamsters extra gevoelig voorde schadelijke effecten van asbest. Amerikaanse en australische onderzoekers vonden bij hamsters en muizen dat het sv40-virus en het meest gevaarlijke blauwe asbest (crocidoliet), elkaar versterken in de mate waarin zij kankerverwekkend zijn. Het sv40-virus alleen veroorzaakte geen mesothelioom, het blauwe asbest alleen veroorzaakte mesothelioom bij 20% van de hamsters. Samen veroorzaakten het virus en de asbest mesothelioom bij 90% van de hamsters. De onderzoeksresultaten gaven aan dat mineraalvezels en virussen bij muizen en hamsters samen kankerverwekkend kunnen zijn en dat dragers van het sv40 virus gevoeliger kunnen zijn voor lagere doses asbestvezels. De vraag is of de werking bij mensen hetzelfde zal zijn. Dit zal nader onderzocht moeten worden. Het sv40 virus was oorspronkelijk een virus dat alleen bij apen voorkwam, maar maar bleek per abuis in de jaren 60 van de vorige eeuw ook in het poliovaccin te zitten. Bron: Kroczysnka, B. et al. (2006). Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters. Proceedings of the National Academy of Sciences of the United States of America, 103.14128-14133. originally published online Sep 11, 2006. Robinson, C. et al. (2006). A novel SV40 tag transgenic model of asbestos-induced mesothelioma: Malignant Transformation Is Dose Dependent. Cancer Res, 66, 10786-94.

Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters

Barbara Kroczynska*, Rochelle Cutrone*, Maurizio Bocchetta*, Haining Yang*, Amira G. Elmishad*, Pamela Vacek*, Maria Ramos-Nino, Brooke T. Mossman*, Harvey I. Pass*, and Michele Carbone*

Abstract


Only a fraction of subjects exposed to asbestos develop malignant mesothelioma (MM), suggesting that additional factors may render some individuals more susceptible. We tested the hypothesis that asbestos and Simian virus (SV40) are cocarcinogens. Asbestos and SV40 in combination had a costimulatory effect in inducing ERK1 2 phosphorylation and activator protein-1 (AP-1) activity in both primary Syrian hamster mesothelial cells (SHM) and primary human mesothelial cells (HM). Ap-1 activity caused the expression and activation of matrix metalloprotease (MMP)-1 and MMP-9, which in turn led to cell invasion. Experiments using siRNA and chemical inhibitors confirmed the specificity of these results. The same effects were observed in HM and SHM. Experiments in hamsters showed strong cocarcinogenesis between asbestos and SV40: SV40 did not cause MM, asbestos caused MM in 20% of hamsters, and asbestos and SV40 together caused MM in 90% of hamsters. Significantly lower amounts of asbestos were sufficient to cause MM in animals infected with SV40. Our results indicate that mineral fibers and viruses can be cocarcinogens and suggest that lower amounts of asbestos may be sufficient to cause MM in individuals infected with SV40.



Robinson, C. et al. (2006). A novel SV40 tag transgenic model of asbestos-induced mesothelioma: Malignant Transformation Is Dose Dependent. Cancer Res, 66, 10786-94.

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.