Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters.
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.
Kroczynska
Barbara
B
Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA.
Cutrone
Rochelle
R
Bocchetta
Maurizio
M
Yang
Haining
H
Elmishad
Amira G
AG
Vacek
Pamela
P
Ramos-Nino
Maria
M
Mossman
Brooke T
BT
Pass
Harvey I
HI
Carbone
Michele
M
D000818:Animals; D017638:Asbestos, Crocidolite / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D002478:Cells, Cultured; D006224:Cricetinae; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008647:Mesocricetus; D008654:Mesothelioma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013539:Simian virus 40 / Q000378:metabolism / Q000472:pathogenicity*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D002273:Carcinogens; C491387:JDP2 protein, human; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D017638:Asbestos, Crocidolite; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1