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

Our plain-English summary of Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters, by B. Kroczynska, R. Cutrone, M. Bocchetta, et al (Proceedings of the National Academy of Sciences of the United States of America, 2006).

The study

• Authors: B. Kroczynska, R. Cutrone, M. Bocchetta, H. Yang, A.G. Elmishad, P. Vacek, M. Ramos-Nino, B.T. Mossman, H.I. Pass, M. Carbone
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2006;103(38):14128-33
• Cited by: 92 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory and animal study tested whether crocidolite asbestos and simian virus 40 (SV40) are cocarcinogens. Primary human and Syrian hamster mesothelial cells were infected with a mutant SV40 strain (dl883), exposed to crocidolite, or both. The combination raised ERK1/2 and AP-1 pathway activity and MMP-1 and MMP-9 levels more than either agent alone. In human mesothelial cells, it also increased cell invasion by 44%, compared with 20% for either agent alone. Blocking the pathway suppressed this effect. Female hamsters received SV40 dl883, crocidolite (0.4 mg once into the chest cavity plus 4 mg in total into the abdomen), or both. No hamster given only SV40 dl883 developed mesothelioma. Crocidolite alone caused peritoneal mesothelioma in 20%. Both together caused mesothelioma in 90%. Mean tumor latency (time from injection until a tumor was detected or the animal became ill) was 30.2 weeks with both agents and 37.6 weeks with crocidolite alone. Pleural mesothelioma occurred only in the combined group. The authors concluded that SV40 infection lowered the amount of crocidolite needed to cause mesothelioma in hamsters.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (tissue culture) experiments on mesothelial cells plus an animal experiment in hamsters
• Who was studied: Primary human mesothelial cells and primary Syrian hamster mesothelial cells in culture. The animal experiment used 21-day-old female Syrian Golden hamsters in groups of 30. The SV40-only and crocidolite-only groups ended with 28 and 29 animals because some died within a day of injection. A control group received tissue culture medium only.
• Exposure: Crocidolite asbestos and SV40 dl883, given alone or together. SV40 dl883 is a mutant SV40 that does not express the small t antigen. The authors chose it because wild-type SV40 can cause mesothelioma in hamsters on its own. Hamsters received one intrapleural injection of 0.4 mg crocidolite and 0.4 mg intraperitoneally every 2 weeks, for a total of 4 mg in the peritoneum. SV40 was injected into the left ventricle of the heart.
• Main results:
  • AP-1 binding activity: in hamster and human mesothelial cells exposed to both agents, there were 2.6- and 3-fold increases respectively, compared with 1.3- to 1.5-fold increases with crocidolite or SV40 dl883 alone.
  • MMP-1 and MMP-9 levels rose most in cells exposed to both agents (2.3- to 2.5-fold).
  • In human mesothelial cells, either agent alone increased the number of invading cells by 20%. Both together increased it by 44%.
  • In human mesothelial cells, blocking ERK1/2 activation or AP-1 activity suppressed the increase in cell invasion caused by asbestos plus SV40 dl883.
  • Hamsters given SV40 dl883 alone developed no mesothelioma, though a few developed lymphomas and sarcomas after a long latency. The article states that wild-type SV40 can cause mesothelioma in hamsters independently of asbestos.
  • In hamsters given crocidolite alone, the 4 mg peritoneal dose caused peritoneal mesothelioma in 20%. The 0.4 mg intrapleural dose caused no pleural mesothelioma.
  • Hamsters given both SV40 dl883 and crocidolite had a significantly higher mesothelioma incidence (90%) and significantly shorter tumor latency.
  • Mean tumor latency was 30.2 weeks in the SV40 dl883 plus crocidolite group and 37.6 weeks in the crocidolite-only group. The article defines tumor latency as the time from injection until the tumor became detectable or the animals became ill, which was also when they were euthanized. It is not stated as a mesothelioma-specific latency.
  • Pleural mesothelioma occurred only in the group given both agents. Of hamsters given SV40 dl883 and 0.4 mg intrapleural crocidolite, 50% developed mesothelioma.
  • No tumors developed in the control group.
• The authors' conclusion: The authors concluded that, in hamsters, SV40 infection lowered the amount of crocidolite needed to cause mesothelioma. They stated that their findings do not question the ability of either agent to cause mesothelioma on its own.
• Limitations the authors state:
  • The authors noted that exposure can be controlled in animals. In humans, by contrast, there is no clear dose-response curve, and people are exposed to different carcinogens over their lifetime.
  • Wild-type SV40 was also tested, but only results with SV40 dl883 were presented, partly because of space constraints.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Crocidolite, SV40, Mesothelial Cells, Mesothelioma, Malignant Mesothelioma, Mineral Fiber.

Related studies

• Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity — M. Bocchetta, I. Di Resta, et al. (2000)
• Patterns of 8-hydroxydeoxyguanosine formation in DNA and indications of oxidative stress in rat and human pleural mesothelial cells after exposure to crocidolite asbestos — H. Fung, Y.W. Kow, et al. (1997)
• DNA damage in bronchial epithelial and mesothelial cells with and without associated crocidolite asbestos fibers — J. Nygren, S. Suhonen, et al. (2004)
• Simian virus 40 infection down-regulates the expression of nitric oxide synthase in human mesothelial cells — E. Aldieri, S. Orecchia, et al. (2004)
• Dielectric changes in membrane properties and cell interiors of human mesothelial cells in vitro after crocidolite asbestos exposure — E. Dopp, L. Jonas, et al. (2000)
• Lung mesothelial cell and fibroblast responses to pleural and alveolar macrophage supernatants and to lavage fluids from crocidolite-exposed rats — I.Y. Adamson, H. Prieditis, et al. (1997)

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