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

doi:10.1073/pnas.0604544103

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

*Thoracic Oncology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153;
Departments of ^†Medical Biostatistics and
^‡Pathology, College of Medicine, University of Vermont, Burlington, VT 05404; and
^§Department of Thoracic Surgery, New York University, New York, NY 10016

Edited by Baruch S. Blumberg, Fox Chase Cancer Center, Philadelphia, PA, and approved July 21, 2006 (received for review June 5, 2006)

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.

Footnotes

^¶To whom correspondence should be addressed at the present address:
Thoracic Oncology Program, Cancer Center of Hawaii, University of Hawaii, 651 IIalo Street, BSB Room 228, Honolulu, HI 96813.
E-mail: mcarbone{at}crch.hawaii.edu
Author contributions: M.C. designed research; B.K., R.C., H.I.P., and M.C. performed research; A.G.E. contributed new reagents/analytic tools; B.K., M.B., H.Y., P.V., M.R.-N., B.T.M., H.I.P., and M.C. analyzed data; and B.K., M.B., and M.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

AP-1,

activator protein 1;

HM,

primary human mesothelial cells;

MM,

malignant mesothelioma;

MMP,

matrix metalloprotease;

SHM,

primary Syrian hamster mesothelial cells;

JDP2,

c-Jun dimerization protein