Toxicological Sciences 68, 331-338 (2002)
Copyright © 2002 by the Society of Toxicology
CARCINOGENICITY |
Accelerated Progression of Asbestos-Induced Mesotheliomas in Heterozygous p53+/- Mice
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912
Asbestos fibers produce diffuse malignant mesotheliomas in chronic rodent inhalation assays or after direct intrapleural or intraperitoneal injection. In vitro models have provided evidence that asbestos fibers are genotoxic carcinogens that can directly or indirectly generate reactive oxygen- and nitrogen-derived species that cause DNA damage. Heterozygous p53+/- mice show an increased incidence and reduced latency of malignant mesotheliomas induced by weekly intraperitoneal injections of crocidolite asbestos fibers. In this study, we investigated whether loss of heterozygosity (LOH) at the p53 tumor-suppressor gene locus contributes to accelerated tumor progression. LOH was found in 50% of the tumors produced in heterozygous p53+/- mice. In contrast to tumors that arise in p53+/+ mice or those that retained one p53 allele, LOH was associated with large tumor masses with central areas of necrosis, local invasion, and penetration of lymphatics. Increased tumor size was not associated with increased levels of cell proliferation as determined by BrdU incorporation, but it was correlated with a reduction in apoptosis as determined morphologically and by the TUNEL assay. Wild-type p53 protein is essential for cell cycle arrest in response to DNA damage and in maintenance of genomic stability. Cell lines established from tumors that showed LOH at the p53 tumor-suppressor gene locus were nearly tetraploid. These results suggest that p53 haplo-insufficiency sensitizes mice to the clastogenic or aneuploidogenic effects of crocidolite asbestos fibers, resulting in a shorter latent period. As solid tumors develop, spontaneous loss of the wild-type allele accompanied by decreased apoptosis and genetic instability is associated with accelerated tumor growth, invasion, and lymphatic dissemination.
Key Words: asbestos fibers; mesothelioma; p53-deficient mice; apoptosis; tumor progression; crocidolite asbestos; genetic instability.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. A. Altomare, C. W. Menges, J. Pei, L. Zhang, K. L. Skele-Stump, M. Carbone, A. B. Kane, and J. R. Testa Activated TNF-{alpha}/NF-{kappa}B signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice PNAS, March 3, 2009; 106(9): 3420 - 3425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.-S. Ge, G.-R. Chen, Q. Dong, B. Akingbemi, C. M. Sottas, M. Santos, S. C. Sealfon, D. J. Bernard, and M. P. Hardy Biphasic Effects of Postnatal Exposure to Diethylhexylphthalate on the Timing of Puberty in Male Rats J Androl, July 1, 2007; 28(4): 513 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Pietruska and A. B. Kane SV40 Oncoproteins Enhance Asbestos-Induced DNA Double-Strand Breaks and Abrogate Senescence in Murine Mesothelial Cells Cancer Res., April 15, 2007; 67(8): 3637 - 3645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tazawa, M. Tatemichi, T. Sawa, I. Gilibert, N. Ma, Y. Hiraku, L. A. Donehower, H. Ohgaki, S. Kawanishi, and H. Ohshima Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53+/- mice Carcinogenesis, January 1, 2007; 28(1): 191 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Altomare, C. A. Vaslet, K. L. Skele, A. De Rienzo, K. Devarajan, S. C. Jhanwar, A. I. McClatchey, A. B. Kane, and J. R. Testa A Mouse Model Recapitulating Molecular Features of Human Mesothelioma Cancer Res., September 15, 2005; 65(18): 8090 - 8095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Cugell and D. W. Kamp Asbestos and the Pleura: A Review Chest, March 1, 2004; 125(3): 1103 - 1117. [Full Text] [PDF]
|
|
|
|
|
|
B. T. Akingbemi, R. Ge, G. R. Klinefelter, B. R. Zirkin, and M. P. Hardy Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances PNAS, January 20, 2004; 101(3): 775 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Upadhyay and D. W. Kamp Asbestos-Induced Pulmonary Toxicity: Role of DNA Damage and Apoptosis Experimental Biology and Medicine, June 1, 2003; 228(6): 650 - 659. [Abstract] [Full Text] [PDF]
|
|