Carcinogenesis Advance Access originally published online on July 20, 2006
Carcinogenesis 2007 28(1):191-198; doi:10.1093/carcin/bgl128
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Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53+/– mice
1 International Agency for Research on Cancer, 150 Cours Albert Thomas 69008 Lyon, France
2 Biochemistry Division, National Cancer Center Research Institute Tokyo, 104-0045, Japan
3 Department of Hygiene and Preventive Medicine, Showa University School of Medicine Tokyo 142-8555, Japan
4 Mie University Graduate School of Medicine, Mie 514-8507 Japan
5 Department of Molecular Virology and Microbiology, Baylor College of Medicine Houston, TX 77030, USA
6 Present address: School of Food and Nutritional Sciences, Graduate School of Nutritional and Environmental Sciences University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
*To whom correspondence should be addressed. Tel: +81 3 3542 2511; Fax: +81 3 3542 2530; Email: dtazawa{at}gan2.res.ncc.go.jp
Chronic inflammation is a recognized risk factor for human cancer at various sites because of persistent oxidative and nitrative tissue damage. Trp53+/– mice show the predisposition to tumor development, such as sarcomas and lymphomas, compared with Trp53+/+ mice. We investigated the effects of chronic inflammation, especially oxidative and nitrative stress, induced by subcutaneous implantation of a plastic plate (10 x 5 x 1 mm) as a foreign body on tumorigenesis in Trp53+/– and Trp53+/+ mice. The plastic plates were implanted at the age of about 11 weeks. Thirty out of 38 Trp53+/– mice (79%) developed sarcomas around the implant (mean time of tumor appearance was 45.8 ± 12.0 weeks of age), whereas only one of 10 Trp53+/+ mice with an implant (10%) developed a tumor, at 56 weeks. No sarcomas developed at a sham-operation site. Two of 10 Trp53+/– mice with no implant (20%) also developed three sarcomas spontaneously at 77, 81 and 84 weeks. Increased immunostaining for markers of oxidative and nitrative stress (8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-nitroguanine and 3-nitrotyrosine) and expression of inducible nitric oxide synthase in tumor cells and inflammatory cells were detected in implant-induced sarcomas compared with spontaneous sarcomas in Trp53+/– mice. Furthermore, p53 loss of heterozygosity was observed in 26 out of 29 implant-induced sarcomas (90%). These results indicate that implanted foreign bodies significantly enhanced sarcoma development in Trp53+/– mice, and this may be associated with increased oxidaive and nitrative stress. Loss of the remaining wild-type p53 allele and loss of p53 function appears to be, at least in part, underlying molecular mechanisms during the development of sarcomas at the implantation site in Trp53+/– mice. Such implant-induced sarcoma development in Trp53+/– mice could be useful for studying molecular mechanisms and developing new strategies for chemoprevention in human carcinogenesis induced by chronic inflammation and/or foreign bodies.