Journal Article

Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in <i>Trp53</i><sup>+/−</sup> mice

Hiroshi Tazawa, Masayuki Tatemichi, Tomohiro Sawa, Isabelle Gilibert, Ning Ma, Yusuke Hiraku, Lawrence A. Donehower, Hiroko Ohgaki, Shosuke Kawanishi and Hiroshi Ohshima

in Carcinogenesis

Volume 28, issue 1, pages 191-198
Published in print July 2006 | ISSN: 0143-3334
Published online January 2007 | e-ISSN: 1460-2180 | DOI:
Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53+/− mice

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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 × 5 × 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.

Journal Article.  4623 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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