Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53+/- mice

Abstract

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.

Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection

“…(37) 8-Nitroguanine is also detected in the colonic gland epithelial cells of a mouse model of inflammatory bowel disease (59) and in soft tissue sarcoma cells in mice after subcutaneous implantation of a plastic plate. (60) These studies indicate that 8-nitroguanine is a potential mutagenic DNA lesion generated during inflammation. Thus, 8-nitroguanine may be used as a predictive marker directly evaluating the risk of inflammation-related carcinogenesis.…”

Beyond foreign‐body‐induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression

“…10 Tazawa et al identified some genes possibly responsible for the development of foreign-body-induced sarcomas. 71 They found that in 79% heterozygous p53-deficient (Trp53 1/2 ) mice with only 1 functional allele in the p53 gene developed spontaneous sarcomas after plastic plate implantation, whereas only 10% of mice with wild-type p53 developed sarcomas. They further demonstrated that the arising tumors have lost the remaining wild-type p53 allele, meaning complete loss of p53 function; this appears to be the underlying molecular mechanism during the development of sarcomas.…”

“…p53 allele is inactivated by an increase of inflammation-mediated RNS. 71 Association between RNS and p53 mutations is evidenced in inflamed lesions of the colon with ulcerative colitis, 72 stomach, 73 brain 74 and breast. 75 The susceptibility to foreign-body-related carcinogenesis does exist across species, and in strain-and gender-dependent manner.…”

Molecular Mechanisms of Inflammation-Induced Carcinogenesis

“…Tazawa et al observed a high incidence of spontaneous autologous tumors in p53 genedisrupted mice after subcutaneous implantation of a small piece of plastic plate [67]. The plastic plate was recognized as foreign body in the mice, and the foreign body-induced inflammation caused the tumor at the implantation site.…”