Tazawa Hiroshi, Tatemichi Masayuki, Sawa Tomohiro, Gilibert Isabelle, Ma Ning, Hiraku Yusuke, Donehower Lawrence A, Ohgaki Hiroko, Kawanishi Shosuke, Ohshima Hiroshi
International Agency for Research on Cancer, 150 Cours Albert Thomas 69008 Lyon, France.
Carcinogenesis. 2007 Jan;28(1):191-8. doi: 10.1093/carcin/bgl128. Epub 2006 Jul 20.
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.
由于持续性氧化和硝化组织损伤，慢性炎症是人体多个部位癌症公认的危险因素。与Trp53+/+小鼠相比，Trp53+/-小鼠显示出肿瘤发生的易感性，如肉瘤和淋巴瘤。我们研究了通过皮下植入塑料板（10×5×1毫米）作为异物所诱导的慢性炎症，尤其是氧化和硝化应激，对Trp53+/-和Trp53+/+小鼠肿瘤发生的影响。塑料板在约11周龄时植入。38只Trp53+/-小鼠中有30只（79%）在植入物周围发生了肉瘤（肿瘤出现的平均时间为45.8±12.0周龄），而10只植入塑料板的Trp53+/+小鼠中只有1只（10%）在56周时发生了肿瘤。假手术部位未发生肉瘤。10只未植入塑料板的Trp53+/-小鼠中有2只（20%）在77、81和84周时也自发发生了3个肉瘤。与Trp53+/-小鼠的自发肉瘤相比，在植入物诱导的肉瘤中检测到氧化和硝化应激标志物（8-氧代-7,8-二氢-2'-脱氧鸟苷、8-硝基鸟嘌呤和3-硝基酪氨酸）的免疫染色增加以及肿瘤细胞和炎症细胞中诱导型一氧化氮合酶的表达。此外，在29个植入物诱导的肉瘤中有26个（90%）观察到p53杂合性缺失。这些结果表明，植入异物显著增强了Trp53+/-小鼠的肉瘤发生，这可能与氧化和硝化应激增加有关。剩余野生型p53等位基因的缺失和p53功能的丧失似乎至少部分是Trp53+/-小鼠植入部位肉瘤发生过程中的潜在分子机制。Trp53+/-小鼠中这种植入物诱导的肉瘤发生可能有助于研究分子机制，并为慢性炎症和/或异物诱导的人类致癌作用开发化学预防的新策略。
