Sakano Katsuhisa, Takahashi Mami, Mutoh Michihiro, Niho Naoko, Komiya Masami, Sato Hidetaka, Tanaka Takuji, Sugimura Takashi, Wakabayashi Keiji
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Carcinogenesis. 2007 Oct;28(10):2193-8. doi: 10.1093/carcin/bgm114. Epub 2007 May 16.
Epidemiologic data suggest that diabetes mellitus type II is a risk factor for several types of cancer, including pancreatic, liver, colon and thyroid cancers. In the present study, effects of diabetes/hyperlipidemia on N-nitrosobis(2-oxopropyl)amine (BOP)-induced cancer development were examined in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, model animals for non-insulin-dependent diabetes mellitus and Long-Evans Tokushima Otsuka (LETO) rats, appropriate controls. Males of both strains were given four subcutaneous injections of BOP (10 mg/kg body wt) or saline on alternative days, starting at 5 weeks of age. BOP induced tumors in a variety of tissues, including the thyroid gland, colon, kidney, liver and lung. The highest yields were noted for thyroid tumors, the incidence (P = 0.0182) and multiplicity (P < 0.001) of BOP-induced thyroid cancers with marked fibrosis being significantly higher in OLETF than in LETO rats. Interestingly, anaplastic thyroid carcinomas were observed limited to the BOP-treated OLETF rats. Additionally, a greater incidence and frequency of aberrant crypt foci, putative precursor lesions for colon tumors, was observed in the BOP-treated OLETF group. However, BOP was ineffective at inducing pancreatic ductal tumors. No thyroid, liver, lung or colon tumors were found in the OLETF and LETO rats receiving the vehicle. Significant increases in serum levels of insulin, glucose, phospholipids, triglycerides and total cholesterol were detected in the OLETF rats compared with the LETO rats, regardless of the treatment. Our results indicate that diabetic/hyperlipidemic state can enhance BOP-induced carcinogenesis of the thyroid gland and to a lesser extent the colon in OLETF rats.
流行病学数据表明，II型糖尿病是包括胰腺癌、肝癌、结肠癌和甲状腺癌在内的几种癌症的危险因素。在本研究中，在大冢长- Evans德岛肥胖（OLETF）大鼠（非胰岛素依赖型糖尿病模型动物）和大冢长- Evans德岛（LETO）大鼠（适当对照）中，研究了糖尿病/高脂血症对N-亚硝基双（2-氧代丙基）胺（BOP）诱导的癌症发生的影响。两种品系的雄性大鼠从5周龄开始，每隔一天皮下注射四次BOP（10 mg/kg体重）或生理盐水。BOP在包括甲状腺、结肠、肾脏、肝脏和肺在内的多种组织中诱导肿瘤。甲状腺肿瘤的发生率最高，BOP诱导的甲状腺癌的发生率（P = 0.0182）和多发性（P < 0.001），OLETF大鼠中伴有明显纤维化的甲状腺癌明显高于LETO大鼠。有趣的是，未分化甲状腺癌仅在接受BOP治疗的OLETF大鼠中观察到。此外，在接受BOP治疗的OLETF组中，观察到结肠肿瘤的假定前体病变——异常隐窝灶的发生率和频率更高。然而，BOP在诱导胰腺导管肿瘤方面无效。接受载体的OLETF和LETO大鼠未发现甲状腺、肝脏、肺或结肠肿瘤。无论治疗如何，与LETO大鼠相比，OLETF大鼠的血清胰岛素、葡萄糖、磷脂、甘油三酯和总胆固醇水平均显著升高。我们的结果表明，糖尿病/高脂血症状态可增强BOP诱导的OLETF大鼠甲状腺癌的发生，并在较小程度上增强结肠癌的发生。
