Tanaka Takuji, Kawabata Kunihiro, Sugie Shigeyuki
Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu City, Gifu 500-8513, Japan.
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu City, Gifu 501-1194, Japan.
World J Oncol. 2017 Aug;8(4):97-104. doi: 10.14740/wjon1038w. Epub 2017 Aug 27.
Obesity and diabetes mellitus are associated with lifestyle-related carcinogenesis. They are also risk factors of esophageal adenocarcinoma, but there are only a few reports on association between obesity/diabetes and development of squamous cell carcinoma in the oral cavity and esophagus. In this study, we therefore aimed to determine whether obesity and diabetes affect oral and esophageal carcinogenesis using model mice of obesity and diabetes, the Tsumura Suzuki obese diabetes (TSOD) and Tsumura Suzuki non-obesity (TSNO) control mice, which were treated with 4-nitroquinoline 1-oxide (4-NQO) to produce tongue and esophageal carcinomas.
We used 28 each of the male TSOD and TSNO mice of 8 weeks of age. They were divided into the 4-NQO-treated group (n = 20) and untreated group (n = 8). 4-NQO was administered to mice in drinking water at a dose level of 20 ppm for 8 weeks. The untreated group was given distilled water without 4-NQO. At 28 experimental weeks, histopathological examination was performed on all organs including tongue and esophagus. We performed analysis of histopathology of all organs which included buccal capsule (a tongue)/esophagus after an experiment start in 28 weeks. Fasting plasma glucose (FPG) and lipid parameters including total cholesterol (T-Cho), triglyceride (TG), high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol were measured and all these parameters were compared between the two genotypes. Also, mRNA expression of eight cytokines including interleukin (IL)-1β, IL-6, IL-17, interferon (IFN)-γ, keratinocyte-derived cytokine (KC), macrophage inflammatory protein (MIP)-1α, MIP-2, and tumor necrosis factor (TNF)-α in the esophageal mucosa was assayed.
4-NQO treatment produced proliferative squamous cell lesions (dysplasia, papilloma and carcinoma) in the tongue and esophagus of both the TSOD and TSNO mice. The incidence and multiplicity of tongue tumors were 30% and 0.45 ± 0.83 in the TSOD mice and 30% and 0.40 ± 0.68 in the TSNO mice. The incidence and multiplicity of esophageal tumors were 70% and 2.25 ± 2.29 in the TSOD mice and 30% and 0.60 ± 1.14 (P < 0.01) in the TSNO mice.
Our findings indicate that the obese and diabetic TSOD mice were susceptible to 4-NQO-induced esophageal carcinogenesis, suggesting risk factors of obese and diabetes for esophageal squamous cell carcinoma. Additionally, the TSOD mice were useful as esophagus carcinogenic model. Our study first reported that 4-NQO induced esophageal cancer in mice.
肥胖和糖尿病与生活方式相关的致癌作用有关。它们也是食管腺癌的危险因素，但关于肥胖/糖尿病与口腔和食管鳞状细胞癌发生之间关联的报道较少。因此，在本研究中，我们旨在使用肥胖和糖尿病模型小鼠，即津村铃木肥胖糖尿病（TSOD）小鼠和津村铃木非肥胖（TSNO）对照小鼠，来确定肥胖和糖尿病是否会影响口腔和食管的致癌作用，这些小鼠用4-硝基喹啉1-氧化物（4-NQO）处理以诱发舌癌和食管癌。
我们使用了28只8周龄的雄性TSOD小鼠和28只8周龄的雄性TSNO小鼠。它们被分为4-NQO处理组（n = 20）和未处理组（n = 8）。以20 ppm的剂量水平将4-NQO添加到小鼠饮用水中，持续8周。未处理组给予不含4-NQO的蒸馏水。在实验第28周时，对包括舌和食管在内的所有器官进行组织病理学检查。在实验开始28周后，我们对所有器官（包括颊囊（舌）/食管）进行了组织病理学分析。测量空腹血糖（FPG）和脂质参数，包括总胆固醇（T-Cho）、甘油三酯（TG）、高密度脂蛋白（HDL）胆固醇和低密度脂蛋白（LDL）胆固醇，并比较这两种基因型之间的所有这些参数。此外，还检测了食管黏膜中包括白细胞介素（IL）-1β、IL-6、IL-17、干扰素（IFN）-γ、角质形成细胞衍生细胞因子（KC）、巨噬细胞炎性蛋白（MIP）-1α、MIP-2和肿瘤坏死因子（TNF）-α在内的8种细胞因子的mRNA表达。
4-NQO处理在TSOD小鼠和TSNO小鼠的舌和食管中均产生了增殖性鳞状细胞病变（发育异常、乳头状瘤和癌）。TSOD小鼠舌肿瘤的发生率和多发率分别为30%和0.45±0.83，TSNO小鼠分别为30%和0.40±0.68。TSOD小鼠食管肿瘤的发生率和多发率分别为70%和2.25±2.29，TSNO小鼠分别为 30%和0.60±1.14（P<0.01）。
我们的研究结果表明，肥胖和糖尿病的TSOD小鼠对4-NQO诱导的食管癌发生敏感，提示肥胖和糖尿病是食管鳞状细胞癌的危险因素。此外，TSOD小鼠可用作食管癌致癌模型。我们的研究首次报道了4-NQO可诱导小鼠发生食管癌。
