Oral cavity and esophageal carcinogenesis modeled in carcinogen-treated mice
Oral cavity and esophageal carcinogenesis modeled in carcinogen-treated mice
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DOI：
10.1158/1078-0432.ccr-0999-3
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发表时间：
2004-01-01
影响因子：
11.5
通讯作者：
Gudas, LJ
中科院分区：
文献类型：
--
作者：
Tang, XH;Knudsen, B;Gudas, LJ
目的：口腔鳞状细胞癌是最常见的人类肿瘤之一，预防这些癌症需要更好地了解致癌过程和模型系统，其中癌症化学预防剂可以进行测试。我们建立了一个小鼠模型，使用致癌物4-硝基喹啉1-氧化物（4-NQO）在饮用水中，以诱导肿瘤发生在小鼠口腔中，实验设计：4-NQO通过舌涂或饮用水提供给两个小鼠品系，CBA和C57 B1/6。比较两组口腔癌的发生率。结果：4-NQO染毒后，CBA和C57 B1/6雌性小鼠舌部均出现巨大的肿瘤。病理学分析表明，扁平鳞状发育不良，外生性乳头状鳞状肿瘤（乳头状瘤），浸润性鳞状细胞癌。免疫组织化学分析表明，4-NQO改变了中间丝蛋白K14和K1的表达模式。K14表达在上皮基底上层，除了基底层，在舌头从致癌剂治疗的动物。与此相反，对照组动物仅在基底层表达K14。此外，我们观察到更多的溴脱氧尿苷染色的舌上皮细胞的4-NQO治疗的小鼠。观察到细胞周期抑制剂p16的表达减少，而4-NQO治疗引起小鼠舌中表皮生长因子受体表达增加。有趣的是，在4-NQO处理的小鼠的食管中也观察到类似的致癌特征，包括多个大的（高达0.5 cm）外生性乳头状鳞状肿瘤和浸润性鳞状细胞癌，溴脱氧尿苷染色增加和K14表达增加。然而，在4-NQO处理小鼠的消化道其余部分（包括前胃、肠和结肠）或肺或肝中未观察到肿瘤。这些结果表明，这种小鼠4-NQO诱导的口腔和食管癌模型模拟人口腔和食管cancerogenication.Conclusions的许多方面：这种小鼠模型的可用性应允许在各种突变和转基因小鼠品系的口腔和食管癌的发展分析。该模型还将允许在各种转基因小鼠品系中测试癌症化学预防药物。
Purpose: Squamous cell carcinoma of the oral cavity is one of the most common human neoplasms, and prevention of these carcinomas requires a better understanding of the carcinogenesis process and a model system in which cancer chemoprevention agents can be tested. We have developed a mouse model using the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in the drinking water to induce tumorigenesis in the mouse oral cavity.Experimental Design: 4-NQO was delivered by tongue painting or drinking water to two mouse strains, CBA and C57B1/6. The incidences of oral cavity carcinogenesis were then compared. In addition, we examined the expression of some of the molecular markers associated with the process of human oral cavity and esophageal carcinogenesis, such as keratin (K) 1, K14, p16, and epidermal growth factor receptor, by immunohistochemistry.Results: After treatment with 4-NQO in the drinking water, massive tumors were observed on the tongues of both CBA and C57B1/6 female mice. Pathological analyses indicated that flat squamous dysplasias, exophytic papillary squamous tumors (papillomas), and invasive squamous cell carcinomas were present. Immunohistochemistry analyses showed that 4-NQO changed the expression patterns of the intermediate filament proteins K14 and K1. K14 was expressed in the epithelial suprabasal layers, in addition to the basal layer, in tongues from carcinogen-treated animals. In contrast, control animals expressed K14 only in the basal layer. Moreover, we observed more bromodeoxyuridine staining in the tongue epithelia of 4-NQO-treated mice. Reduced expression of the cell cycle inhibitor, p16,was observed, whereas 4-NQO treatment caused an increase in epidermal growth factor receptor expression in the mouse tongues. Interestingly, similar features of carcinogenesis, including multiple, large (up to 0.5 cm) exophytic papillary squamous tumors and invasive squamous cell carcinomas, increased bromodeoxyuridine staining, and increased K14 expression, were also observed in the esophagi of 4-NQO-treated mice. However, no tumors were observed in the remainder of digestive tract (including the forestomach, intestine, and colon) or in the lungs or livers of 4-NQO-treated mice. These results indicate that this murine 4-NQO-induced oral and esophageal carcinogenesis model simulates many aspects of human oral cavity and esophageal carcinogenesis.Conclusions: The availability of this mouse model should permit analysis of oral cavity and esophageal cancer development in various mutant and transgenic mouse strains. This model will also allow testing of cancer chemo-preventive drugs in various transgenic mouse strains.