Oral cancer causes significant global mortality and has a five‐year survival rate of around 64%. Poor prognosis results from late‐stage diagnosis, highlighting an important need to develop better approaches to detect oral premalignant lesions (OPLs) and identify which OPLs are at highest risk of progression to oral squamous cell carcinoma (OSCC). An appropriate animal model that reflects the genetic, histologic, immunologic, molecular and gross visual features of human OSCC would aid in the development and evaluation of early detection and risk assessment strategies. Here, we present an experimental PIK3CA + 4NQO transgenic mouse model of oral carcinogenesis that combines the PIK3CA oncogene mutation with oral exposure to the chemical carcinogen 4NQO, an alternate experimental transgenic mouse model with PIK3CA as well as E6 and E7 mutations, and an existing wild‐type mouse model based on oral exposure to 4NQO alone. We compare changes in dorsal and ventral tongue gross visual appearance, histologic features and molecular biomarker expression over a time course of carcinogenesis. Both transgenic models exhibit cytological and architectural features of dysplasia that mimic human disease and exhibit slightly increased staining for Ki‐67, a cell proliferation marker. The PIK3CA + 4NQO model additionally exhibits consistent lymphocytic infiltration, presents with prominent dorsal and ventral tongue tumours, and develops cancer quickly relative to the other models. Thus, the PIK3CA + 4NQO model recapitulates the multistep genetic model of human oral carcinogenesis and host immune response in carcinogen‐induced tongue cancer, making it a useful resource for future OSCC studies.

中文翻译：

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具有化学致癌物暴露的PIK3CA转基因小鼠模型模拟了人类口腔舌癌的发生。

口腔癌会导致严重的全球性死亡，并且五年生存率约为64％。晚期诊断会导致预后不良，这凸显了开发更好的方法来检测口腔癌前病变（OPL）并确定哪些OPL发生口腔鳞状细胞癌（OSCC）风险最高的重要需求。反映人类OSCC的遗传，组织学，免疫学，分子和总体视觉特征的适当动物模型将有助于早期检测和风险评估策略的开发和评估。在这里，我们介绍了一个实验性PIK3CA + 4NQO口腔癌发生的转基因小鼠模型，将PIK3CA致癌基因突变与口服暴露于化学致癌物4NQO结合，具有PIK3CA以及E6和E7突变的替代实验转基因小鼠模型，以及基于口服暴露于以下物质的现有野生型小鼠模型仅4NQO。我们比较了在一段时间的致癌过程中背侧和腹侧舌头总体视觉外观，组织学特征和分子生物标志物表达的变化。两种转基因模型均具有模仿人类疾病的不典型增生的细胞学和结构特征，并且对细胞增殖标志物Ki-67的染色略有增加。PIK3CA + 4NQO模型还表现出一致的淋巴细胞浸润，表现出明显的背侧和腹侧舌肿瘤，并相对于其他模型迅速发展为癌症。因此，PIK3CA + 4NQO模型概括了人类口腔致癌和宿主免疫应答在致癌物诱发的舌癌中的多步骤遗传模型，使其成为未来OSCC研究的有用资源。