文章：

在舌癌发生与化学预防模型中诱导性敲除TgfbR1和Pten

Inducible TgfbR1 and Pten deletion in a model of tongue carcinogenesis and chemoprevention 

原文发布日期：2023-05-25 

英文摘要：

Head and neck squamous cell carcinoma (HNSCC) is a significant public health problem, with a need for novel approaches to chemoprevention and treatment. Preclinical models that recapitulate molecular alterations that occur in clinical HNSCC patients are needed to better understand molecular and immune mechanisms of HNSCC carcinogenesis, chemoprevention, and efficacy of treatment. We optimized a mouse model of tongue carcinogenesis with discrete quantifiable tumors via conditional deletion of Tgfβr1 and Pten by intralingual injection of tamoxifen. We characterized the localized immune tumor microenvironment, metastasis, systemic immune responses, associated with tongue tumor development. We further determined the efficacy of tongue cancer chemoprevention using dietary administration of black raspberries (BRB). Three Intralingual injections of 500 µg tamoxifen to transgenic K14 Cre, floxed Tgfbr1, Pten (2cKO) knockout mice resulted in tongue tumors with histological and molecular profiles, and lymph node metastasis similar to clinical HNSCC tumors. Bcl2, Bcl-xl, Egfr, Ki-67, and Mmp9, were significantly upregulated in tongue tumors compared to surrounding epithelial tissue. CD4+ and CD8 + T cells in tumor-draining lymph nodes and tumors displayed increased surface CTLA-4 expression, suggestive of impaired T-cell activation and enhanced regulatory T-cell activity. BRB administration resulted in reduced tumor growth, enhanced T-cell infiltration to the tongue tumor microenvironment and robust antitumoral CD8+ cytotoxic T-cell activity characterized by greater granzyme B and perforin expression. Our results demonstrate that intralingual injection of tamoxifen in Tgfβr1/Pten 2cKO mice results in discrete quantifiable tumors suitable for chemoprevention and therapy of experimental HNSCC. 

摘要翻译： 

头颈部鳞状细胞癌（HNSCC）是一个重大的公共卫生问题，亟需创新的化学预防和治疗方法。为更好地理解HNSCC致癌作用的分子与免疫机制、化学预防及治疗疗效，需要能重现临床HNSCC患者分子改变特征的临床前模型。我们通过他莫昔芬舌内注射条件性敲除Tgfβr1和Pten，优化了具有可量化离散肿瘤的舌癌小鼠模型，并系统阐述了舌肿瘤发展过程中的局部免疫肿瘤微环境、转移特征、全身免疫应答变化。我们进一步通过膳食补充黑树莓（BRB）评估了舌癌化学预防效果。对转基因K14 Cre、Tgfbr1和Pten双条件性敲除（2cKO）小鼠进行三次500μg他莫昔芬舌内注射后，产生的舌肿瘤在组织学特征、分子表达谱及淋巴结转移方面与临床HNSCC肿瘤高度相似。与周围上皮组织相比，舌肿瘤中Bcl2、Bcl-xl、Egfr、Ki-67和Mmp9显著上调。肿瘤引流淋巴结和肿瘤中的CD4+、CD8+T细胞表面CTLA-4表达增加，提示T细胞活化受损且调节性T细胞活性增强。黑树莓干预显著抑制了肿瘤生长，增强了舌肿瘤微环境中T细胞浸润，并诱导了以颗粒酶B和穿孔素高表达为特征的强效抗肿瘤CD8+细胞毒性T细胞活性。本研究证实，通过舌内注射他莫昔芬在Tgfβr1/Pten双敲除小鼠中诱导的可量化离散肿瘤模型，适用于实验性HNSCC的化学预防和治疗研究。

原文链接：

Inducible TgfbR1 and Pten deletion in a model of tongue carcinogenesis and chemoprevention