Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer.
Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer.
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DOI：
10.1158/1078-0432.ccr-11-3211
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发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Palena C
中科院分区：
文献类型：
--
作者：
Roselli M;Fernando RI;Guadagni F;Spila A;Alessandroni J;Palmirotta R;Costarelli L;Litzinger M;Hamilton D;Huang B;Tucker J;Tsang KY;Schlom J;Palena C
上皮-间质转化（EMT）是肿瘤进展、转移和耐药的关键因素。T-box转录因子Brachyury最近被鉴定为人类癌细胞中EMT的驱动因子。本研究的目的是表征Brachyury作为肺癌治疗的潜在靶点。采用PCR和免疫组化方法检测Brachyury在人肺肿瘤和成人正常组织中的表达。在具有不同Brachyury表达水平的肿瘤组织中分析Brachyury基因拷贝数和启动子甲基化状态。还相对于Brachyury水平评估了肺癌细胞对T细胞裂解和EGFR激酶抑制的敏感性。我们的研究结果表明，Brachyury蛋白表达在41%的原发性肺癌，包括48%的腺癌和25%的鳞状细胞癌。除正常睾丸和部分甲状腺组织外，本研究中评价的大多数正常组织均为Brachyury蛋白表达阴性。Brachyury特异性T细胞可以裂解Brachyury阳性肿瘤，并且Brachyury的水平对应于肿瘤细胞对EGFR激酶抑制的抗性。我们假设Brachyury阳性肿瘤细胞的消除可能能够预防和/或减少肿瘤扩散和转移的建立。Brachyury特异性T细胞系在体外裂解Brachyury阳性肿瘤细胞的能力支持了用于治疗肺癌的基于Brachyury的免疫治疗方法的开发。
The epithelial-mesenchymal transition (EMT) is emerging as a critical factor for the progression and metastasis of carcinomas, as well as drug resistance. The T-box transcription factor Brachyury has been recently characterized as a driver of EMT in human carcinoma cells. The purpose of this study was to characterize Brachyury as a potential target for lung cancer therapy. The expression of Brachyury was evaluated by PCR and by immunohistochemistry in human lung tumors and adult normal tissues. Brachyury gene copy number and promoter methylation status were analyzed in tumor tissues with various levels of Brachyury expression. Lung carcinoma cells’ susceptibility to T-cell lysis and EGFR kinase inhibition were also evaluated relative to the levels of Brachyury. Our results demonstrated Brachyury protein expression in 41% of primary lung carcinomas, including 48% of adenocarcinomas and 25% of squamous cell carcinomas. With the exception of normal testis and some thyroid tissues, the majority of normal tissues evaluated in this study were negative for the expression of Brachyury protein. Brachyury-specific T cells could lyse Brachyury positive tumors and the level of Brachyury corresponded to resistance of tumor cells to EGFR kinase inhibition. We hypothesize that the elimination of Brachyury-positive tumor cells may be able to prevent and/or diminish tumor dissemination and the establishment of metastases. The ability of Brachyury-specific T-cell lines to lyse Brachyury-positive tumor cells, in vitro, supports the development of Brachyury-based immunotherapeutic approaches for the treatment of lung cancer.