中国学者基于上皮-间质转化对循环肿瘤细胞亚组激素受体状态进行分析
循环肿瘤细胞（CTC）是痕量存在于外周血中的各类肿瘤细胞的统称。大部分CTC在进入外周血后发生凋亡或被吞噬，少数能够逃逸并种植发展成为转移灶，增加肿瘤患者死亡风险。患者体内CTC类型和数量的改变可实时反映患者的肿瘤状态和治疗效果，CTC基因分析结果可用于指导实时个体化治疗。由于只需抽取5～10ml血液，CTC检测方便、无创、无副作用，可以根据需要随时检测。根据国际权威肿瘤研究和治疗机构估计，CTC检测在肿瘤实时监测领域的运用将超越PET-CT等目前昂贵且有辐射危害的医学影像检查，成为肿瘤实时监测的主要手段。
虽然CTC计数已被证明是转移性乳腺癌预后指标，但是CTC的异质性，如在上皮-间质转化（EMT）中的变化，可能限制其广泛临床应用前景。
2016年9月1日，美国《肿瘤标靶》在线发表中国医学科学院北京协和医学院附属肿瘤医院、广州益善生物技术、北京桓兴肿瘤医院的CTC异质性原理验证研究报告，基于上皮-间质转化对CTC亚组激素受体状态进行了分析。
该研究为了调查一个基于CTC异质性潜在效用的简单可行检测方法，从CTC的EMT表型和ER/PR状态角度出发，对28例转移性乳腺癌患者外周血标本进行了分析。根据上皮和间质标记物，采用CanPatrol的CTC富集技术识别不同的CTC亚群，包括上皮为主的CTC、生物表型上皮/间质CTC、间质为主的CTC。
CanPatrol是中国独立研发且拥有完全核心自主知识产权的CTC检测二代技术，结合了纳米技术与多重RNA原位分析技术的优势，无须依赖特定生物标志物，对所有CTC进行分离与分型，是目前国际上唯一能同步实现CTC分离和分型的检测技术，而且分离获得的CTC还可用于全面基因分析，指导肿瘤实时个 体化治疗。CanPatrol技术彻底解决一代技术只能分离一种CTC细胞的致命缺陷，赋予了CTC检测在肿瘤治疗中全新的价值：实时动态监测、实时疗效评估和实时个体化治疗。
此外，根据3个参考基因表达水平确定每个CTC的激素受体（HR）状态，并根据其特征由高水平表达至不表达分为4级。
结果发现，根据EMT表型，不同CTC亚组分级随原发肿瘤HR表达状态而不同。相对于组织和CTC的HR状态，CTC从高水平表达到不表达HR的变化趋势与原发肿瘤HR状态有显著相关性。
因此，该研究结果可能为此简单可行检测方法通过实时方式用于预后分析和个体化内分泌治疗的潜在应用提供依据并被进一步大规模研究证实。
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Oncotarget. 2016 Sep 1. [Epub ahead of print]
Analysis of the hormone receptor status of circulating tumor cell subpopulations based on epithelial-mesenchymal transition: a proof-of-principle study on the heterogeneity of circulating tumor cells.
Guan X, Ma F, Liu S, Wu S, Xiao R, Yuan L, Sun X, Yi Z, Yang H, Xu B.
Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; SurExam Bio-Tech, Guangzhou Technology Innovation Base, Science City, China; Huanxing Cancer Hospital, Beijing, China.
Although the enumeration of circulating tumor cells (CTCs) has been demonstrated to be a prognostic indicator in metastatic breast cancer, the heterogeneous characteristics of CTCs, such as variations in the epithelial-mesenchymal transition (EMT), may limit its broad clinical application. To investigate an uncomplicated and practicable detection approach based on the potential utility of the heterogeneity of CTCs from the standpoint of the EMT phenotype and ER/PR status of CTCs, an analysis was conducted using peripheral blood samples obtained from 28 metastatic breast cancer patients. The CanPatrol CTC enrichment technique was used to identify different CTC subpopulations, including epithelial-dominated CTCs, biophenotypic epithelial/mesenchymal CTCs, and mesenchymal-dominated CTCs, according to epithelial and mesenchymal markers. Furthermore, the hormone receptor (HR) status of each CTC was determined based on the expression levels of three reference genes and was characterized by four levels, which ranged from high-level expression to non-expression. We subsequently concluded that based on EMT phenotypes, the order of different CTC subgroups differed according to the HR expression status of the primary tumor. With respect to the HR status between tissues and CTCs, the variation tendency from high-level expression to non-expression of HR in CTCs was significantly correlated with the HR status of the primary tumor. The findings could provide evidence for the potential application of this uncomplicated and practicable detection approach for prognostic analysis and individualized endocrine therapeutic direction in a real-time manner via confirmation in further large-scale trials.
KEYWORDS: breast cancer; circulating tumor cells; epithelial-mesenchymal transition; hormone receptor; subpopulations
PMID: 27602758
DOI: 10.18632/oncotarget.11787