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中华腔镜泌尿外科杂志(电子版) ›› 2025, Vol. 19 ›› Issue (06) : 705 -713. doi: 10.3877/cma.j.issn.1674-3253.2025.06.004

专家论坛

循环肿瘤细胞在膀胱癌诊断和预后中的应用进展
李瑞芳1,2,3,4, 王明帅3, 邢念增1,2,3,4,†()   
  1. 1030001　太原，山西医科大学生化教研室
    2030013　太原，山西省肿瘤医院/中国医学科学院肿瘤医院山西医院/山西医科大学附属肿瘤医院泌尿外科
    3100021　北京，国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院泌尿外科
    4100021　北京，中国医学科学院肿瘤医院分子肿瘤学国家重点实验室
  • 收稿日期:2025-02-28 出版日期:2025-12-01
  • 通信作者: 邢念增
  • 基金资助:
    国家重点研发计划(2023YFC2507000)

Advances in the application of circulating tumor cells in the diagnosis and prognosis of bladder cancer

Ruifang Li1,2,3,4, Mingshuai Wang3, Nianzeng Xing1,2,3,4,†()   

  1. 1Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
    2Department of Urology, Shanxi Cancer Hospital/Chinese Academy of Medical Sciences Cancer Hospital Shanxi Hospital/Shanxi Medical University Affiliated Cancer Hospital, Taiyuan 030013, China
    3National Cancer Center/National Cancer Clinical Medical Research Center/ Department of Urology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China
    4State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China
  • Received:2025-02-28 Published:2025-12-01
  • Corresponding author: Nianzeng Xing
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李瑞芳, 王明帅, 邢念增. 循环肿瘤细胞在膀胱癌诊断和预后中的应用进展[J/OL]. 中华腔镜泌尿外科杂志(电子版), 2025, 19(06): 705-713.

Ruifang Li, Mingshuai Wang, Nianzeng Xing. Advances in the application of circulating tumor cells in the diagnosis and prognosis of bladder cancer[J/OL]. Chinese Journal of Endourology(Electronic Edition), 2025, 19(06): 705-713.

膀胱癌是我国最常见的泌尿系肿瘤之一，通常以膀胱镜检查和组织活检作为诊断和随访的金标准。但膀胱镜检查具有侵入性且费用昂贵，导致患者依从性差，难以广泛用于常规筛查。循环肿瘤细胞（CTC）作为液体活检的一部分，因其操作无创、简便且成本相对较低的特点，在肿瘤早期诊断、预后评估以及个体化治疗等方面均有着较为广泛的运用。与其他液体活检方法相比，CTC保留了完整的细胞信息，对膀胱尿路上皮癌患者的预后和疗效预测具有潜在的临床价值。本文系统综述了CTC富集和检测技术，探讨其在膀胱癌诊断和治疗中的临床应用，并根据目前的研究进展提出了CTC技术未来发展的前景和挑战。

关键词: 循环肿瘤细胞, 液体活检, 尿路上皮癌, 膀胱癌, 精准医学, 生物标志物, 个体化治疗

Bladder cancer (BC) is one of the most common genitourinary tumors in China, traditionally diagnosed and monitored through cystoscopy and tissue biopsy, which are considered as the gold standard. However, the invasive nature and high cost of cystoscopy often lead to poor patient compliance, limiting its utility in routine screening. Circulating tumor cells (CTCs), a promising liquid biopsy approach, offer the advantages of being non-invasive, convenient, and cost-effective, with broad applications in early cancer diagnosis, prognostic evaluation, and personalized treatment. Compared to other liquid biopsy methods, CTCs preserve intact cellular information, which holds potential clinical value for predicting prognosis and therapeutic efficacy in patients with bladder urothelial carcinoma. This review systematically summarizes the enrichment and detection techniques of CTCs, explores their clinical applications in the diagnosis and treatment of bladder cancer, and discusses the future prospects and challenges of CTC technology in light of recent research advances.

Key words: Circulating tumor cells, Liquid biopsy, Urothelial carcinoma, Bladder cancer, Precision medicine, Biomarker, Personalized therapy
表1 循环肿瘤细胞（CTC）发展简史
参考文献 事件
Galvis等[2] 1869年，澳大利亚Thomas Ashworth在做解剖实验时发现CTC
Fidler等[3] 1889年，英国外科医师Steven Paget提出"种子与土壤"假设
Jaiswal[6] 1968年，美国Elizabeth Hay在鸡胚胎原条发育形成的研究中正式提出上皮间充质转化的概念
Balmain等[7]和Terranova等[8] 1976年，美国Peter Nowell提出肿瘤学中的经典理论即克隆演化理论完善CTC的概念
Rushton等[9] 2004年，美国食品和药品监督管理局通过"CellSearch技术在乳腺癌预后检测"的应用
Heitzer等[10] 2013年，利用单细胞测序技术发现CTC与原发或转移肿瘤组织存在相同的基因变异谱，为CTC作为"液体活检"技术奠定基础
中国临床肿瘤学会[11] 2019年，中国临床肿瘤学会（CSCO）将CTC纳入临床指南
图1 使用TUMORFISHER技术捕获循环肿瘤细胞（CTC）并进行荧光染色注：图a~c为三种不同CKmix荧光强度（低、中、高）的阳性CTC；图d为白细胞对照组；定义具有细胞核（由阳性DAPI确定）包含在细胞质内（由阳性细胞角蛋白7，18，20-异硫氰酸荧光素染色确定）表达、缺乏CD45表达（由阴性CD45-别藻蓝蛋白染色确定）为阳性CTC
表2 膀胱癌中主要循环肿瘤细胞（CTC）检测与分离技术及其应用
参考文献 CTC富集类型 CTC富集技术 CTC检测技术 临床目的 患者数量 优势 不足
Rink等[19] 阳性富集 CellSearch® ICC 预测预后 100例基层浸润性膀胱癌 分析全面 组间差异较大
Naoe等[23] 阳性富集 CellSearch® ICC 辅助治疗，识别转移 12例非转移性尿路上皮癌和14例转移性尿路上皮癌 分析全面 灵敏度中等
Busetto等[24] 阳性富集 CellSearch®、CELLection Dynabeads ICC、RT-PCR 预测复发、进展 155例非基层浸润性膀胱癌 分析全面 对比维度有限
Nicolazzo等[25] 阳性富集 CellSearch® ICC 预测预后 102例非基层浸润性膀胱癌 高灵敏度 缺乏随访数据
Niu等[26] 阳性富集 Graphene oxide (GO) microfluidic chip ICC、RNA-Seq 识别肿瘤相关RNA特征对转移性膀胱癌的预后预测潜力 15例膀胱癌 多维分析高灵敏度 样本数少，价格昂贵
Karl等[27] 阳性富集 CellSearch® ICC 评估疾病状态，监测化疗反应 5例膀胱癌 自动化 样本数少，观察时间短
Okegawa等[28] 阳性富集 CellSearch® ICC 预后评估，疾病监测 16例非转移性尿路上皮癌和20例转移性尿路上皮癌 分析全面 灵敏度中等
Rink等[29] 阳性富集 CellSearch® ICC 预测预后 48例非转移性晚期膀胱癌和5例转移性晚期膀胱癌 高灵敏度 缺乏多变量分析
Abrahamsson等[30] 阳性富集 CellSearch® ICC 检测早期转移，预测预后 88例膀胱尿路上皮癌 分析全面 缺乏随访数据
Krupa等[31] 阳性富集 Epic Science ICC 预测治疗反应，监测治疗效果 33例膀胱癌，肾癌，前列腺癌 高灵敏度 样本数少
Liu等[32] 阴性富集 SE-iFISH FISH 预测预后，结合Ki67评估预后风险 84例膀胱癌 多维度分析 灵敏度中等
Yang等[33] 阴性富集 SE-iFISH FISH 预测预后 196例膀胱癌 分析全面 稳定性不足
表3 不同生物标志物在膀胱癌CTC检测中的临床应用
参考文献 CTC富集技术 CTC分离和检测技术 检测分子标志物 患者数量（阳性率） 临床意义
Rink等[19] CellSearch® FISH HER2 100例≥1个CTC(23%) 未明确指出标志物意义
Krupa等[31] Epic Sciences ICC pan-CK、DAPI、CD45、PD-L1 33例≥1个CTC(73%) 未明确指出标志物意义
Jin等[34] CellCollector® ICC CK、DAPI、CD45、PD-L1 216例> 2个CTC(23%) 与肿瘤大小、分期、分级均相关(P<0.01)，其他标志物与肿瘤组织PD-L1表达相关(P=0.01)
Anantharaman等[35] Epic Science IF、FISH、CNV PD-L1、CK 25例≥1个CTC(80%) 高PD-L1加CTC负荷的患者中位OS较短
Bergmann等[36] CellSearch® ICC PD-L1、vimentin 49例≥1个CTC(32.7%) CTC与更差的OS显著相关(P<0.001)
Suh等[37] CytoGen ICC PD-L1、EpCAM、vimentin、CK 25例 PD-L1表达状态可以在CTC水平上分析的可能性
Bergmann等[38] CellSearch®
CTC-Kit、CXC-Kit		 ICC CK、DAPI、CD45、PD-L1 93例M0≥1个CTC(22.6%)
33例M1≥1个CTC(51.5%)		 未明确指出标志物意义
Nini等[39] CellSearch® PCR HER2 13例≥1个CTC(46.1%) 建立联合检测的技术改善循环肿瘤细胞识别
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