循环肿瘤细胞的检测及其在鼻咽癌中的研究进展

doi:10.12114/j.issn.1007-9572.2020.00.151

摘要/Abstract

摘要： 循环肿瘤细胞（CTCs）是指从原发肿瘤或转移灶中脱落进入机体循环系统的肿瘤细胞，与肿瘤的复发、转移密切相关。CTCs作为一种新型的生物标志物，其在乳腺癌、前列腺癌、结直肠癌等多种类型肿瘤的早期诊断、疗效评价及预后评估等方面的作用已得到了证实。近年来，CTCs在鼻咽癌的相关研究中也取得了一定的进展。本文就CTCs的特性、检测方法及其在鼻咽癌中的研究进展做一综述，以为CTCs的临床应用提供参考。

关键词: 肿瘤细胞, 循环；特性；检测；鼻咽肿瘤；综述

Abstract: Circulating tumor cells （CTCs） refer to tumor cells that have shed into the circulatory system from primary tumors or metastases，which are closely related to tumor recurrence and metastasis.CTCs，emerging as novel tumor biomarkers，whose value has been confirmed in the early diagnosis，efficacy evaluation and prognosis evaluation of various types of tumors，such as breast cancer，prostate cancer and colorectal cancer.In recent years，CTCs have also been studied in nasopharyngeal carcinoma.This review mainly focuses on CTCs' characteristics，detection and the research progress in nasopharyngeal carcinoma，aiming to give a reference for clinical application of CTCs.

Key words: Neoplasstic cells, circulating；Characteristics；Detection；Nasopharyngeal neoplasms；Review

曾蕾,杨凯旋. 循环肿瘤细胞的检测及其在鼻咽癌中的研究进展[J]. 中国全科医学, 2021, 24(8): 1022-1027. DOI: 10.12114/j.issn.1007-9572.2020.00.151.
ZENG Lei,YANG Kaixuan. Circulating Tumor Cells Detection and Progress in Nasopharyngeal Carcinoma　[J]. Chinese General Practice, 2021, 24(8): 1022-1027. DOI: 10.12114/j.issn.1007-9572.2020.00.151.

参考文献

［1］ASHWORTH T R.A case of cancer in which cells similar to those in the tumours were seen in the blood after death［J］．Aus Med J，1869，14：146-147.
［2］FORTE V A，BARRAK D K，ELHODAKY M，et al．The potential for liquid biopsies in the precision medical treatment of breast cancer［J］．Cancer Biol Med，2016，13（1）：19-40．DOI：10.28092/j.issn.2095-3941.2016.0007.
［3］TAMMINGA M，GROEN H H，HILTERMANN T J.Investigating CTCs in NSCLC-a reaction to the study of Jia-Wei Wan：a preliminary study on the relationship between circulating tumor cells count and clinical features in patients with non-small cell lung cancer［J］．J Thorac Dis，2016，8（6）：1032-1036．DOI：10.21037/jtd.2016.04.17.
［4］WILBAUX M，TOD M，DE BONO J，et al．A joint model for the kinetics of CTC count and PSA concentration during treatment in metastatic castration-resistant prostate cancer［J］．CPT Pharmacometrics Syst Pharmacol，2015，4（5）：277-285．DOI：10.1002/psp4.34.
［5］COHEN S J，PUNT C J，IANNOTTI N，et al．Relationship of circulating tumor cells to tumor response，progression-free survival，and overall survival in patients with metastatic colorectal cancer［J］．J Clin Oncol，2008，26（19）：3213-3221．DOI：10.1200/JCO.2007.15.8923.
［6］HONG B，ZU Y L.Detecting circulating tumor cells：current challenges and new trends［J］．Theranostics，2013，3（6）：377-394．DOI：10.7150/thno.5195.
［7］KHOO B L，GRENCI G，JING T Y，et al．Liquid biopsy and therapeutic response：circulating tumor cell cultures for evaluation of anticancer treatment［J］．Sci Adv，2016，2（7）：e1600274．DOI：10.1126/sciadv.1600274.
［8］LU S H，TSAI W S，CHANG Y H，et al．Identifying cancer origin using circulating tumor cells［J］．Cancer Biol Ther，2016，17（4）：430-438．DOI：10.1080/15384047.2016.1141839.
［9］HüSEMANN Y，GEIGL J B，SCHUBERT F，et al．Systemic spread is an early step in breast cancer［J］．Cancer Cell，2008，13（1）：58-68．DOI：10.1016/j.ccr.2007.12.003.
［10］COMAN D R，DELONG R P，MCCUTCHEON M.Studies on the mechanisms of metastasis；the distribution of tumors in various organs in relation to the distribution of arterial emboli［J］．Cancer Res，1951，11（8）：648-651.
［11］安成，程实，王涛，等．循环肿瘤细胞生物物理特性的研究［J］．检验医学与临床，2016，13（9）：1280-1283．DOI：10.3969/j.issn.1672-9455.2016.09.053.http://www.cnki.com.cn/article/cjfdtotal-jyyl201609054.htm.
［12］ALLARD W J，MATERA J，MILLER M C，et al．Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases［J］．Clin Cancer Res，2004，10（20）：6897-6904．DOI：10.1158/1078-0432.CCR-04-0378.
［13］PANTEL K，DENèVE E，NOCCA D，et al．Circulating epithelial cells in patients with benign colon diseases［J］．Clin Chem，2012，58（5）：936-940．DOI：10.1373/clinchem.2011.175570.
［14］CAULEY C E，PITMAN M B，ZHOU J H，et al．Circulating epithelial cells in patients with pancreatic lesions：clinical and pathologic findings［J］．J Am Coll Surg，2015，221（3）：699-707．DOI：10.1016/j.jamcollsurg.2015.05.014.
［15］CRISAN D，RUARK D S，DECKER D A，et al．Detection of circulating epithelial cells after surgery for benign breast disease［J］．Mol Diagn，2000，5（1）：33-38．DOI：10.1007/bf03262020.
［16］FRANKEN B，DE GROOT M R，MASTBOOM W J，et al．Circulating tumor cells，disease recurrence and survival in newly diagnosed breast cancer［J］．Breast Cancer Res，2012，14（5）：R133．DOI：10.1186/bcr3333.
［17］HANAHAN D，WEINBERG R A.Hallmarks of cancer：the next generation［J］．Cell，2011，144（5）：646-674．DOI：10.1016/j.cell.2011.02.013.
［18］THIERY J P，ACLOQUE H，HUANG R Y J，et al．Epithelial-mesenchymal transitions in development and disease［J］．Cell，2009，139（5）：871-890．DOI：10.1016/j.cell.2009.11.007.
［19］SABBAH M，EMAMI S，REDEUILH G，et al．Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers［J］．Drug Resist Updat，2008，11（4/5）：123-151．DOI：10.1016/j.drup.2008.07.001.
［20］POLYAK K，WEINBERG R A.Transitions between epithelial and mesenchymal states：acquisition of malignant and stem cell traits［J］．Nat Rev Cancer，2009，9（4）：265-273．DOI：10.1038/nrc2620.
［21］TALBOT L J，BHATTACHARYA S D，KUO P C.Epithelial-mesenchymal transition，the tumor microenvironment，and metastatic behavior of epithelial malignancies［J］．Int J Biochem Mol Biol，2012，3（2）：117-136.
［22］LIU X，YUN F，SHI L，et al．Roles of signaling pathways in the epithelial-mesenchymal transition in cancer［J］．Asian Pac J Cancer Prev，2015，16（15）：6201-6206．DOI：10.7314/apjcp.2015.16.15.6201.
［23］SAITOH M.Epithelial-mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-β signaling during tumor progression［J］．Cancer Sci，2015，106（5）：481-488．DOI：10.1111/cas.12630.
［24］PANTEL K，SPEICHER M R.The biology of circulating tumor cells［J］．Oncogene，2016，35（10）：1216-1224．DOI：10.1038/onc.2015.192.
［25］BALASUBRAMANIAN P，LANG J C，JATANA K R，et al．Multiparameter analysis，including EMT markers，on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck［J］．PLoS One，2012，7（7）：e42048．DOI：10.1371/journal.pone.0042048.
［26］GROVER P K，CUMMINS A G，PRICE T J，et al．Circulating tumour cells：the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research［J］．Ann Oncol，2014，25（8）：1506-1516．DOI：10.1093/annonc/mdu018.
［27］GASCH C，OLDOPP T，MAUERMANN O，et al．Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2-negative metastatic breast cancer［J］．Mol Oncol，2016，10（8）：1330-1343．DOI：10.1016/j.molonc.2016.07.005.
［28］ORTIZ V，YU M.Analyzing circulating tumor cells one at a time［J］．Trends Cell Biol，2018，28（10）：764-775．DOI：10.1016/j.tcb.2018.05.004.
［29］FARACE F，MASSARD C，VIMOND N，et al．A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas［J］．Br J Cancer，2011，105（6）：847-853．DOI：10.1038/bjc.2011.294.
［30］JACOB K，SOLLIER C，JABADO N.Circulating tumor cells：detection，molecular profiling and future prospects［J］．Expert Rev Proteomics，2007，4（6）：741-756．DOI：10.1586/14789450.4.6.741.
［31］BHUVANENDRAN NAIR GOURIKUTTY S，CHANG C P，PUIU P D.Microfluidic immunomagnetic cell separation from whole blood［J］．J Chromatogr B Analyt Technol Biomed Life Sci，2016，1011：77-88．DOI：10.1016/j.jchromb.2015.12.016.
［32］CRISTOFANILLI M.Circulating tumor cells，disease progression，and survival in metastatic breast cancer［J］．Semin Oncol，2006，33（3 Suppl 9）：S9-14．DOI：10.1053/j.seminoncol.2006.03.016.
［33］DE BONO J S，SCHER H I，MONTGOMERY R B，et al．Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer［J］．Clin Cancer Res，2008，14（19）：6302-6309．DOI：10.1158/1078-0432.CCR-08-0872.
［34］ALIX-PANABIèRES C，PANTEL K.Technologies for detection of circulating tumor cells：facts and vision［J］．Lab Chip，2014，14（1）：57-62．DOI：10.1039/c3lc50644d.
［35］NAGRATH S，SEQUIST L V，MAHESWARAN S，et al．Isolation of rare circulating tumour cells in cancer patients by microchip technology［J］．Nature，2007，450（7173）：1235-1239．DOI：10.1038/nature06385.
［36］SEQUIST L V，NAGRATH S，TONER M，et al．The CTC-chip：an exciting new tool to detect circulating tumor cells in lung cancer patients［J］．J Thorac Oncol，2009，4（3）：281-283．DOI：10.1097/JTO.0b013e3181989565.
［37］SAUCEDO-ZENI N，MEWES S，NIESTROJ R，et al．A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire［J］．Int J Oncol，2012，41（4）：1241-1250．DOI：10.3892/ijo.2012.1557.
［38］GORGES T M，PENKALLA N，SCHALK T，et al．Enumeration and molecular characterization of tumor cells in lung cancer patients using a novel in vivo device for capturing circulating tumor cells［J］．Clin Cancer Res，2016，22（9）：2197-2206．DOI：10.1158/1078-0432.CCR-15-1416.
［39］THEIL G，FISCHER K，WEBER E，et al．The use of a new CellCollector to isolate circulating tumor cells from the blood of patients with different stages of prostate cancer and clinical outcomes—a proof-of-concept study［J］．PLoS One，2016，11（8）：e0158354．DOI：10.1371/journal.pone.0158354.
［40］PAOLETTI C，HAYES D F.Circulating tumor cells［J］．Adv Exp Med Biol，2016，882：235-258．DOI：10.1007/978-3-319-22909-6_10.
［41］RAWAL S，YANG Y P，COTE R，et al．Identification and quantitation of circulating tumor cells［J］．Annu Rev Anal Chem （Palo Alto Calif），2017，10（1）：321-343．DOI：10.1146/annurev-anchem-061516-045405.
［42］MARRINUCCI D，BETHEL K，KOLATKAR A，et al．Fluid biopsy in patients with metastatic prostate，pancreatic and breast cancers［J］．Phys Biol，2012，9（1）：016003．DOI：10.1088/1478-3975/9/1/016003.
［43］XENIDIS N，IGNATIADIS M，APOSTOLAKI S，et al．Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer［J］．J Clin Oncol，2009，27（13）：2177-2184．DOI：10.1200/JCO.2008.18.0497.
［44］STATHOPOULOU A，VLACHONIKOLIS I，MAVROUDIS D，et al．Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer：evaluation of their prognostic significance［J］．J Clin Oncol，2002，20（16）：3404-3412．DOI：10.1200/JCO.2002.08.135.
［45］IGNATIADIS M，XENIDIS N，PERRAKI M，et al．Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer［J］．J Clin Oncol，2007，25（33）：5194-5202．DOI：10.1200/JCO.2007.11.7762.
［46］ANDREOPOULOU E，YANG L Y，RANGEL K M，et al．Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer：AdnaGen AdnaTest BreastCancer Select/DetectTM versus Veridex CellSearchTM system［J］．Int J Cancer，2012，130（7）：1590-1597．DOI：10.1002/ijc.26111.
［47］ZONG Y S，SHAM J S，NG M H，et al．Immunoglobulin A against viral capsid antigen of Epstein-Barr virus and indirect mirror examination of the nasopharynx in the detection of asymptomatic nasopharyngeal carcinoma［J］．Cancer，1992，69（1）：3-7.
［48］CHEN C，SHEN L J，LI B F，et al．Smoking is a poor prognostic factor for male nasopharyngeal carcinoma treated with radiotherapy［J］．Radiother Oncol，2014，110（3）：409-415．DOI：10.1016/j.radonc.2013.08.003.
［49］SOUSA H，MESQUITA L，RIBEIRO J，et al．Polymorphisms in host immune response associated genes and risk of nasopharyngeal carcinoma development in Portugal［J］．Immunobiology，2016，221（2）：145-152．DOI：10.1016/j.imbio.2015.09.015.
［50］SUN Y，LI W F，CHEN N Y，et al．Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma：a phase 3，multicentre，randomised controlled trial［J］．Lancet Oncol，2016，17（11）：1509-1520．DOI：10.1016/S1470-2045（16）30410-7.
［51］SUN X M，SU S F，CHEN C Y，et al．Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma：an analysis of survival and treatment toxicities［J］．Radiother Oncol，2014，110（3）：398-403．DOI：10.1016/j.radonc.2013.10.020.
［52］ZHANG J，SHI H S，JIANG T T，et al．Circulating tumor cells with karyotyping as a novel biomarker for diagnosis and treatment of nasopharyngeal carcinoma［J］．BMC Cancer，2018，18（1）：1133．DOI：10.1186/s12885-018-5034-x.
［53］GREENE F L，EDGE S，SCHILSKY R L.Ajcc cancer staging manual［M］．8th ed.New York：Springer，2017：53.
［54］LI F，LIU J Y，SONG D，et al．Circulating tumor cells in the blood of poorly differentiated nasal squamous cell carcinoma patients：correlation with treatment response［J］．Acta Otolaryngol，2016，136（11）：1164-1167．DOI：10.1080/00016489.2016.1201861.
［55］HE C Y，HUANG X J，SU X，et al．The association between circulating tumor cells and Epstein-Barr virus activation in patients with nasopharyngeal carcinoma［J］．Cancer Biol Ther，2017，18（11）：888-894．DOI：10.1080/15384047.2017.1281493.
［56］伍勇，翁成荫，方喜生，等．循环肿瘤细胞与鼻咽癌临床病理参数的相关性研究［J］．中国医药科学，2015，9：17-19，98.
WU Y，WENG C Y，FANG X S，et al．Correlation of circulating tumor cells with clinicopathological parameters in patients with nasopharyngeal carcinoma［J］．China Medicine and Pharmacy，2015，9：17-19，98.
［57］吴君心，贺俊彦，杜开新，等．鼻咽癌患者外周血循环肿瘤细胞的检测及其与预后的相关性［J］．现代肿瘤医学，2017，25（7）：1035-1039．DOI：10.3969/j.issn.1672-4992.2017.07.010.
WU J X，HE J Y，DU K X，et al．Detection of circulating tumor cells in peripheral blood of patients with nasopharyngeal carcinoma and evaluate its prognostic value［J］．Journal of Modern Oncology，2017，25（7）：1035-1039．DOI：10.3969/j.issn.1672-4992.2017.07.010.
［58］SI Y F，LAN G P，DENG Z X，et al．Distribution and clinical significance of circulating tumor cells in nasopharyngeal carcinoma［J］．Jpn J Clin Oncol，2016，46（7）：622-630．DOI：10.1093/jjco/hyw046.
［59］EGEBLAD M，WERB Z.New functions for the matrix metalloproteinases in cancer progression［J］．Nat Rev Cancer，2002，2（3）：161-174．DOI：10.1038/nrc745.
［60］VIZOSO F J，GONZáLEZ L O，CORTE M D，et al．Study of matrix metalloproteinases and their inhibitors in breast cancer［J］．Br J Cancer，2007，96（6）：903-911．DOI：10.1038/sj.bjc.6603666.
［61］ZHOU D N，DENG Y F，LI R H，et al．Concurrent alterations of RAGE，RECK，and MMP9 protein expression are relevant to Epstein-Barr virus infection，metastasis，and survival in nasopharyngeal carcinoma［J］．Int J Clin Exp Pathol，2014，7（6）：3245-3254.
［62］LIU Z，LI L X，YANG Z X，et al．Increased expression of MMP9 is correlated with poor prognosis of nasopharyngeal carcinoma［J］．BMC Cancer，2010，10：270．DOI：10.1186/1471-2407-10-270.
［63］YOU R，LIU Y P，LIN M，et al．Relationship of circulating tumor cells and Epstein-Barr virus DNA to progression-free survival and overall survival in metastatic nasopharyngeal carcinoma patients［J］．Int J Cancer，2019，145（10）：2873-2883．DOI：10.1002/ijc.32380.

[1]	张孝钦，陈玄一，邬盛昌. 循环肿瘤细胞在晚期非小细胞肺癌化疗疗效监测及预后预测中的价值研究[J]. 中国全科医学, 2020, 23(2): 183-188.
[2]	李哲，刘风玲. 循环肿瘤细胞预测早期膀胱癌肿瘤微转移研究进展[J]. 中国全科医学, 2015, 18(6): 711-713.