JTD专栏 JTD Column

肺癌循环肿瘤源性生物标志物

Published at: 2013年第33卷第6期

Klaus Pantel 1 , Harriet Wikman 1 , CatherineAlix-Panabières 2 , AlineTaenzer 1
1 Department of Tumour Biology, Centre of Experimental Medicine, University Cancer Center Hamburg, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
2 University Medical Centre, University Montpellier 1, Saint-Eloi Hospital, Institute of Research in Biotherapy, Laboratory of Rare Human Circulating Cells, Montpellier, France; University Medical Centre, Laboratory of Cell and Hormonal Biology, Arnaud de Villeneuve Hospital, Montpellier, France; University Institute of Clinical Research UM1 - EA2415 - Epidemiology, Biostatistics & Public Health, France
通讯作者 Pantel Klaus Email: pantel@uke.uni-hamburg.de
DOI: 10.3978/j.issn.2095-6959.10.3978/j.issn.2095-6959.
基金:

摘要

美国国立卫生研究院生物标志物定义工作组将生物标志物定义为“一种具有能客观测量同时可用于评价一般生物过程、发病过程或医疗干预相关药物反应的指示物”[1]。大量正在进行的肺癌相关研究致力于探讨用于早期诊断和高风险预测的气道上皮细胞、痰液、呼气、尿液和血液中的生物标志物。在此,着重评述肺癌的循环生物标志物,尤其是循环肿瘤细胞(circulating tumor cells,CTCs)与循环核酸(circulating nucleic acids,CNAs)

关键词: 肺癌

Circulating tumor-derived biomarkers in lung cancer

Abstract

The NIH Biomarkers Definition Working Group defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological responses to a therapeutic intervention” (1). In lung cancer, an enormous research effort is underway related to biomarkers in airway epithelial cells, sputum, breath, urine and blood for early diagnosis or prediction of high risk. Here, we will focus on blood as the source of biomarker research and in particular comment on circulating tumor cells (CTCs) and circulating nucleic acids.

美国国立卫生研究院生物标志物定义工作组将生物标志物定义为“一种具有能客观测量同时可用于评价一般生物过程、发病过程或医疗干预相关药物反应的指示物”[1]。大量正在进行的肺癌相关研究致力于探讨用于早期诊断和高风险预测的气道上皮细胞、痰液、呼气、尿液和血液中的生物标志物。在此,着重评述肺癌的循环生物标志物,尤其是循环肿瘤细胞(circulating tumor cells,CTCs)与循环核酸(circulating nucleic acids,CNAs)。

肿瘤细胞通过血液循环播散是实体肿瘤(包括肺癌)进展的关键环节。小细胞肺癌(small-cell lung cancer,SCLC)在诊断时被认为是全身性疾病,而非小细胞肺癌(non-small cell lung cancer,NSCLC)(如果在早期发现)似乎是局限性疾病,然而其具有向骨髓、大脑和肝等远处器官转移的高度潜力。以往研究[2]表明:在无明显临床或影像学转移表现的NSCLC患者中,采用细胞角蛋白检测骨髓中播散的肿瘤细胞,常可检测到肿瘤细胞转移至骨髓中,甚至在I期患者中亦可检出。

因此,肿瘤细胞血液播散在SCLC 和NSCLC中均属于早期事件。但是骨髓取样是侵入性操作,外周血取样检测肿瘤细胞血液播散更易于操作。血清/血浆样本易于收集,并可在生物样本库中存储多年。

当前使用的高灵敏度的富集和检测方法可以在外周血单细胞水平中检出CTCs[3]。肺癌的CTCs研究大多数采用CellSearch®系统、上皮肿瘤细胞大小分选法(size of epithelial tumour cells,ISET)过滤装置或CTC芯片检测CTCs。CellSearch®系统或CTC芯片都采用上皮细胞特异性黏附分子(epithelial cell adhesion molecule,EpCAM)捕获CTCs[4]。CellSearch®系统在NSCLC 患者中的检出率为23%~85%,其检出率与疾病分期相关,在I和II期患者中,2个CTCs以上的检出率为0~17%[5-6]。总的来说,这个系统在NSCLC中检出CTCs数量较低(如只有25% IV期患者的7.5 mL血标本中检出3个或者更多CTCs),而SCLC患者CTC数量显著较高,60%~86%局限期或广泛期疾病患者的7.5 mL 血标本中检出3个以上CTCs[7-8]。究其原因,有人提出假说,认为NSCLC患者CTCs中有相当多的一部分发生上皮-间质转化(epithelial-mesenchymal transition,EMT),即上皮细胞标志蛋白如EpCAM表达下调。这些发生间质转化的CTCs在以EpCAM为基础的检测技术中(如CellSearch®系统)将不被检出,出现假阴性。因此,在NSCLC患者中,采用非EpCAM为基础的检测技术,CTCs检出率可能会增加。正如上所说,采用ISET过滤技术,I/II期NSCLC患者CTCs检出率约37%,III/IV期患者高达80%以上[9]。另外,ISET过滤装置可捕获到团簇状的CTCs(含有其他细胞类型),即CTC微栓子(CTC microemboli,CTM)[9-10]。CTMs的细胞成分是非均质的,其生物学意义仍然是未来研究的主题。

除CTC分析外,肿瘤源性游离核酸(cell-free nucleic acids,cfNA)的检测/表征,如坏死/凋亡肿瘤细胞和活性肿瘤细胞通过外泌体释放到血液中的DNA和微RNA(microRNA,miR),在过去的几年中也受到大量关注。根据疾病分期,cfNA可来源于原发肿瘤和/或(微)转移,甚或CTCs[11]。cfNA具有肿瘤特异性的基因突变,因此可作为筛查肺癌基因突变的辅助方法[12]。近年来研究表明通过检测cfNA,可提供肺癌靶向治疗基因(如EGF受体)或重要分子转导基因(如KRAS)的突变情况,将来可指导肺癌的靶向治疗[13]

最近,循环miRs(具有多重调节功能的非编码小RNAs)作为一种循环生物标志物受到了关注。在肺癌患者中,与健康人群或良性肺部疾病患者相比,多种循环miRs出现升高或下降[14]。如Roth等[15]报道肺癌患者循环miR10b,miR141和 miR155水平,与良性肺肿瘤患者相比,显著升高。这些改变反映了肺癌发生与发展相关的病理生理过程。确定循环miRs作为肺癌的生物标志物在临床上的应用,尚需进行大规模前瞻性研究。

CTCs和cfNA的检测及其意义是目前癌症转化研究的一个热点。CTCs和cfNA作为生物标志物的研究目标包括:1)肺癌筛选;2)转移复发和转移进展的风险评估;3)治疗分级和实时监测;4)治疗靶点和耐药机制的鉴定。近年来,关于肺癌的循环生物标志物的研究有大量报道,但需要多中心临床研究证实,并采用无病生存或总生存期等作为研究终点。


参考文献

Mok TS. Personalized medicine in lung cancer: what we need to know[J]. Nat Rev Clin Oncol, 2011, 8(11): 661-668.

Riethdorf S, Wikman H, Pantel K. Review: Biological relevance of disseminated tumor cells in cancer patients[J]. Int J Cancer, 2008, 123(9): 1991-2006.

Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells[J]. Nat Rev Cancer, 2008, 8(5): 329-340.

O’Flaherty JD, Gray S, Richard D, et al. Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer[J]. Lung Cancer, 2012, 76(1): 19-25.

Krebs MG, Sloane R, Priest L, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer[J]. J Clin Oncol, 2011, 29(12): 1556-1563.

Tanaka F, Yoneda K, Kondo N, et al. Circulating tumor cell as a diagnostic marker in primary lung cancer[J]. Clin Cancer Res, 2009, 15(22): 6980-6986.

Hou JM, Krebs MG, Lancashire L, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer[J]. J Clin Oncol, 2012, 30(5): 525-532.

Naito T, Tanaka F, Ono A, et al. Prognostic impact of circulating tumor cells in patients with small cell lung cancer[J]. J Thorac Oncol, 2012, 7(3): 512-519.

Krebs MG, Hou JM, Sloane R, et al. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches[J]. J Thorac Oncol, 2012, 7(2): 306-315.

Lecharpentier A, Vielh P, Perez-Moreno P, et al. Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer[J]. Br J Cancer, 2011, 105(9): 1338-1341.

Alix-Panabières C, Schwarzenbach H, Pantel K. Circulating tumor cells and circulating tumor DNA[J]. Annu Rev Med, 2012, 63: 199-215.

Zhang R, Shao F, Wu X, et al. Value of quantitative analysis of circulating cell free DNA as a screening tool for lung cancer: a meta-analysis[J]. Lung Cancer, 2010, 69(2): 225-231.

Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells[J]. N Engl J Med, 2008, 359(4): 366-377.

Wang Q, Wang S, Wang H, et al. MicroRNAs: novel biomarkers for lung cancer diagnosis, prediction and treatment[J]. Exp Biol Med (Maywood), 2012, 237(3): 227-235.

Roth C, Kasimir-Bauer S, Pantel K, et al. Screening for circulating nucleic acids and caspase activity in the peripheral blood as potential diagnostic tools in lung cancer[J]. Mol Oncol, 2011, 5(3): 281-291.


comments powered by Disqus

全文

引用

引用本文: Pantel Klaus, Wikman Harriet , Alix-Panabières Catherine, Taenzer Aline. 肺癌循环肿瘤源性生物标志物[J]. 临床与病理杂志, 2013, 33(6): 476-477.
Cite this article as: Klaus Pantel, Harriet Wikman, Catherine Alix-Panabières, Aline Taenzer . Circulating tumor-derived biomarkers in lung cancer[J]. Journal of Clinical and Pathological Research, 2013, 33(6): 476-477.