Nanou Afroditi, Coumans Frank A W, van Dalum Guus, Zeune Leonie L, Dolling David, Onstenk Wendy, Crespo Mateus, Fontes Mariane Sousa, Rescigno Pasquale, Fowler Gemma, Flohr Penny, Brune Christoph, Sleijfer Stefan, de Bono Johann S, Terstappen Leon W M M
Department of Medical Cell BioPhysics, MIRA Institute, University of Twente, Enschede, the Netherlands.
Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, the Netherlands.
Oncotarget. 2018 Apr 10;9(27):19283-19293. doi: 10.18632/oncotarget.25019.
The presence of Circulating Tumor Cells (CTCs) in Castration-Resistant Prostate Cancer (CRPC) patients is associated with poor prognosis. In this study, we evaluated the association of clinical outcome in 129 CRPC patients with CTCs, tumor-derived Extracellular Vesicles (tdEVs) and plasma levels of total (CK18) and caspase-cleaved cytokeratin 18 (ccCK18).
CTCs and tdEVs were isolated with the CellSearch system and automatically enumerated. Cut-off values dichotomizing patients into favorable and unfavorable groups of overall survival were set on a retrospective data set of 84 patients and validated on a prospective data set of 45 patients. Plasma levels of CK18 and ccCK18 were assessed by ELISAs.
CTCs, tdEVs and both cytokeratin plasma levels were significantly increased in CRPC patients compared to healthy donors (HDs). All biomarkers except for ccCK18 were prognostic showing a decreased median overall survival for the unfavorable groups of 9.2 vs 21.1, 8.1 vs 23.0 and 10.0 vs 21.5 months respectively. In multivariable Cox regression analysis, tdEVs remained significant.
Automated CTC and tdEV enumeration allows fast and reliable scoring eliminating inter- and intra- operator variability. tdEVs provide similar prognostic information to CTC counts.
去势抵抗性前列腺癌（CRPC）患者循环肿瘤细胞（CTC）的存在与预后不良相关。在本研究中，我们评估了129例CRPC患者的临床结局与CTC、肿瘤衍生细胞外囊泡（tdEV）以及总细胞角蛋白18（CK18）和半胱天冬酶切割的细胞角蛋白18（ccCK18）血浆水平之间的关联。
使用CellSearch系统分离并自动计数CTC和tdEV。在84例患者的回顾性数据集中设定将患者分为总生存有利和不利组的临界值，并在45例患者的前瞻性数据集中进行验证。通过酶联免疫吸附测定法评估CK18和ccCK18的血浆水平。
与健康供体（HD）相比，CRPC患者的CTC、tdEV以及两种细胞角蛋白血浆水平均显著升高。除ccCK18外，所有生物标志物均具有预后意义，不利组的中位总生存期分别为9.2个月对21.1个月、8.1个月对23.0个月和10.0个月对21.5个月，均有所降低。在多变量Cox回归分析中，tdEV仍然具有显著性。
自动计数CTC和tdEV可实现快速可靠的评分，消除了操作者间和操作者内的变异性。tdEV提供与CTC计数相似的预后信息。
