Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers.
Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers.
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DOI：
10.1158/0008-5472.can-16-2072
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发表时间：
2017-09-15
期刊：
影响因子：
11.2
通讯作者：
Nagrath S
中科院分区：
文献类型：
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作者：
Murlidhar V;Reddy RM;Fouladdel S;Zhao L;Ishikawa MK;Grabauskiene S;Zhang Z;Lin J;Chang AC;Carrott P;Lynch WR;Orringer MB;Kumar-Sinha C;Palanisamy N;Beer DG;Wicha MS;Ramnath N;Azizi E;Nagrath S
转移的早期检测可以通过循环肿瘤细胞（CTC）来辅助，其也显示出预测早期复发的潜力。由于早期外周血中CTC数量有限，我们研究了在肿瘤手术切除期间获取的肺静脉血中的CTC。在围手术期从肺癌患者中抽取肺静脉（PV）和外周静脉（Pe）血液样本，并使用微流体装置评估CTC负荷。从36名患者的108份血液样本中分析，与术前Pe（p<0.0001）和术中Pe（p<0.001）血液相比，PV具有显著更高的CTC数量。在50%的患者中观察到具有大量CTC的CTC簇，PV通常显示更大的簇。长期监测表明，存在集群在术前Pe血液预测预后不良的趋势。通过RT-qPCR的基因表达分析揭示了PV和Pe样品中p53信号传导和细胞外基质参与的富集。在62.5%的PV样品和59.2%的Pe样品中检测到Ki 67表达，其中大多数（72.7%）PV中Ki 67表达阳性的患者具有单个CTC而不是簇。基因本体分析揭示了CTC簇中细胞迁移和免疫相关途径的富集，表明了循环中簇的存活优势。簇显示治疗抗性的特征，表明这些细胞的侵袭性。因此，从肺癌的早期阶段分离的CTC预测不良预后，并且可以被询问以确定预测复发的生物标志物。
Early detection of metastasis can be aided by circulating tumor cells (CTCs), which also show potential to predict early relapse. Due to the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared to pre-operative Pe (p<0.0001) and intra-operative Pe (p<0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long term surveillance indicated that presence of clusters in pre-operative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence.