小细胞肺癌患者外周血中循环肿瘤细胞的表型特征
Phenotypic characterization of circulating tumor cells in the peripheral blood of patients with small cell lung cancer.
作者信息
Messaritakis Ippokratis, Politaki Eleni, Kotsakis Athanasios, Dermitzaki Eleftheria-Kleio, Koinis Filippos, Lagoudaki Eleni, Koutsopoulos Anastasios, Kallergi Galatea, Souglakos John, Georgoulias Vassilis
机构信息
Laboratory of Tumor Cell Biology, Medical School, University of Crete, Heraklion, Greece.
Department of Medical Oncology, University General Hospital of Heraklion, Crete, Greece.
出版信息
PLoS One. 2017 Jul 18;12(7):e0181211. doi: 10.1371/journal.pone.0181211. eCollection 2017.
BACKGROUND
To evaluate the phenotypic heterogeneity of circulating tumor cells (CTCs) based on the expression of proliferative, apoptotic and Epithelial-to-Mesenchymal Transmission (EMT) markers during front-line treatment in patients with small cell lung cancer (SCLC) and to evaluate their clinical relevance.
METHODS
CTCs from 108 chemotherapy-naïve patients with SCLC were analyzed by double immunofluorescence staining using anti-Ki67, anti-M30, anti-Vimentin along with anti-CKs antibodies. In 83 patients CTCs were also enumerated using the CellSearch.
RESULTS
Sequential samples were available from 76 and 48 patients after one-treatment cycle and on disease progression (PD), respectively, for immunofluorescence and from 50 and 36 patients after one-cycle and on PD, respectively, for CellSearch. At baseline, 60.2% of the patients had detectable CTCs by either method. Both proliferative (CK67+) and non-proliferative (Ki67-), apoptotic (M30+) and non-apoptotic (M30-) as well as EMT (Vim+) CTCs were present in the same patient. Among 22 patients without detectable CTCs by CellSearch, CK+/Ki67+ and CK+/Vim+ CTCs could be detected in 6 (27.3%) and 6 (27.3%) patients, respectively. One-chemotherapy cycle reduced both the incidence of detection (p<0.001) and the absolute number (p<0.001) of CTCs; conversely, on PD both the incidence of detection and the number of CTCs were significantly increased (p = 0.002 and p = 0.04, respectively). Multivariate analysis revealed that the increased number of Vim+ CTCs at baseline and of non-apoptotic CTCs on PD could be emerged as independent prognostic factors associated with decreased OS(p = 0.009 and p = 0.023, respectively).
CONCLUSIONS
CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs represent distinct subpopulations of CTCs in patients with SCLC, can be detected even in the absence of detectable CTCs by CellSearch; CK+/Ki67+ and CK+/Vim+ CTCs are associated with unfavorable clinical outcome.
背景
评估小细胞肺癌（SCLC）患者一线治疗期间基于增殖、凋亡和上皮-间质转化（EMT）标志物表达的循环肿瘤细胞（CTC）的表型异质性，并评估其临床相关性。
方法
采用抗Ki67、抗M30、抗波形蛋白以及抗细胞角蛋白（CK）抗体，通过双重免疫荧光染色分析108例未经化疗的SCLC患者的CTC。83例患者还使用CellSearch系统对CTC进行计数。
结果
分别有76例和48例患者在一个治疗周期后及疾病进展（PD）时可获得用于免疫荧光检测的序贯样本，分别有50例和36例患者在一个周期后及PD时可获得用于CellSearch检测的样本。基线时，两种方法均可检测到60.2%的患者有CTC。增殖性（CK67+）和非增殖性（Ki67-）、凋亡性（M30+）和非凋亡性（M30-）以及EMT（Vim+）的CTC可同时存在于同一患者体内。在22例CellSearch检测不到CTC的患者中，分别有6例（27.3%）和6例（27.3%）患者可检测到CK+/Ki67+和CK+/Vim+的CTC。一个化疗周期降低了CTC的检测率（p<0.001）和绝对数量（p<0.001）；相反，在PD时，CTC的检测率和数量均显著增加（分别为p = 0.002和p = 0.04）。多因素分析显示，基线时Vim+ CTC数量增加以及PD时非凋亡性CTC数量增加可作为与总生存期降低相关的独立预后因素（分别为p = 0.009和p = 0.023）。
结论
CK+/Ki67+、CK+/M30+和CK+/Vim+的CTC代表SCLC患者中不同的CTC亚群，即使在CellSearch检测不到CTC的情况下也可检测到；CK+/Ki67+和CK+/Vim+的CTC与不良临床结局相关。
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