Mego M, Cholujova D, Minarik G, Sedlackova T, Gronesova P, Karaba M, Benca J, Cingelova S, Cierna Z, Manasova D, Pindak D, Sufliarsky J, Cristofanilli M, Reuben J M, Mardiak J
2nd Department of Oncology, Faculty of Medicine, Comenius University, Klenova 1, 833 10, Bratislava, Slovak Republic.
Translational Research Unit, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
BMC Cancer. 2016 Feb 19;16:127. doi: 10.1186/s12885-016-2143-2.
Cytokines are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients.
This study included 147 chemotherapy naïve PBC patients. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoetic cells using RossetteSep™ negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (Twist1, Snail1, Slug, Zeb1) and epithelial (Ck19) gene transcripts by qRT-PCR. The concentrations of 51 plasma cytokines were measured using multiplex bead arrays.
CTCs were detected in 25.2% patients. CTCs exhibiting only epithelial markers (CTC_EP) and only EMT markers (CTC_EMT) were present evenly in 11.6% patients, while CTCs co-expressing both markers were detected in 2.0% patients. Patients with presence of CTC_EP in peripheral blood had significantly elevated levels of plasma IFN-α2, IL-3, MCP-3, β-NGF, SCF, SCGF-β, TNF-β and SDF-1 compared to patients without CTC_EP. CTC_EP exhibited overexpression of SDF-1 receptor and CXCR4, but not other corresponding cytokine receptor, and in multivariate analysis SDF-1 was independently associated with CTC_EP. There was an inverse correlation between CTC_EMT and plasma cytokines CTACK, β-NGF and TRAIL, while presence of either subtype of CTCs was associated with increased level of TGF-β2.
Using cytokine profiling, we identified cytokines associated with CTCs subpopulations in peripheral blood of PBC. Our data suggest that CXCR4-SDF-1 axis is involved in mobilization and trafficking of epithelial CTCs.
细胞因子参与癌症侵袭和转移。循环肿瘤细胞（CTC）在肿瘤播散中起关键作用，并且是乳腺癌患者独立的生存预测指标。本研究旨在评估原发性乳腺癌（PBC）患者中CTC与血浆细胞因子之间的相关性。
本研究纳入了147例未经化疗的PBC患者。使用RossetteSep™阴性选择试剂盒去除外周血单个核细胞（PBMC）中的造血细胞。通过qRT-PCR检测从去除CD45的PBMC中提取的RNA中EMT（Twist1、Snail1、Slug、Zeb1）和上皮（Ck19）基因转录本的表达。使用多重珠阵列测量51种血浆细胞因子的浓度。
25.2%的患者检测到CTC。仅表现上皮标志物的CTC（CTC_EP）和仅表现EMT标志物的CTC（CTC_EMT）在11.6%的患者中均匀存在，而同时表达两种标志物的CTC在2.0%的患者中被检测到。外周血中存在CTC_EP的患者与无CTC_EP的患者相比，血浆IFN-α2、IL-3、MCP-3、β-NGF、SCF、SCGF-β、TNF-β和SDF-1水平显著升高。CTC_EP表现出SDF-1受体和CXCR4的过表达，但未表现出其他相应细胞因子受体的过表达，并且在多变量分析中SDF-1与CTC_EP独立相关。CTC_EMT与血浆细胞因子CTACK、β-NGF和TRAIL呈负相关，而任何一种CTC亚型的存在都与TGF-β2水平升高相关。
通过细胞因子谱分析，我们在PBC患者外周血中鉴定出与CTC亚群相关的细胞因子。我们的数据表明CXCR4-SDF-1轴参与上皮性CTC的动员和运输。
