肿瘤微环境中的浆细胞样树突状细胞通过 CXCR4/SDF-1 轴促进乳腺癌淋巴结转移。

Tumor microenvironmental plasmacytoid dendritic cells contribute to breast cancer lymph node metastasis via CXCR4/SDF-1 axis.

机构信息

Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt.

Princess Margaret Cancer Center, University Health Network, 610 University Ave, Toronto, ON, M5G 2M9, Canada.

出版信息

Breast Cancer Res Treat. 2019 Apr;174(3):679-691. doi: 10.1007/s10549-019-05129-8. Epub 2019 Jan 10.

DOI:10.1007/s10549-019-05129-8

PMID:30632021

Abstract

PURPOSE

Plasmacytoid dendritic cells (PDCs) infiltration into breast cancer tissues is associated with poor prognosis. Also, CXCR4 shows compelling evidences to be exploited by cancer cells to migrate to distant sites. The present study investigated lymph node metastasis in the light of PDCs infiltration and the potential cross talk with CXCR4/SDF-1 chemokine axis.

METHODS

We assessed circulating PDCs proportions drained from the axillary tributaries, and the in situ expression of both CD303 and CXCR4 in breast cancer patients with positive lymph nodes (pLN) and negative lymph nodes (nLN) using immunohistochemistry and flow cytometry. We also analyzed the expression of SDF-1 in lymph nodes of pLN and nLN patients. We studied the effect of the secretome of PDCs of pLN and nLN patients on the expression of CXCR4 and activation of NF-κB in human breast cancer cell lines SKBR3 and MCF-7. TNF-α mRNA expression level in PDCs from both groups was determined by qPCR.

RESULTS

Our findings indicate increased infiltration of PDCs in breast cancer tissues of pLN patients than nLN patients, which correlates with CXCR4 cells percentage. Interestingly, SDF-1 is highly immunostained in lymph nodes of pLN patients compared to nLN patients. Our in vitro experiments demonstrate an upregulation of NF-κB expression and CXCR4 cells upon stimulation with PDCs secretome of pLN patients than those of nLN patients. Also, PDCs isolated from pLN patients exhibited a higher TNF-α mRNA expression than nLN patients. Treatment of MCF-7 cell lines with TNF-α significantly upregulates CXCR4 expression.

CONCLUSIONS

Our findings suggest a potential role for microenvironmental PDCs in breast cancer lymph node metastasis via CXCR4/SDF-1 axis.

摘要

目的

浆细胞样树突状细胞（PDCs）浸润乳腺癌组织与预后不良有关。此外，趋化因子受体 4（CXCR4）为肿瘤细胞转移到远处部位提供了有力的证据。本研究通过 PDCs 浸润以及与 CXCR4/SDF-1 趋化因子轴的潜在串扰，调查淋巴结转移。

方法

我们使用免疫组织化学和流式细胞术评估了从腋窝支流引流的循环 PDCs 比例，以及在有阳性淋巴结（pLN）和阴性淋巴结（nLN）的乳腺癌患者中 CD303 和 CXCR4 的原位表达。我们还分析了 pLN 和 nLN 患者淋巴结中 SDF-1 的表达。我们研究了 pLN 和 nLN 患者 PDCs 分泌组对人乳腺癌细胞系 SKBR3 和 MCF-7 中 CXCR4 表达和 NF-κB 激活的影响。通过 qPCR 测定了两组 PDCs 中 TNF-α mRNA 的表达水平。

结果

我们的研究结果表明，pLN 患者的乳腺癌组织中 PDCs 的浸润增加，与 CXCR4 细胞百分比相关。有趣的是，与 nLN 患者相比，pLN 患者淋巴结中 SDF-1 的免疫染色强度更高。我们的体外实验表明，与 nLN 患者相比，pLN 患者 PDCs 分泌组刺激后 NF-κB 表达和 CXCR4 细胞上调。此外，与 nLN 患者相比，pLN 患者分离的 PDCs 中 TNF-α mRNA 的表达水平更高。TNF-α 处理 MCF-7 细胞系可显著上调 CXCR4 表达。