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

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.

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Acknowledgements

This work was conducted in Cancer Biology Research Laboratory (CBRL), Department of Zoology, Faculty of Science, Cairo University, Egypt. We thank Dr. Eslam El-Ghonaimy and Dr. Hossam Taha Mohamed (Researchers at CBRL, Faculty of Science, Cairo University) for their help in Western blotting and qPCR experiments, respectively.

Funding

This study was funded by Cairo University, Scientific Research Sector (SAI, HH, SE, MMM).

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Correspondence to Ramy Gadalla.

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All authors declare that there is no conflict of interest regarding the publication of this article.

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All procedures performed in the study were in accordance with the ethical standards of Ain shams University research ethics committee, the Egyptian national research committee and with the 1964 Helsinki Declaration and its later amendments.

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Informed consent was obtained from all individual participants included in the study.

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Gadalla, R., Hassan, H., Ibrahim, S.A. et al. Tumor microenvironmental plasmacytoid dendritic cells contribute to breast cancer lymph node metastasis via CXCR4/SDF-1 axis. Breast Cancer Res Treat 174, 679–691 (2019). https://doi.org/10.1007/s10549-019-05129-8

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Keywords

  • Plasmacytoid dendritic cells
  • CXCR4
  • Breast cancer
  • Lymph node metastasis