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Endothelial CXCR7 regulates breast cancer metastasis

Oncogene volume 35, pages 1716–1724 (2016)Cite this article

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Abstract

Atypical chemokine receptor CXCR7 (ACKR3) functions as a scavenger receptor for chemokine CXCL12, a molecule that promotes multiple steps in tumor growth and metastasis in breast cancer and multiple other malignancies. Although normal vascular endothelium expresses low levels of CXCR7, marked upregulation of CXCR7 occurs in tumor vasculature in breast cancer and other tumors. To investigate effects of endothelial CXCR7 in breast cancer, we conditionally deleted this receptor from vascular endothelium of adult mice, generating CXCR7ΔEND/ΔEND animals. CXCR7ΔEND/ΔEND mice appeared phenotypically normal, although these animals exhibited a modest 35±3% increase in plasma CXCL12 as compared with control. Using two different syngeneic, orthotopic tumor implant models of breast cancer, we discovered that CXCR7ΔEND/ΔEND mice had significantly greater local recurrence of cancer following resection, elevated numbers of circulating tumor cells and more spontaneous metastases. CXCR7ΔEND/ΔEND mice also showed greater experimental metastases following intracardiac injection of cancer cells. These results establish that endothelial CXCR7 limits breast cancer metastasis at multiple steps in the metastatic cascade, advancing understanding of CXCL12 pathways in tumor environments and informing ongoing drug development targeting CXCR7 in cancer.

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Acknowledgements

We thank Dr Mark Penfold and ChemoCentryx for CXCR7 loxP mice and antibody 11G8. Dr Jun-Lin Guan provided SCL CreERT through courteous permission of Dr Glenn Begley. We thank Dr Aaron Robida from the University of Michigan Flow Cytometry Core for assistance. Research was supported by United States National Institute of Health grants R21CA182333, R01CA136553, R01CA142750, R01CA170198 and P50CA093990.

Author Contributions

ACS, JF, SPC, KS and GDL performed experiments and analyzed data. KEL contributed new reagents. SZ and SLC performed GSEA analyses. KEL and GDL conceptualized and directed the research. ACS, JF, SPC and GDL wrote the manuscript.

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Authors and Affiliations

  1. Department of Radiology, University of Michigan Center for Molecular Imaging, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA

    A C Stacer, J Fenner, A Xiao, A Salomonnson, K E Luker & G D Luker

  2. Department of Biomedical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA

    S P Cavnar & G D Luker

  3. Department of Radiation Oncology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA

    S Zhao

  4. Depatment of Chemical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA

    S L Chang

  5. Department of Microbiology and Immunology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA

    G D Luker

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  1. A C Stacer
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Stacer, A., Fenner, J., Cavnar, S. et al. Endothelial CXCR7 regulates breast cancer metastasis. Oncogene 35, 1716–1724 (2016). https://doi.org/10.1038/onc.2015.236

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