Abstract
Macrophages, which are abundant in the tumour microenvironment, enhance malignancy1. At metastatic sites, a distinct population of metastasis-associated macrophages promotes the extravasation, seeding and persistent growth of tumour cells2. Here we define the origin of these macrophages by showing that Gr1-positive inflammatory monocytes are preferentially recruited to pulmonary metastases but not to primary mammary tumours in mice. This process also occurs for human inflammatory monocytes in pulmonary metastases of human breast cancer cells. The recruitment of these inflammatory monocytes, which express CCR2 (the receptor for chemokine CCL2), as well as the subsequent recruitment of metastasis-associated macrophages and their interaction with metastasizing tumour cells, is dependent on CCL2 synthesized by both the tumour and the stroma. Inhibition of CCL2–CCR2 signalling blocks the recruitment of inflammatory monocytes, inhibits metastasis in vivo and prolongs the survival of tumour-bearing mice. Depletion of tumour-cell-derived CCL2 also inhibits metastatic seeding. Inflammatory monocytes promote the extravasation of tumour cells in a process that requires monocyte-derived vascular endothelial growth factor. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer3,4,5,6. Our data provide the mechanistic link between these two clinical associations and indicate new therapeutic targets for treating metastatic breast cancer.
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Acknowledgements
This work was supported by grants from the NIH to J.W.P. (NIH PO1 CA100324 and RO1 CA131270) and to the Albert Einstein Cancer Center Core (P30 CA 13330). We thank J. Massague for 4173 cells and N. Ferrara for the Vegfaflox/flox mice. We also thank P. Marsters for statistical analyses and M. Thompson, F. Shi, C. Ferrante, F. McCabe, H. Millar-Quinn and D. Wiley for discussions and technical assistance.
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B-Z.Q., L.A.S. and J.W.P. conceived the ideas and designed the experiments. B-Z.Q., J.L., H.Z., T.K., J.Z., L.R.C. and E.A.K. performed the experiments. B-Z.Q., J.L., L.A.S. and J.W.P. analysed the data. B-Z.Q., L.A.S. and J.W.P. wrote the paper.
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Supplementary Information
The file contains Supplementary Figures 1-11 with legends, Supplementary Movie legends and additional references. (PDF 703 kb)
Supplementary Movie 1
The movie shows representative 3D reconstructed confocal images of tumor cells (CFP, blue) and macrophages (GFP, green) 24 hours after tumor cell tail veininjection in mice treated with control Ab (see Supplementary Information file for full legend). (AVI 2244 kb)
Supplementary Movie 2
The movie shows representative 3D reconstructed confocal images of tumor cells (CFP, blue) and macrophages (GFP, green) 24 hours after tumor cell tail vein injection in mice treated with anti-mouse CCL2 Ab (see Supplementary Information file for full legend). (AVI 1529 kb)
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Qian, BZ., Li, J., Zhang, H. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011). https://doi.org/10.1038/nature10138
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DOI: https://doi.org/10.1038/nature10138
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