CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis (original) (raw)

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 _Vegfa_flox/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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Authors and Affiliations

  1. Department of Developmental and Molecular Biology, Center for the Study of Reproductive Biology and Women’s Health, Albert Einstein College of Medicine, New York, 10461, New York, USA
    Bin-Zhi Qian, Jiufeng Li, Hui Zhang, Takanori Kitamura & Jeffrey W. Pollard
  2. Flow Cytometry Core Facility, Albert Einstein College of Medicine, New York, 10461, New York, USA
    Jinghang Zhang
  3. Ortho Biotech Oncology R&D, 145 King of Prussia Road, Radnor, 19087, Pennsylvania, USA
    Liam R. Campion, Elizabeth A. Kaiser & Linda A. Snyder

Authors

  1. Bin-Zhi Qian
  2. Jiufeng Li
  3. Hui Zhang
  4. Takanori Kitamura
  5. Jinghang Zhang
  6. Liam R. Campion
  7. Elizabeth A. Kaiser
  8. Linda A. Snyder
  9. Jeffrey W. Pollard

Contributions

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.

Corresponding author

Correspondence toJeffrey W. Pollard.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information (download PDF )

The file contains Supplementary Figures 1-11 with legends, Supplementary Movie legends and additional references. (PDF 703 kb)

Supplementary Movie 1 (download AVI )

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 (download AVI )

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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  1. Jorge Joven 30 November 2011, 13:12
    CCL2 and cancer: should we consider a multi-targeted therapeutic approach?
    Excellent data provided by Qian et al1 further support the notion that inflammatory cells represent not only a host response against tumours but an actual contribution to breast cancer and metastasis development. However, the proposed model, although clinically plausible, may be modulated in humans and probably overstates the role of CCL2. Obesity is associated with increased macrophage infiltration in breast tumours2 and the setting of obesity-related metabolic disorders represents a complicated tumorigenic scenario3. Among them, the secretion of multiple cytokines, including CCL2, can activate macrophages and other inflammatory cells promoting cancer. However, the CC chemokine system is highly redundant, intriguingly ubiquitous and, in mice, the cognate receptor CCR2 as well as CCL8 and CCL12, which are structurally and functionally similar to CCL2, are equally expressed in lung and most other tissues4. Further, the lack of CCL2 in mice limits but not suppresses the accumulation of macrophages in tissues and CCL8 as well as interleukin-3 mRNA are overexpressed in the aorta to substitute for the function of CCL2 suggesting a possible role for alternative inflammatory pathways5. Further, circulating and tissue CCL2 are also bound by non-functional receptors that exhibit strong chemokine binding capacities and are likely used to regulate CCL2 behaviour especially in endothelial and smooth muscle cells. The chemokine receptor Darc (Duffy antigen receptor for chemokines) should be especially considered in evaluating the actual effect of CCL26. Evidences are accumulating suggesting that Darc-mediated chemokine sequestration helps determine tumour microenvironment, angiogenesis and metastasis7. A genetic variant (rs12075) forms the basis for Duffy blood groups, shows an extremely high population differentiation and mediates changes in CCL2 function. Whether this may have clinical importance remains uncertain but it may be speculated that these mechanisms may be active in the difference in prevalence of breast tumours among populations.
    CCL2 is obviously a therapeutic target but proposed procedures are potentially toxic. The continuous administration of dietary polyphenols, however, is safe and particularly effective in decreasing the tissue expression and circulating amounts of CCL28. It is time to consider non-acute inflammation as an indication for preventive rather than therapeutic measures that may be achieved evaluating and/or modifying the relationships between food consumption, genetic background, microbiomes and immune systems.
    1.&#009Qian, B.Z., et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225 (2011).

2.&#009Morris, P.G., et al. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 4, 1021-1029 (2011).
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4.&#009Rodríguez-Sanabria, F., et al. Tissue distribution and expression of paraoxonases and chemokines in mouse: the ubiquitous and joint localisation suggests a systemic and coordinated role. J Mol Histol 41, 379-386 (2010).
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