CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

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 cancer^3,4,5,6. 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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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.

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   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).
   3.&#009Khandekar, M.J., et al. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 11, 886-895 (2011).
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   5.&#009Rull, A., et al. Expression of cytokine genes in the aorta is altered by the deficiency in MCP-1: effect of a high-fat, high-cholesterol diet. Cytokine 50,121-128 (2010).
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   7.&#009Bandyopadhyay, S., et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12, 933-938 (2006).
   8.&#009Beltrán-Debón, R., et al. The aqueous extract of Hibiscus sabdariffa calices modulates the production of monocyte chemoattractant protein-1 in humans. Phytomedicine 17, 186-191 (2010).