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Sci. Signal., 19 July 2011
Vol. 4, Issue 182, p. ec199
[DOI: 10.1126/scisignal.4182ec199]

EDITORS' CHOICE

Cancer Recruiting Trouble

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Macrophages are found in tumor microenvironments, where they promote malignancy, and at metastatic sites, where as metastasis-associated macrophages they enhance the extravasation and growth of tumor cells. To determine the origin of these cells, Qian et al. labeled two distinct subpopulations of mouse monocytes (which differentiate into macrophages) with green fluorescent protein and tracked their movement after they were injected into mice that had mammary tumors with lung metastases. Whereas monocytes of the "resident" subset were preferentially recruited to the primary tumors, "inflammatory" monocytes were more abundant at metastatic sites. Inflammatory, but not resident, monocytes have the chemokine receptor CCR2, which binds to the chemokine CCL2, and a neutralizing antibody against mouse CCL2 (anti-mCCL2) blocked the recruitment of inflammatory monocytes to lungs containing metastatic tumor cells. Similarly, the recruitment of human inflammatory monocytes to the lungs of mice injected with human metastatic breast cancer cells was reduced by anti-mCCL2; however, an antibody against human CCL2 also reduced the extent of inflammatory monocyte recruitment, indicating that CCL2 was derived from both the tumor and the surrounding tissue. Transendothelial migration assays showed that tumor cell migration was enhanced by the presence of macrophages on the basolateral side of the endothelial layer. Transcriptome analysis showed that the gene encoding vascular endothelial growth factor A (VEGFA) was more highly expressed in inflammatory than in resident monocytes, and macrophages deficient in VEGFA failed to induce the transendothelial migration of tumor cells in vitro. Furthermore, the number of lung tumors that formed from metastatic cells injected into mice containing VEGFA-deficient monocytes was reduced compared with that in mice with normal monocytes. Together, these data suggest that the recruitment of a subpopulation of monocytes to metastatic sites by CCL2 promotes the extravasation of metastatic tumor cells and provides potential therapeutic targets against metastatic breast cancer.

B.-Z. Qian, J. Li, H. Zhang, T. Kitamura, J. Zhang, L. R. Campion, E. A. Kaiser, L. A. Snyder, J. W. Pollard, CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011). [PubMed]

Citation: J. F. Foley, Recruiting Trouble. Sci. Signal. 4, ec199 (2011).



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