CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis

By Binzhi Qian, Jiu-feng Li, Hui Zhang, T. Kitamura, Jinghang Zhang, Liam R. Campion, Elizabeth A. Kaiser, L. Snyder, J. Pollard. Nature, 2011

2,679 citations recorded by the source corpus.

Macrophages, which are abundant in the tumour microenvironment, enhance malignancy. At metastatic sites, a distinct population of metastasis-associated macrophages promotes the extravasation, seeding and persistent growth of tumour cells. 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. Our data provide the mechanistic link between these two clinical associations and indicate new therapeutic targets for treating metastatic breast cancer.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/dd6871df340e83ecd615f52f2c5f512bf3cc9b4e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. A. Mantovani
2. Lisa M. Coussens
3. J. Pollard
4. A. Sica
5. P. Allavena
6. F. Balkwill
7. R. Weinberg
8. A. Mildner

In Oncology

1. A. Mantovani
2. Lisa M. Coussens
3. J. Pollard
4. A. Sica
5. R. Weinberg
6. P. Allavena
7. Zena Werb
8. F. Balkwill

Citations in the corpus

• Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment (2016, background): “CCL2/CCR2 antagonist [95, 96] and CSF-1 inhibitory antibodies or Yondelis (trabectedin) [97] were effective in blocking recruitment of macrophages in tumor sites.”
• Developmental and Functional Heterogeneity of Monocytes. (2018, background): “to the metastatic site in a CCL2-CCR2 dependent fashion and, once embedded within this niche, these recruited monocyte-derived cells promote the survival and growth of the metastatic tumour (Qian et al., 2011).”
• Tumor-associated macrophages: from mechanisms to therapy (2014, background): “Nevertheless, several recent studies suggest that most TAM subpopulations arise from the Ly6C+ population of circulating mouse monocytes in grafted tumors (Movahedi et al., 2010), primary mouse mammary tumors (Franklin et al., 2014), and in lung metastases (Qian et al., 2011).”
• EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “In particular, the recruitment of CCR2+ inflammatory monocytes in response to CCL2 secretion by carcinoma or host cells can facilitate extravasation and subsequent metastatic growth in the lung parenchyma (Qian et al., 2011; Wolf et al., 2012).”
• Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “The accumulation of immunoinhibitory subpopulations (M-MDSCs) in the TME finally contributes to CD8 + T cell growth and IFN-γ production restriction [242].”
• Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart (2014, neutral): “Mouse strains used included Mlc2v-Cre, Rosa26-DTR, Rosa26-td, Flt3-Cre, CSF1R-MerCre, and CCR2 (9, 16, 17, 19, 23, 24).”