Journal Article

CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

Qian, Bin-Zhi, Pollard, Jeffrey W., Zhang, Hui, Zhang, Jinghang, Kaiser, Elizabeth A., Kitamura, Takanori, Campion, Liam R., Li, Jiufeng, Snyder, Linda A.

2011

Overview

Monocyte recruitment in metastasis Macrophages are abundant in tumours, where they promote tumorigenesis and metastasis. Jeffrey Pollard and colleagues now identify inflammatory monocytes as a precursor population for the macrophages that promote breast cancer metastasis to the lung or bone. These cells are recruited through the cytokine CCL2 and promote tumour-cell extravasation (by producing the signal protein VEGF) and the seeding of metastases. These findings can explain the poor prognosis for breast cancer patients with elevated expression of CCL2. Macrophages, which are abundant in the tumour microenvironment, enhance malignancy 1 . At metastatic sites, a distinct population of metastasis-associated macrophages promotes the extravasation, seeding and persistent growth of tumour cells 2 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2504/342 / 692/420/2780 / 692/699/67/1347 / 692/699/67/322 / Animals / Biological and medical sciences / Breast cancer / Breast Neoplasms - pathology / CD11b Antigen - metabolism / Chemokine CCL2 - antagonists & inhibitors / Chemokine CCL2 - metabolism / Female / Genetic aspects / GPI-Linked Proteins - metabolism / Gynecology. Andrology. Obstetrics / Health aspects / Humanities and Social Sciences / Humans / Inflammation - pathology / letter / Lipopolysaccharide Receptors - metabolism / Lung Neoplasms - secondary / Lungs / Macrophages / Macrophages - pathology / Mammary gland diseases / Medical sciences / Metastasis / Mice / Monocytes / Monocytes - metabolism / Monocytes - pathology / multidisciplinary / Neoplasm Metastasis - drug therapy / Neoplasm Transplantation / Physiological aspects / Pneumology / Receptor, Macrophage Colony-Stimulating Factor - metabolism / Receptors, CCR2 - antagonists & inhibitors / Receptors, CCR2 - metabolism / Receptors, IgG - metabolism / Recruitment / Rodents / Science / Science (multidisciplinary) / Tumor Microenvironment / Tumors / Tumors of the respiratory system and mediastinum / Vascular Endothelial Growth Factor A - metabolism