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CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis.

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.

Pubmed ID: 21654748

Authors

  • Qian BZ
  • Li J
  • Zhang H
  • Kitamura T
  • Zhang J
  • Campion LR
  • Kaiser EA
  • Snyder LA
  • Pollard JW

Journal

Nature

Publication Data

July 14, 2011

Associated Grants

  • Agency: Medical Research Council, Id: G1002033
  • Agency: NCI NIH HHS, Id: P01 CA100324
  • Agency: NCI NIH HHS, Id: P01 CA100324
  • Agency: NCI NIH HHS, Id: P01 CA100324-10
  • Agency: NCI NIH HHS, Id: R01 CA131270
  • Agency: NCI NIH HHS, Id: R01 CA131270
  • Agency: NCI NIH HHS, Id: R01 CA131270-05

Mesh Terms

  • Animals
  • Antigens, CD11b
  • Antigens, CD14
  • Breast Neoplasms
  • Chemokine CCL2
  • Female
  • GPI-Linked Proteins
  • Humans
  • Inflammation
  • Lung Neoplasms
  • Macrophages
  • Mice
  • Monocytes
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Receptor, Macrophage Colony-Stimulating Factor
  • Receptors, CCR2
  • Receptors, IgG
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A