Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis

Nature. 2014 Nov 6;515(7525):130-3. doi: 10.1038/nature13862. Epub 2014 Oct 22.


Secretion of C-C chemokine ligand 2 (CCL2) by mammary tumours recruits CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites, and CCL2 neutralization in mice inhibits metastasis by retaining monocytes in the bone marrow. Here we report a paradoxical effect of CCL2 in four syngeneic mouse models of metastatic breast cancer. Surprisingly, interruption of CCL2 inhibition leads to an overshoot of metastases and accelerates death. This is the result of monocyte release from the bone marrow and enhancement of cancer cell mobilization from the primary tumour, as well as blood vessel formation and increased proliferation of metastatic cells in the lungs in an interleukin (IL)-6- and vascular endothelial growth factor (VEGF)-A-dependent manner. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals. CCL2 has been implicated in various neoplasias and adopted as a therapeutic target. However, our results call for caution when considering anti-CCL2 agents as monotherapy in metastatic disease and highlight the tumour microenvironment as a critical determinant of successful anti-metastatic therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / cytology
  • Blood Vessels / drug effects
  • Blood Vessels / growth & development
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology*
  • Cell Proliferation / drug effects
  • Chemokine CCL2 / antagonists & inhibitors*
  • Chemokine CCL2 / metabolism*
  • Disease Models, Animal
  • Female
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / metabolism
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Mice
  • Monocytes / cytology
  • Monocytes / metabolism
  • Neoplasm Metastasis* / drug therapy
  • Neovascularization, Pathologic* / drug therapy
  • Survival Analysis
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism


  • Chemokine CCL2
  • Interleukin-6
  • Vascular Endothelial Growth Factor A