A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis

Cancer Cell. 2014 May 12;25(5):605-20. doi: 10.1016/j.ccr.2014.03.021.


The close vicinity of cancer cells undergoing epithelial-mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) at the invasive front of tumors suggests that these two cell type may mutually interact. We show that mesenchymal-like breast cancer cells activate macrophages to a TAM-like phenotype by GM-CSF. Reciprocally, CCL18 from TAMs induces cancer cell EMT, forming a positive feedback loop, in coculture systems and humanized mice. Inhibition of GM-CSF or CCL18 breaks this loop and reduces cancer metastasis. High GM-CSF expression in breast cancer samples is associated with more CCL18(+) macrophages, cancer cell EMT, enhanced metastasis, and reduced patient survival. These findings suggest that a positive feedback loop between GM-CSF and CCL18 is important in breast cancer metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Chemokines, CC / antagonists & inhibitors
  • Chemokines, CC / blood
  • Chemokines, CC / metabolism*
  • Epithelial-Mesenchymal Transition*
  • Feedback, Physiological
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Granulocyte-Macrophage Colony-Stimulating Factor / blood
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Humans
  • MCF-7 Cells
  • Macrophages / immunology
  • Macrophages / pathology*
  • Mesoderm / cytology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis
  • Neoplasm Transplantation


  • CCL18 protein, human
  • Chemokines, CC
  • Granulocyte-Macrophage Colony-Stimulating Factor

Associated data

  • GEO/GSE51938