Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer

Am J Respir Crit Care Med. 2015 Feb 15;191(4):437-47. doi: 10.1164/rccm.201406-1137OC.


Rationale: Recent studies indicate that tumor-associated macrophages (MΦ) with an M2 phenotype can influence cancer progression and metastasis, but the regulatory pathways remain poorly characterized.

Objectives: This study investigated the role of tumor-associated MΦ in lung cancer.

Methods: Coculturing of MΦ with mouse Lewis lung carcinoma (LLC1) and 10 different human lung cancer cell lines (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) caused up-regulation of CCR2/CCL2 and CX3CR1/CX3CL1 in both the cancer cells and the MΦ.

Measurements and main results: In the MΦ-tumor cell system, IL-10 drove CCR2 and CX3CR1 up-regulation, whereas CCL1, granulocyte colony-stimulating factor, and MIP1α were required for the up-regulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and MΦ M2 polarization. In vivo, MΦ depletion (clodronate, MΦ Fas-induced apoptosis mice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated MΦ toward M1 polarization, suppressed tumor vessel growth, and enhanced survival (metastasis model). Furthermore, mice treated with CCR2 antagonist mimicked genetic ablation of CCR2, showing reduced tumor growth and metastasis. In human lung cancer samples, tumor MΦ infiltration and CCR2 expression correlated with tumor stage and metastasis.

Conclusions: Tumor-associated MΦ play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between MΦ and cancer cells via CCR2 and CX3CR1 signaling as a central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression.

Keywords: CCR2; CX3CR1; lung cancer; macrophages; microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Animals
  • Biomarkers, Tumor / metabolism*
  • CX3C Chemokine Receptor 1
  • Carcinoma, Large Cell / metabolism*
  • Carcinoma, Large Cell / pathology
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Chemokine CCL2 / metabolism
  • Chemokine CX3CL1 / metabolism
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Macrophages / metabolism*
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Receptor Cross-Talk
  • Receptors, CCR2 / metabolism
  • Receptors, Chemokine / metabolism
  • Up-Regulation


  • Biomarkers, Tumor
  • CCL2 protein, human
  • CCR2 protein, human
  • CX3C Chemokine Receptor 1
  • CX3CL1 protein, human
  • CX3CR1 protein, human
  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Chemokine CX3CL1
  • Cx3cl1 protein, mouse
  • Cx3cr1 protein, mouse
  • Receptors, CCR2
  • Receptors, Chemokine