Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway

Cancer Cell. 2012 Jul 10;22(1):91-105. doi: 10.1016/j.ccr.2012.05.023.


Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Extravasation of Diagnostic and Therapeutic Materials*
  • Janus Kinase 2 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR2 / metabolism*
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Ccr2 protein, mouse
  • Receptors, CCR2
  • STAT5 Transcription Factor
  • JAK2 protein, human
  • Janus Kinase 2
  • p38 Mitogen-Activated Protein Kinases