Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer

Cancer Res. 2016 Sep 1;76(17):4970-80. doi: 10.1158/0008-5472.CAN-15-3541. Epub 2016 Jun 30.


Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remain poorly understood. Here, we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle that generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. Cancer Res; 76(17); 4970-80. ©2016 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / pathology*
  • Cell Adhesion / physiology
  • Cell Line, Tumor
  • Female
  • Heterografts
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / pathology*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction / physiology
  • Stilbenes / pharmacology
  • Transcriptome
  • Tumor Microenvironment / physiology*


  • Antineoplastic Agents
  • Stilbenes
  • pterostilbene
  • MET protein, human
  • Proto-Oncogene Proteins c-met