Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3

Cell Rep. 2016 Oct 25;17(5):1344-1356. doi: 10.1016/j.celrep.2016.09.083.


While chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice.

Keywords: VEGF-C; chemotherapy; host response; lymphangiogenesis; macrophages; metastatis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Female
  • Glucuronidase / metabolism
  • Humans
  • Lymphangiogenesis* / drug effects
  • Lymphatic Vessels / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Mice, Inbred BALB C
  • Neoplasm Metastasis
  • Paclitaxel / pharmacology*
  • Phenotype
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor C / blood
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*


  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3
  • heparanase
  • Glucuronidase
  • Cathepsins
  • Paclitaxel