Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model

Cancer Gene Ther. 2008 Dec;15(12):776-86. doi: 10.1038/cgt.2008.43. Epub 2008 Jul 25.


Cancer metastasis contributes significantly to cancer mortality and is facilitated by lymphangiogenesis and angiogenesis. Vascular endothelial growth factor-C (VEGF-C) and VEGF-A are involved in lymphangiogenesis and angiogenesis. To inhibit metastasis, combination therapy with vector-based small interfering RNA (siRNA) against VEGF-C and/or VEGF-A was conducted on murine metastatic mammary cancer. Syngeneic, inoculated, metastatic mammary cancers received direct intratumoral injection of plasmid siRNA vector targeting VEGF-C (psiRNA-VEGF-C), VEGF-A (psiRNA-VEGF-A), both VEGF-C and VEGF-A (both psiRNA-VEGF-C and psiRNA-VEGF-A vectors injected, referred to as the psiRNA-VEGF-C+A group) or a scrambled sequence (psiRNA-SCR) as control, once a week for 8 weeks. Gene electrotransfer was performed on the tumors after each injection. Tumor volume was significantly lower in the psiRNA-VEGF-A and the psiRNA-VEGF-C+A groups throughout the study. Lymph node metastasis was significantly less frequent in all therapeutic groups, whereas the multiplicity of lung metastases was significantly lower in the psiRNA-VEGF-C+A group only. All siRNA therapeutic groups showed a significant reduction in the number of dilated lymphatic vessels containing intraluminal cancer cells and microvessel density. Our data suggest that specific silencing of the VEGF-C or VEGF-A gene alone can inhibit lymph node metastasis. However, combination siRNA therapy targeting both VEGF-C and VEGF-A inhibits both lymph node and lung metastasis, rendering this combined therapy more beneficial than either alone. The observed anti-metastatic activity of siRNA-expressing vectors targeting VEGF-C or VEGF-A may be of high clinical significance in the treatment of metastatic breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Combined Modality Therapy
  • Female
  • Genetic Vectors
  • Lung Neoplasms / secondary*
  • Lymph Nodes / metabolism
  • Lymphatic Metastasis
  • Mammary Neoplasms, Experimental / pathology*
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Microvessels / metabolism
  • Neoplasm Metastasis
  • RNA, Small Interfering / therapeutic use*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor C / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor C / metabolism


  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C