Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model

Br J Cancer. 2009 Oct 6;101(7):1100-6. doi: 10.1038/sj.bjc.6605296.


Background: Vascular endothelial growth factor receptor-3 (VEGFR-3) signalling mediates lymphangiogenesis and lymphatic invasion; however, the effect of VEGFR-3 inhibition on the lymph node (LN) metastasis remains unclear. The aim of this study is to clarify the benefit of a VEGFR-3 inhibitor Ki23057 for LN metastasis.

Methods: Ki23057 was administered orally to gastric cancer models created by orthotopic inoculation of diffuse-type gastric cancer cells, OCUM-2MLN. The effects of Ki23057 on lymphatic vessel invasion, lymphatic vessel density, and VEGFR-3 phosphorylation were examined by immunostaining or immunoblotting.

Results: Ki23057 inhibited the autophosphorylation of VEGFR-3, with IC50 values of 4.3 nM in the cell-free kinase assay. Murine gastric cancer models created by the orthotopic inoculation of OCUM-2MLN cells showed the diffusely infiltrating growth and frequently developed LN metastasis. The oral administration of Ki23057 significantly (P<0.01) reduced the size of orthotopic tumours and the number of the metastatic LN in gastric cancer models. The degree of lymphatic invasion and lymphangiogenesis was significantly (P<0.05) lower in the gastric tumours treated by Ki23057. Ki23057 inhibited the phosphorylation of VEGFR-3 of lymphatic endothelial cells in gastric tumours.

Conclusion: The inhibition of lymphangiogenesis targeting VEGFR-3 phosphorylation is a therapeutic strategy for inhibiting LN metastasis of diffuse-type gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Glycoproteins / analysis
  • Humans
  • Lymphangiogenesis / drug effects
  • Lymphatic Metastasis / prevention & control*
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation
  • Quinolines / pharmacology
  • Quinolines / therapeutic use*
  • Stomach Neoplasms / blood supply
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / pathology
  • Vascular Endothelial Growth Factor C / analysis
  • Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism


  • Glycoproteins
  • Ki23057
  • Membrane Transport Proteins
  • Quinolines
  • Vascular Endothelial Growth Factor C
  • Xlkd1 protein, mouse
  • vascular endothelial growth factor C, mouse
  • Vascular Endothelial Growth Factor Receptor-3