The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells

Cancer Cell. 2006 Mar;9(3):209-23. doi: 10.1016/j.ccr.2006.02.018.


Flt-4, a VEGF receptor, is activated by its specific ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis. This report provides evidence that the VEGF-C/Flt-4 axis enhances cancer cell mobility and invasiveness and contributes to the promotion of cancer cell metastasis. VEGF-C/Flt-4-mediated invasion and metastasis of cancer cells were found to require upregulation of the neural cell adhesion molecule contactin-1 through activation of the Src-p38 MAPK-C/EBP-dependent pathway. Examination of tumor tissues from various types of cancers revealed high levels of Flt-4 and VEGF-C expression that correlated closely with clinical metastasis and patient survival. The VEGF-C/Flt-4 axis, through upregulation of contactin-1, may regulate the invasive capacity in different types of cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cell Movement
  • Contactin 1
  • Contactins
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Lymphatic Metastasis / pathology
  • Male
  • Mice
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Invasiveness / pathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*


  • CNTN1 protein, human
  • Cell Adhesion Molecules, Neuronal
  • Cntn1 protein, mouse
  • Contactin 1
  • Contactins
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3
  • Mitogen-Activated Protein Kinases