Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis

Blood. 2000 Jul 15;96(2):546-53.


Vascular endothelial growth factor (VEGF) plays a major role in tumor angiogenesis. VEGF-C, however, is thought to stimulate the growth of lymphatic vessels because an expression of its specific receptor, VEGF receptor-3 (VEGFR-3), was demonstrated to be restricted to lymphatic vessels. Here we demonstrate that the inactivation of VEGFR-3 by a novel blocking monoclonal antibody (mAb) suppresses tumor growth by inhibiting the neo-angiogenesis of tumor-bearing tissues. Although VEGFR-3 is not expressed in adult blood vessels, it is induced in vascular endothelial cells of the tumor-bearing tissues. Hence, VEGFR-3 is another receptor tyrosine kinase involved in tumor-induced angiogenesis. Micro-hemorrhage in the tumor-bearing tissue was the most conspicuous histologic finding specific to AFL4 mAb-treated mice. Scanning microscopy demonstrated disruptions of the endothelial lining of the postcapillary venule, probably the cause of micro-hemorrhage and the subsequent collapse of the proximal vessels. These findings suggest the involvement of VEGFR-3 in maintaining the integrity of the endothelial lining during angiogenesis. Moreover, our results suggest that the VEGF-C/VEGFR-3 pathway may serve another candidate target for cancer therapy. (Blood. 2000;96:546-553)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Blotting, Western
  • Endothelium, Vascular / pathology*
  • Enzyme-Linked Immunosorbent Assay
  • Glioblastoma
  • Mice
  • Mice, Nude
  • Microscopy, Electron, Scanning
  • Neoplasm Transplantation
  • Neoplasms, Experimental / blood supply*
  • Neovascularization, Pathologic / pathology*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / immunology
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / immunology
  • Receptors, Growth Factor / physiology*
  • Receptors, Vascular Endothelial Growth Factor
  • Transfection
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • Receptors, Growth Factor
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor