Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis.
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)
Kubo
H
H
Departments of Gastroenterological Surgery and Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan. kubofit@kuhp.kyoto-u.ac.jp
Fujiwara
T
T
Jussila
L
L
Hashi
H
H
Ogawa
M
M
Shimizu
K
K
Awane
M
M
Sakai
Y
Y
Takabayashi
A
A
Alitalo
K
K
Yamaoka
Y
Y
Nishikawa
S I
SI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005909:Glioblastoma; D051379:Mice; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D017978:Receptors, Growth Factor; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor