Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis.
Expression of angiogenic and lymphangiogenic factors by tumours may influence the route of metastatic spread. Vascular endothelial growth factor (VEGF) is a regulator of tumour angiogenesis, but studies of the inhibition of solid tumour growth by neutralizing anti-VEGF antibodies indicated that other angiogenic factors may be involved. VEGF-D may be an alternative regulator because like VEGF it is angiogenic and it activates VEGF receptor-2 (VEGFR-2), an endothelial cell receptor which is a key signalling molecule in tumour angiogenesis. This study reports the generation of monoclonal antibodies to the receptor-binding domain of VEGF-D and the use of these antibodies to localize VEGF-D in malignant melanoma. VEGF-D was detected in tumour cells and in vessels adjacent to immunopositive tumour cells, but not in vessels distant from the tumours. These findings are consistent with a model in which VEGF-D, secreted by tumour cells, activates endothelial cell receptors and thereby contributes to the regulation of tumour angiogenesis and possibly lymphangiogenesis. In addition, VEGF-D was detected in the vascular smooth muscle, but not the endothelium, of vessels in adult colon. The endothelium of these vessels was negative for VEGFR-2 and VEGFR-3. As VEGF receptors can be up-regulated on endothelium in response to vessel damage and ischaemia, these findings of a specific localization of VEGF-D in smooth muscle of the blood vessels suggest that VEGF-D produced by vascular smooth muscle could play a role in vascular repair by stimulating the proliferation of endothelial cells.
Achen
M G
MG
Ludwig Institute for Cancer Research, Post Office Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia. Marc.achen@ludwig.edu.au
Williams
R A
RA
Minekus
M P
MP
Thornton
G E
GE
Stenvers
K
K
Rogers
P A
PA
Lederman
F
F
Roufail
S
S
Stacker
S A
SA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D003106:Colon / Q000098:blood supply; D016228:Endothelial Growth Factors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000502:physiology; D042643:Vascular Endothelial Growth Factor D
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D017978:Receptors, Growth Factor; D042643:Vascular Endothelial Growth Factor D