Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro.
Exponential tumor growth is angiogenesis-dependent. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent angiogenic inducers that act synergistically in vivo and in vitro. We assessed the effect of specific inhibitors of VEGF receptor (VEGFR)-2 tyrosine kinase activity in in vivo and in vitro models of VEGF- and bFGF-induced angiogenesis. In an implant mouse model of angiogenesis, VEGFR-2 inhibitors completely blocked angiogenesis induced by VEGF, and, surprisingly, also inhibited the effect of bFGF to various extents. In vitro, VEGF- and bFGF-induced bovine microvascular and aortic endothelial (BME and BAE) cell collagen gel invasion could be blocked by the VEGFR-2 inhibitors by 100 and approximately 90%, respectively. Similar results were obtained with VEGFR-1-IgG and VEGFR-3-IgG fusion proteins and with VEGFR-2 blocking antibodies. Both BME and BAE cells produce VEGF and VEGF-C, which is not modulated by bFGF. Thus, the unexpected inhibition of bFGF-induced angiogenesis by VEGFR-2 antagonists reveals a requirement for endogenous VEGF and VEGF-C in this process. These findings broaden the spectrum of mediators of angiogenesis that can be inhibited by VEGFR-2 antagonists and highlight the importance of these compounds as agents for inhibiting tumor growth sustained by both VEGF and bFGF.
Tille
J C
JC
Department of Morphology, Geneva University Medical Center, Basel, Switzerland.
Wood
J
J
Mandriota
S J
SJ
Schnell
C
C
Ferrari
S
S
Mestan
J
J
Zhu
Z
Z
Witte
L
L
Pepper
M S
MS
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D007074:Immunoglobulin G; D008222:Lymphokines; D010793:Phthalazines; D011725:Pyridines; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C404768:vatalanib; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor