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Vol. 299, Issue 3, 1073-1085, December 2001
Department of Morphology, Geneva University Medical Center, Basel,
Switzerland (J.-C.T., S.J.M., M.S.P.); Oncology Research, Novartis
Pharma, Basel, Switzerland (J.W., C.S., S.F., J.M.); and ImClone
Systems Inc., New York, New York (Z.Z, L.W.)
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
~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.
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