Solid
tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are
vascular endothelial growth factor-A (
VEGF-A), the key angiogenic stimulant, and
VEGF-C, a primary mediator of lymphangiogenesis. Small molecule
tyrosine kinase inhibitors offer the potential to inhibit more than one
kinase and impede
tumor growth by multiple mechanisms. However, their potency toward individual targets can vary.
Cediranib (
RECENTIN;
AZD2171) is an inhibitor of
VEGF signaling that has been shown in experimental models to prevent
VEGF-A-induced angiogenesis and primary
tumor growth, yet the effects of
cediranib on
VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of
cediranib against
VEGFR-3 and its associated signaling events compared with its activity against
VEGFR-2, we used the receptor-specific
ligands VEGF-E and VEGF-C156S. In human endothelial cells,
cediranib inhibited
VEGF-E-induced phosphorylation of
VEGFR-2 and VEGF-C156S-induced phosphorylation of
VEGFR-3 at concentrations of </=1nmol/L and inhibited activation of downstream signaling molecules. Additionally,
cediranib blocked VEGF-C156S-induced and
VEGF-E-induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo,
cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by
VEGF-E-expressing and VEGF-C156S-expressing adenoviruses, respectively.
Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing
VEGF-A or
VEGF-C and compromised the blood and lymphatic vasculatures of
VEGF-C-expressing
tumors.
Cediranib may, therefore, be an effective means of preventing
tumor progression, not only by inhibiting
VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting
VEGFR-3 activity and lymphangiogenesis.