The molecular and cellular pathways that support the maintenance and stability of
tumor neovessels are not well defined. The efficacy of microtubule-disrupting agents, such as
combretastatin A4 phosphate (CA4P), in inducing rapid regression of specific subsets of
tumor neovessels has opened up new avenues of research to identify factors that support
tumor neoangiogenesis. Herein, we show that CA4P selectively targeted endothelial cells, but not smooth muscle cells, and induced regression of unstable nascent
tumor neovessels by rapidly disrupting the molecular engagement of the endothelial cell-specific junctional molecule
vascular endothelial-cadherin (
VE-cadherin) in vitro and in vivo in mice. CA4P increases endothelial cell permeability, while inhibiting endothelial cell migration and capillary tube formation predominantly through disruption of
VE-cadherin/
beta-catenin/Akt signaling pathway, thereby leading to rapid vascular collapse and
tumor necrosis. Remarkably, stabilization of
VE-cadherin signaling in endothelial cells with adenovirus E4 gene or ensheathment with smooth muscle cells confers resistance to CA4P. CA4P synergizes with low and nontoxic doses of neutralizing mAbs to
VE-cadherin by blocking assembly of neovessels, thereby inhibiting
tumor growth. These data suggest that the microtubule-targeting agent CA4P selectively induces regression of unstable
tumor neovessels, in part through disruption of
VE-cadherin signaling. Combined treatment with anti-
VE-cadherin agents in conjunction with microtubule-disrupting agents provides a novel synergistic strategy to selectively disrupt assembly and induce regression of nascent
tumor neovessels, with minimal toxicity and without affecting normal stabilized vasculature.