Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling
Loïc Vincent, Pouneh Kermani, Lauren M. Young, Joseph Cheng, Fan Zhang, Koji Shido, George Lam, Heidi Bompais-Vincent, Zhenping Zhu, Daniel J. Hicklin, Peter Bohlen, David J. Chaplin, Chad May, Shahin Rafii
Loïc Vincent, Pouneh Kermani, Lauren M. Young, Joseph Cheng, Fan Zhang, Koji Shido, George Lam, Heidi Bompais-Vincent, Zhenping Zhu, Daniel J. Hicklin, Peter Bohlen, David J. Chaplin, Chad May, Shahin Rafii
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Research Article Angiogenesis

Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling

Abstract

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/β-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.

Authors

Loïc Vincent, Pouneh Kermani, Lauren M. Young, Joseph Cheng, Fan Zhang, Koji Shido, George Lam, Heidi Bompais-Vincent, Zhenping Zhu, Daniel J. Hicklin, Peter Bohlen, David J. Chaplin, Chad May, Shahin Rafii

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Treatment with CA4P and neutralizing mAb against VE-cadherin (BV13) prom...
Treatment with CA4P and neutralizing mAb against VE-cadherin (BV13) promotes B16 melanoma tumor necrosis. (A) Growth curves of IgG control–, CA4P-, anti–VE-cadherin– (BV13), or CA4P plus anti–VE-cadherin– (BV13) treated tumors. B16 melanoma cells were injected subcutaneously into the dorsa of C57BL/6 mice. Treatment was initiated after 10 days and mice injected every 2 days. Mice in the CA4P group received an i.v. injection of CA4P at 5 mg/kg; the anti–VE-cadherin group received an i.p. injection of 10 μg of mAb against VE-cadherin (BV13); the combined group received CA4P at 5 mg/kg plus 10 μg of mAb against VE-cadherin (BV13); and the control group received 10 μg of IgG antibody. Tumor size was measured until day 8 after the first injection, and tumor volumes were measured. The data represent the mean value of the tumor volume ± SEM (**P < 0.01, #P < 0.001 compared with IgG control group; n = 9). (B) Histopathological analysis of CA4P- and anti–VE-cadherin– (BV13) treated B16 melanoma tumors. Animals were sacrificed at day 8 after first injection. Shown here are H&E-stained paraffin sections demonstrating areas of necrosis (arrows) with CA4P and mAb against VE-cadherin (BV13) treatment. Arrowhead shows area of hemorrhage. Magnification: ×20. Scale bar, 80 μm. (C) Induction of tumor necrosis. Cell death within paraffin tumor sections was detected by TUNEL. Red staining represents positive signals within the tumors (blue cells are the negative, living cells). Arrows show areas of necrosis. Magnification: ×20. Scale bar, 80 μm.