Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling.
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.
Vincent
Loïc
L
Department of Genetic Medicine and Division of Hematology and Oncology, Howard Hughes Medical Institute, Weill Medical College of Cornell University, New York, New York 10021, USA. vincentloicmy@yahoo.com
Kermani
Pouneh
P
Young
Lauren M
LM
Cheng
Joseph
J
Zhang
Fan
F
Shido
Koji
K
Lam
George
G
Bompais-Vincent
Heidi
H
Zhu
Zhenping
Z
Hicklin
Daniel J
DJ
Bohlen
Peter
P
Chaplin
David J
DJ
May
Chad
C
Rafii
Shahin
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015820:Cadherins / Q000502:physiology*; D002196:Capillaries / Q000254:growth & development; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D051176:beta Catenin / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; D015820:Cadherins; D013267:Stilbenes; D051176:beta Catenin; C058728:fosbretabulin