TY  - JOUR
A1  - Reis, Marco
A1  - Czupalla, Cathrin Jacqueline
A1  - Ziegler, Nicole
A1  - Devraj, Kavi
A1  - Zinke, Jenny
A1  - Seidel, Sascha
A1  - Heck, Rosario
A1  - Thom, Sonja
A1  - Macas, Jadranka
A1  - Bockamp, Ernesto
A1  - Fruttiger, Marcus
A1  - Taketo, Makoto Mark
A1  - Dimmeler, Stefanie
A1  - Plate, Karl
A1  - Liebner, Stefan
T1  - Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression
T2  - Journal of experimental medicine
N2  - Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy.
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/32367
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-323675
SN  - 1540-9538
SN  - 0022-1007
N1  - Copyright © 2012 Reis et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
VL  - 209
IS  - 9
SP  - 1611
EP  - 1627
PB  - Rockefeller Univ. Press
CY  - New York, NY
ER  -