Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression.
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.
Institute of Neurology (Edinger Institute) and 2 Institute for Cardiovascular Regeneration, Johann Wolfgang Goethe University Frankfurt Medical School, 60590 Frankfurt am Main, Germany.
Marco
M
Reis
Cathrin J
CJ
Czupalla
Nicole
N
Ziegler
Kavi
K
Devraj
Jenny
J
Zinke
Sascha
S
Seidel
Rosario
R
Heck
Sonja
S
Thom
Jadranka
J
Macas
Ernesto
E
Bockamp
Marcus
M
Fruttiger
Makoto M
MM
Taketo
Stefanie
S
Dimmeler
Karl H
KH
Plate
Stefan
S
Liebner
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D002135:Calcium-Binding Proteins; D016543:Central Nervous System Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005910:Glioma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C501127:Dkk1 protein, mouse; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020574:Proto-Oncogene Proteins c-sis; C090140:Whn protein; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin