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Cited by 167Angiogenesis and VEGF in CancerBarrier Structure and Function StudiesGlioma Diagnosis and Treatment

Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

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Reis, Marco, Czupalla, Cathrin J., Ziegler, Nicole, Devraj, Kavi, Zinke, Jenny, Seidel, Sascha, Heck, Rosario, Thom, Sonja +7 more·2012·Journal of Experimental Medicine
DOI 10.1084/jem.20111580PMC PMC3428944
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Abstract

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.

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  • β-catenin regulates PDGF-B, the ligand for PDGFRβ, promoting mural cell recruitment and BBB integrity.

    “β‐catenin also regulates PDGF‐B, the ligand for PDGFRβ, promoting mural cell recruitment and BBB integrity, 68 a mechanism potentially underlying the vascular protection observed with APOE3Ch ‐EVs.”

    From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [68]

    The Results and Discussion (page unavailable) report that endothelial β-catenin signaling increases PDGF-B, contributing to smooth-muscle-cell/pericyte recruitment and improved barrier properties in glioma vessels. The passages do not identify PDGFRβ as PDGF-B’s receptor, so that specific part of the attributed claim is not verified by our copy. (LLM, conf=0.85)

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Authors
Reis, M., Czupalla, C. J., Ziegler, N., Devraj, K., Zinke, J., Seidel, S., Heck, R., Thom, S., Macas, J., Bockamp, E., Fruttiger, M., Taketo, M. M., Dimmeler, S., Plate, K. H., & Liebner, S.
Affiliations
  • Goethe University Frankfurt (DE)
  • University College London (GB)
  • Johannes Gutenberg University Mainz (DE)
  • Kyoto University (JP)
Corresponding author
Liebner, Stefan
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2012-08-20
Volume
209
Issue
9
Pages
1611-1627
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20111580
PMC
PMC3428944
OpenAlex
W2143979909
Cited by
167
References
2
Citations by year
2026: 7 · 2025: 7 · 2024: 16 · 2023: 17 · 2022: 11 · 2021: 13 · 2020: 10 · 2019: 7 · 2018: 10 · 2017: 17 · 2016: 9 · 2015: 16 · 2014: 16 · 2013: 9 · 2012: 2
FWCI
5.52
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Keywords
Wnt/β-catenin signaling, glioma angiogenesis, tumor vasculature normalization, PDGF-B, endothelial cells, blood-brain barrier, Dll4-Notch signaling, DKK1, Wnt1, anti-angiogenic therapy
MeSH terms
Animals, Blood-Brain Barrier, Brain Neoplasms, Calcium-Binding Proteins, Endothelium, Vascular, Female, Glioma, Humans, Membrane Proteins, Mice, Nude, Neovascularization, Pathologic, Central Nervous System Neoplasms, Proto-Oncogene Proteins c-sis, Xenograft Model Antitumor Assays, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Wnt1 Protein, beta Catenin, Mice, Forkhead Transcription Factors, Wnt Signaling Pathway, Neoplasm Grading

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