ArticleCancer research2014
Novel paracrine modulation of Notch-DLL4 signaling by fibulin-3 promotes angiogenesis in high-grade gliomas.
Article in Cancer research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 49 citations in OpenAlex.
- Dissecting the aberrant vasculature of glioblastoma: mechanisms and therapeutic targets.Cancer metastasis reviews · 2026Review
- Inhibition of Extracellular Matrix Protein Fibulin-3 Reduces Immunosuppressive Signaling and Increases Macrophage Activation in Glioblastoma.Cancer research communications · 2025Article
- [Fibulin-3 Regulates Tissue Inhibitor of Metalloproteinases 3 to Inhibit Senescence in Intervertebral Disc Nucleus Pulposus Cells].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2024Article
- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- Prenatal nicotine exposure leads to epigenetic alterations in peripheral nervous system signaling genes in the testis of the rat.Epigenetics & chromatin · 2024Article
- Molecular Mechanisms in Genetic Aortopathy-Signaling Pathways and Potential Interventions.International journal of molecular sciences · 2023Review
- Development and validation of an immune infiltration/tumor proliferation-related Notch3 nomogram for predicting survival in patients with primary glioblastoma.Frontiers in genetics · 2023Article
- Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment.Cancer metastasis reviews · 2022Review
- Preferential Antibody and Drug Conjugate Targeting of the ADAM10 Metalloprotease in Tumours.Cancers · 2022Article
- The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling.Frontiers in oncology · 2022Article
- Fibulin-3 Deficiency Protects Against Myocardial Injury Following Ischaemia/ Reperfusion inFrontiers in cardiovascular medicine · 2022Article
- Article
- Spatial regulation and generation of diversity in signaling pathways.Journal of biosciences · 2021Review
- Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective.Frontiers in cell and developmental biology · 2021Review
- The Pathophysiological Significance of Fibulin-3.Biomolecules · 2020Review
- The expression of Fibulin-3 in ovarian cancer and its relationship with prognosis.Translational cancer research · 2020Article
- EFEMP1 Overexpression Contributes to Neovascularization in Age-Related Macular Degeneration.Frontiers in pharmacology · 2020Article
- Radioimmunotherapy (RIT) in Brain Tumors.Nuclear medicine and molecular imaging · 2019Review
- The matrix protein Fibulin-3 promotes KISS1R induced triple negative breast cancer cell invasion.Oncotarget · 2018Article
- Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
High-grade gliomas are characterized by exuberant vascularization, diffuse invasion, and significant chemoresistance, resulting in a recurrent phenotype that makes them impossible to eradicate in the long term. Targeting protumoral signals in the glioma microenvironment could have significant impact against tumor cells and the supporting niche that facilitates their growth. Fibulin-3 is a protein secreted by glioma cells, but absent in normal brain, that promotes tumor invasion and survival. We show here that fibulin-3 is a paracrine activator of Notch signaling in endothelial cells and promotes glioma angiogenesis. Fibulin-3 overexpression increased tumor VEGF levels, microvascular density, and vessel permeability, whereas fibulin-3 knockdown reduced vessel density in xenograft models of glioma. Fibulin-3 localization in human glioblastomas showed dense fiber-like condensations around tumor blood vessels, which were absent in normal brain, suggesting a remarkable association of this protein with tumor endothelium. At the cellular level, fibulin-3 enhanced endothelial cell motility and association to glioma cells, reduced endothelial cell sprouting, and increased formation of endothelial tubules in a VEGF-independent and Notch-dependent manner. Fibulin-3 increased ADAM10/17 activity in endothelial cells by inhibiting the metalloprotease inhibitor TIMP3; this resulted in increased Notch cleavage and increased expression of DLL4 independently of VEGF signaling. Inhibition of ADAM10/17 or knockdown of DLL4 reduced the proangiogenic effects of fibulin-3 in culture. Taken together, these results reveal a novel, proangiogenic role of fibulin-3 in gliomas, highlighting the relevance of this protein as an important molecular target in the tumor microenvironment.
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Registered trials
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