CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis
Roberta Lugano, … , Elisabetta Dejana, Anna Dimberg
Roberta Lugano, … , Elisabetta Dejana, Anna Dimberg
Published May 15, 2018
Citation Information: J Clin Invest. 2018;128(8):3280-3297. https://doi.org/10.1172/JCI97459.
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Research Article Oncology Vascular biology

CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis

Abstract

Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is upregulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates β1 integrin signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytic cleavage. The CD93-MMRN2 complex was required for activation of β1 integrin, phosphorylation of focal adhesion kinase (FAK), and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of β1 integrin and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

Authors

Roberta Lugano, Kalyani Vemuri, Di Yu, Michael Bergqvist, Anja Smits, Magnus Essand, Staffan Johansson, Elisabetta Dejana, Anna Dimberg

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Figure 2

CD93 colocalizes with MMRN2 in growing retinal vasculature and regulates filopodia protrusions and vessel sprouting.

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CD93 colocalizes with MMRN2 in growing retinal vasculature and regulates...
(A) CD93 and MMRN2 immunofluorescent staining in the sprouting front of P6 WT mouse retina. The vasculature is visualized by isolectin B4. Scale bars: 20 μm. High-magnification picture shows CD93 localized in the filopodia and CD93/MMRN2 colocalization in the sprouting front. Arrowheads indicate secreted MMRN2 residing in the extracellular matrix close to the filopodia. (B) CD93 and MMRN2 staining in the retinal plexus region. High magnification shows CD93/MMRN2 colocalization in the vasculature. Arrowheads indicate secreted MMRN2. Scale bars: 20 μm. (C) Radial expansion of vessels in WT and CD93–/– mouse retina. The red line indicates the extension of the vascular network. Scale bars: 150 μm. (D) Vascular sprouts at the front of the retinal vasculature in WT and CD93–/– mice. The length of the endothelial sprouting front is indicated by a dotted line. Nuclei were visualized by ERG (blue). Scale bars: 50 μm. (E) Filopodia protrusions in WT and CD93–/– mice. Red dots indicate filopodia in the sprouting front. Scale bars: 20 μm. (F) Quantification of radial expansion in WT (n = 14) and CD93–/– (n = 7) mice. Values indicate the vessel migration length expressed in micrometers. Values represent mean ± SEM; 2-tailed t test. (G) Quantification of the sprouting front length in WT (n = 7), CD93+/– (n = 4), and CD93–/– (n = 7) mice. Values indicate the length of the sprouts relative to the migrating front length. (H) Filopodia quantification in WT (n = 5), CD93+/– (n = 4), and CD93–/– (n = 5) mice. Values indicate the number of filopodia per 100 μm vessel length. *P < 0.05, **P < 0.01; 1-way ANOVA with Dunnett’s multiple-comparisons test.