CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis
Roberta Lugano, Kalyani Vemuri, Di Yu, Michael Bergqvist, Anja Smits, Magnus Essand, Staffan Johansson, Elisabetta Dejana, Anna Dimberg
Roberta Lugano, Kalyani Vemuri, Di Yu, Michael Bergqvist, Anja Smits, Magnus Essand, Staffan Johansson, Elisabetta Dejana, Anna Dimberg
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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 9

MMRN2 and fibronectin expression is increased in human high-grade glioma.

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MMRN2 and fibronectin expression is increased in human high-grade glioma...
(A and B) Immunohistochemical staining of MMRN2 (A) and fibronectin (B) in nontumor control brain and WHO grade II, grade III, and grade IV human glioma tissue. (C and D) Semiquantitative scoring of the fraction of MMRN2-positive (C) and fibronectin-positive (D) blood vessels in human glioma tissue microarrays. The frequency of positively staining vessels in 235 samples from human glioma and nontumor control brain was scored in a blinded fashion on a scale from 0 to 3 (0, no vessels stained; 1, minority of vessels stained; 2, majority of vessels stained; 3 strong staining in the majority of vessels). Results were averaged and plotted as percentage of samples per score in nontumor control brain (2 biopsies), WHO grade II (65 biopsies), grade III (29 biopsies), and grade IV samples (69 biopsies); *P < 0.005, **P < 0.0001; 1-way ANOVA with Tukey’s post-test. (E–G) Comparison between scoring of MMRN2 and CD93 (E), of fibronectin and CD93 (F), and of fibronectin and MMRN2 (G) in low-grade glioma (LGG, WHO grade II). *P < 0.05 vs. <1 score; #P < 0.05 vs. 1–2 score; 1-way ANOVA with Tukey’s post-test. Comparison between scoring of MMRN2 and CD93 (H), of fibronectin and CD93 (I), and of fibronectin and MMRN2 (J) in high-grade glioma (HGG, WHO grade III–IV). *P < 0.05, **P < 0.005, ***P < 0.0001 vs. <1 score; 1-way ANOVA with Tukey’s post-test.