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J Clin Invest. 2018 Aug 1;128(8):3280-3297. doi: 10.1172/JCI97459. Epub 2018 Jun 25.

CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.

Author information

1
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
2
Centre for Research and Development, Uppsala University, Gävle Hospital, Gävle, Sweden.
3
Department of Radiation Sciences and Oncology, Umeå University Hospital, Umeå, Sweden.
4
Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
5
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
6
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
7
Vascular Biology Unit, FIRC Institute of Molecular Oncology, Milan, Italy.

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.

KEYWORDS:

Brain cancer; Fibronectin; Oncology; Vascular Biology; endothelial cells

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