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CD93 promotes ?1 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 ?1 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 ?1 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 ?1 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.

SUBMITTER: Lugano R 

PROVIDER: S-EPMC6063507 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Lugano Roberta R   Vemuri Kalyani K   Yu Di D   Bergqvist Michael M   Smits Anja A   Essand Magnus M   Johansson Staffan S   Dejana Elisabetta E   Dimberg Anna A  

The Journal of clinical investigation 20180625 8


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 e  ...[more]

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