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CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed) Published
Abstract [en]

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 up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-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 proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, 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 integrin-β1 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.

Place, publisher, year, edition, pages
2018. Vol. 128, no 8, p. 3280-3297
Keywords [en]
Brain cancer, Fibronectin, Oncology, Vascular Biology, endothelial cells
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-350902DOI: 10.1172/JCI97459ISI: 000440461500015PubMedID: 29763414OAI: oai:DiVA.org:uu-350902DiVA, id: diva2:1206494
Funder
Swedish Cancer Society, CAN 2014/832Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, CAN 2015/1216Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075Swedish Research Council, 2016-02495Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-11-08Bibliographically approved

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Lugano, RobertaYu, DiBergqvist, MichaelSmits, AnjaEssand, MagnusJohansson, StaffanDejana, ElisabettaDimberg, Anna

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Lugano, RobertaYu, DiBergqvist, MichaelSmits, AnjaEssand, MagnusJohansson, StaffanDejana, ElisabettaDimberg, Anna
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Science for Life Laboratory, SciLifeLabVascular BiologyDepartment of Immunology, Genetics and PathologyClinical ImmunologyCentre for Research and Development, GävleborgNeurologyDepartment of Medical Biochemistry and Microbiology
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