title: Elevated expression of the C-type lectin CD93 in the glioblastoma vasculature regulates cytoskeletal rearrangements that enhance vessel function and reduce host survival.
abstract: Glioblastoma is an aggressive brain tumor characterized by an abnormal blood vasculature that is hyperpermeable. Here, we report a novel role for CD93 in regulating angiogenesis in this setting by modulating cell-cell and cell-matrix adhesion of endothelial cells. Tissue microarray analysis demonstrated that vascular expression of CD93 was correlated with poor survival in a clinical cohort of patients with high-grade astrocytic glioma. Similarly, intracranial growth in the GL261 mouse model of glioma was delayed significantly in CD93(-/-) hosts, resulting in improved survival compared with wild-type mice. This effect was associated with increased vascular permeability and decreased vascular perfusion of tumors, indicating reduced vessel functionality in the absence of CD93. RNAi-mediated attenuation of CD93 in endothelial cells diminished VEGF-induced tube formation in a three-dimensional collagen gel. CD93 was required for efficient endothelial cell migration and proper cell polarization in vitro. Further, in endothelial cells where CD93 was attenuated, decreased cell spreading led to a severe reduction in cell adhesion, a lack of proper cell contacts, a loss of VE-cadherin, and aberrant actin stress fiber formation. Our results identify CD93 as a key regulator of glioma angiogenesis and vascular function, acting via cytoskeletal rearrangements required for cell-cell and cell-matrix adhesion.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Elise
authors.initials: E
authors.lastname: Langenkamp
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lugano
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, Neurology, University Hospital Uppsala, Uppsala, Sweden.
authors.forename: Tamador Elsir Abu
authors.initials: TE
authors.lastname: Elhassan
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Georganaki
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Wesam
authors.initials: W
authors.lastname: Bazzar
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lööf
authors.affiliation: Department of Neurology, University Medicine Goettingen, Göttingen, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Trendelenburg
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Department of Neuroscience, Neurology, University Hospital Uppsala, Uppsala, Sweden. Department of Neurology, Danish Epilepsy Center, Dianalund, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Smits
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. Anna.Dimberg@igp.uu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
mesh_terms: D008841:Actin Cytoskeleton / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001932:Brain Neoplasms / Q000098:blood supply* / Q000401:mortality / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D002199:Capillary Permeability / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005909:Glioblastoma / Q000098:blood supply* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D022502:Stress Fibers / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D011951:Receptors, Complement; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C467484:VEGFA protein, human; C032402:complement 1q receptor