Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival
2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 21, 4504-4516 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2015. Vol. 75, no 21, 4504-4516 p.
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-269008DOI: 10.1158/0008-5472.CAN-14-3636ISI: 000365602200009PubMedID: 26363010OAI: oai:DiVA.org:uu-269008DiVA: diva2:881945
FunderSwedish Cancer Society, CAN 2011/862Swedish Childhood Cancer Foundation, PR2013-0107, PROJ11/083Swedish Research Council, 2013-3797, 2008-2853