TY  - JOUR
A1  - Dudvarski Stanković, Nevenka
A1  - Bicker, Frank
A1  - Keller, Stefanie
A1  - Jones, David T. W.
A1  - Harter, Patrick Nikolaus
A1  - Kienzle, Arne
A1  - Gillmann, Clarissa
A1  - Arnold, Philipp
A1  - Golebiewska, Anna
A1  - Keunen, Olivier
A1  - Giese, Alf
A1  - Deimling, Andreas von
A1  - Bäuerle, Tobias
A1  - Niclou, Simone P.
A1  - Mittelbronn, Michel Guy André
A1  - Ye, Weilan
A1  - Pfister, Stefan
A1  - Schmidt, Mirko Hans Heinrich
T1  - EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors
T2  - EMBO molecular medicine
N2  - Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti‐VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression‐free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives. In an attempt to improve the efficacy of anti‐VEGF treatment, we explored the role of the egfl7 gene in malignant glioma. We found that the encoded extracellular matrix protein epidermal growth factor‐like protein 7 (EGFL7) was secreted by glioma blood vessels but not glioma cells themselves, while no major role could be assigned to the parasitic miRNAs miR‐126/126*. EGFL7 expression promoted glioma growth in experimental glioma models in vivo and stimulated tumor vascularization. Mechanistically, this was mediated by an upregulation of integrin α5β1 on the cellular surface of endothelial cells, which enhanced fibronectin‐induced angiogenic sprouting. Glioma blood vessels that formed in vivo were more mature as determined by pericyte and smooth muscle cell coverage. Furthermore, these vessels were less leaky as measured by magnetic resonance imaging of extravasating contrast agent. EGFL7‐inhibition using a specific blocking antibody reduced the vascularization of experimental gliomas and increased the life span of treated animals, in particular in combination with anti‐VEGF and the chemotherapeutic agent temozolomide. Data allow for the conclusion that this combinatorial regimen may serve as a novel treatment option for GBM.
KW  - angiogenesis
KW  - EGFL7
KW  - endothelial cell
KW  - glioblastoma
KW  - integrin
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50262
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-502623
SN  - 1757-4684
SN  - 1757-4676
N1  - This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
VL  - 10
IS  - 9, e8420
SP  - 1
EP  - 19
PB  - Wiley-VCH ; MBO Press
CY  - Weinheim ; Heidelberg
ER  -