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.