Abstract
Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor (APLNR) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived APLN massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the APLN-knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, APLN depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when APLN expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM.
Highlights
Glioblastoma (GBM) is the most frequent and most aggressive primary brain tumor [1], and, -despite intensive efforts including recent advances of anti-GBM treatment modalities, there are still only limited therapeutic options, offering patients only an average survival time of one year after diagnosis, at best [2,3]
apelin gene (APLN) is co-expressed with Vascular endothelial growth factor—A (VEGFA) [19,37], suggesting a cooperative function of apelin and VEGFA in paracrine signaling from tumor to endothelial cells during GBM angiogenesis
The vascular APLN RNA signal was highest in the tumor regions where human VEGFA RNA was detected
Summary
Glioblastoma (GBM) is the most frequent and most aggressive primary brain tumor [1], and, -despite intensive efforts including recent advances of anti-GBM treatment modalities, there are still only limited therapeutic options, offering patients only an average survival time of one year after diagnosis, at best [2,3]. We found abundant APLN expression in the pseudo-palisading areas of GBM In these hypoxic regions, APLN is co-expressed with VEGFA [19,37], suggesting a cooperative function of apelin and VEGFA in paracrine signaling from tumor to endothelial cells during GBM angiogenesis. APLN is co-expressed with VEGFA [19,37], suggesting a cooperative function of apelin and VEGFA in paracrine signaling from tumor to endothelial cells during GBM angiogenesis All these data hint towards a vascular function for apelin/APLNR signaling during GBM growth. Our data demonstrates that the endothelial APLN signal can serve as an alternative target to reduce GBM growth by blocking sprouting angiogenesis
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