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Apelin signaling controls glioblastoma neo-vascularization

Roland E. Kälin, Neurosurgical Research, Clinic for Neurosurgery, University Clinics Munich, Munich, Germany; Anne Jarczewski, Department of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, Germany; Stefanie Kälin, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany; Giorgia Mastrella, Neurosurgical Research, Clinic for Neurosurgery, University Clinics Munich, Munich, Germany;Mengzhuo Hou, Neurosurgical Research, Clinic for Neurosurgery, University Clinics Munich, Munich, Germany; Raymond Monk, Department of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, Germany; Per Ø. Sakariassen, Department of Biomedicine, University of Bergen, Bergen, Norway: Hrvoje Miletic,Department of Biomedicine, University of Bergen, Bergen, Norway; Rolf Bjerkvig,Department of Biomedicine, University of Bergen, Bergen, Norway; Frank L. Heppner, Department of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, Germany;Rainer Glass, Neurosurgical Research, Clinic for Neurosurgery, University Clinics Munich, Munich, Germany;


Glioblastoma mulitforme (GBM) present with an abundant and aberrant tumor vasculature. While solid tumor growth largely depends on angiogenesis, the situation in GBM is less clear because of its invasive manifestation. Although VEGFA is central for pathological neo-vascularization, anti-angiogenic therapy targeting VEGFA failed in GBM patients.
We have previously established the neuroendocrine hormone apelin as a novel angiogenic factor and described its upregulation in GBM. Now, we investigated the functional role of apelin signaling during brain tumor development.
In a serial implantation model for invasive human GBM we found that upregulation of apelin and its receptor correlated with the induction of the angiogenic switch. Using orthotopic U87 xenografts, transduced with control- or apelin-shRNA, we studied the specific contribution of glioma-derived apelin to glioma formation. Depletion of apelin massively reduced the glioma vascular network. Additional blockage of the endothelial apelin signal using Apelin-KO mice completely abolished tumor angiogenesis, reduced glioma volume and increased survival. Interestingly, apelin-depleted cells changed their cell behavior towards vessel cooption. Using a murine model of GBM by implanting PDFGb/p53KO NPCs into Apelin-KO mice, we consistently demonstrated an increase in glioma cell invasion but a decrease in glioma angiogenesis and expansion. Finally, direct infusion of bioactive apelin-13 rescued the vascular phenotype.
In summary, we have shown that apelin directly regulates glioma angiogenesis and affects glioma growth. Thus, apelin and its G-protein coupled receptor may constitute an attractive because drugable target for anti-angiogenic glioma therapy.

Format: Oral communication

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