Apelin Controls Angiogenesis-Dependent Glioblastoma Growth

• Published in: International journal of molecular sciences 2020-06, Vol.21 (11), p.4179
• Main Authors: Frisch, Anne, Kälin, Stefanie, Monk, Raymond, Radke, Josefine, Heppner, Frank L, Kälin, Roland E
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Apelin - genetics; Apelin - metabolism; Brain cancer; Brain Neoplasms - blood supply; Brain Neoplasms - diagnostic imaging; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain tumors; Cell Line, Tumor; Depletion; FDA approval; Functional analysis; Gene Expression Regulation, Neoplastic; Genes; Genetic engineering; Glioblastoma; Glioblastoma - blood supply; Glioblastoma - diagnostic imaging; Glioblastoma - drug therapy; Glioblastoma - mortality; Humans; Hybridization; Hypoxia; Intercellular Signaling Peptides and Proteins - pharmacology; Ligands; Magnetic Resonance Imaging; Mice, Knockout; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - diagnostic imaging; Neoplasms, Experimental - mortality; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Phenotypes; Solid tumors; Tumor Microenvironment; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21114179

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 ( ) and its receptor ( ) 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 massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the -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, depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when 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.