biostudies-literatureMichaelsen SRNovo NordiskThe Danish Cancer SocietyTorben & Alice FrimodtsDanish Cancer SocietyNovo Nordisk Fonden1462-1474https://www.ebi.ac.uk/biostudies/studies/S-EPMC6176801biostudies-literatureUnknown20(11)Background:Glioblastoma ranks among the most lethal cancers, with current therapies offering only palliation. Paracrine vascular endothelial growth factor (VEGF) signaling has been targeted using anti-angiogenic agents, whereas autocrine VEGF/VEGF receptor 2 (VEGFR2) signaling is poorly understood. Bevacizumab resistance of VEGFR2-expressing glioblastoma cells prompted interrogation of autocrine VEGF-C/VEGFR2 signaling in glioblastoma. Methods:Autocrine VEGF-C/VEGFR2 signaling was functionally investigated using RNA interference and exogenous ligands in patient-derived xenograft lines and primary glioblastoma cell cultures in vitro and in vivo. VEGF-C expression and interaction with VEGFR2 in a matched pre- and post-bevacizumab treatment cohort were analyzed by immunohistochemistry and proNeuro-oncologyVEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance.PMC6176801R148-A10151R146-A9511NNF17OC0026056NNF16OC0023146Pedersen HNedergaard MKLassen UUrup TBroholm HMeulengracht CHamerlik PPoulsen HSMajewski WBrennum JStaberg MSkjoth-Rasmussen JKjær ALukacova SStockhausen MTJensen KEMichaelsen SRVillingshoj MfalseVEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance.Background:Glioblastoma ranks among the most lethal cancers, with current therapies offering only palliation. Paracrine vascular endothelial growth factor (VEGF) signaling has been targeted using anti-angiogenic agents, whereas autocrine VEGF/VEGF receptor 2 (VEGFR2) signaling is poorly understood. Bevacizumab resistance of VEGFR2-expressing glioblastoma cells prompted interrogation of autocrine VEGF-C/VEGFR2 signaling in glioblastoma. Methods:Autocrine VEGF-C/VEGFR2 signaling was functionally investigated using RNA interference and exogenous ligands in patient-derived xenograft lines and primary glioblastoma cell cultures in vitro and in vivo. VEGF-C expression and interaction with VEGFR2 in a matched pre- and post-bevacizumab treatment cohort were analyzed by immunohistochemistry and pro2018-01-01T00:00:00Z2018 Oct2025-04-18T16:10:43.161Z2019-03-27T00:02:24ZS-EPMC61768012993933910.1093/neuonc/noy103