VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance
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VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. / Michaelsen, Signe R; Staberg, Mikkel; Pedersen, Henriette; Jensen, Kamilla E; Majewski, Wiktor; Broholm, Helle; Nedergaard, Mette K; Meulengracht, Christopher; Urup, Thomas; Villingshøj, Mette; Lukacova, Slávka; Skjøth-Rasmussen, Jane; Brennum, Jannick; Kjær, Andreas; Lassen, Ulrik; Stockhausen, Marie-Thérése; Poulsen, Hans S; Hamerlik, Petra.
I: Neuro-Oncology, Bind 20, Nr. 11, 2018, s. 1462-1474.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance
AU - Michaelsen, Signe R
AU - Staberg, Mikkel
AU - Pedersen, Henriette
AU - Jensen, Kamilla E
AU - Majewski, Wiktor
AU - Broholm, Helle
AU - Nedergaard, Mette K
AU - Meulengracht, Christopher
AU - Urup, Thomas
AU - Villingshøj, Mette
AU - Lukacova, Slávka
AU - Skjøth-Rasmussen, Jane
AU - Brennum, Jannick
AU - Kjær, Andreas
AU - Lassen, Ulrik
AU - Stockhausen, Marie-Thérése
AU - Poulsen, Hans S
AU - Hamerlik, Petra
PY - 2018
Y1 - 2018
N2 - 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 proximity ligation assay.Results: VEGF-C was expressed by patient-derived xenograft glioblastoma lines, primary cells, and matched surgical specimens before and after bevacizumab treatment. VEGF-C activated autocrine VEGFR2 signaling to promote cell survival, whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression. Supporting potential translational significance, targeting VEGF-C impaired tumor growth in vivo, with superiority to bevacizumab treatment.Conclusions: Our results demonstrate VEGF-C serves as both a paracrine and an autocrine pro-survival cytokine in glioblastoma, promoting tumor cell survival and tumorigenesis. VEGF-C permits sustained VEGFR2 activation and tumor growth, where its inhibition appears superior to bevacizumab therapy in improving tumor control.
AB - 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 proximity ligation assay.Results: VEGF-C was expressed by patient-derived xenograft glioblastoma lines, primary cells, and matched surgical specimens before and after bevacizumab treatment. VEGF-C activated autocrine VEGFR2 signaling to promote cell survival, whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression. Supporting potential translational significance, targeting VEGF-C impaired tumor growth in vivo, with superiority to bevacizumab treatment.Conclusions: Our results demonstrate VEGF-C serves as both a paracrine and an autocrine pro-survival cytokine in glioblastoma, promoting tumor cell survival and tumorigenesis. VEGF-C permits sustained VEGFR2 activation and tumor growth, where its inhibition appears superior to bevacizumab therapy in improving tumor control.
U2 - 10.1093/neuonc/noy103
DO - 10.1093/neuonc/noy103
M3 - Journal article
C2 - 29939339
VL - 20
SP - 1462
EP - 1474
JO - Neuro-Oncology
JF - Neuro-Oncology
SN - 1522-8517
IS - 11
ER -
ID: 216511004