VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

In: Neuro-Oncology, Vol. 20, No. 11, 2018, p. 1462-1474.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Michaelsen, SR, Staberg, M, Pedersen, H, Jensen, KE, Majewski, W, Broholm, H, Nedergaard, MK, Meulengracht, C, Urup, T, Villingshøj, M, Lukacova, S, Skjøth-Rasmussen, J, Brennum, J, Kjær, A, Lassen, U, Stockhausen, M-T, Poulsen, HS & Hamerlik, P 2018, 'VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance', Neuro-Oncology, vol. 20, no. 11, pp. 1462-1474. https://doi.org/10.1093/neuonc/noy103

APA

Michaelsen, S. R., Staberg, M., Pedersen, H., Jensen, K. E., Majewski, W., Broholm, H., ... Hamerlik, P. (2018). VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro-Oncology, 20(11), 1462-1474. https://doi.org/10.1093/neuonc/noy103

Vancouver

Michaelsen SR, Staberg M, Pedersen H, Jensen KE, Majewski W, Broholm H et al. VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. Neuro-Oncology. 2018;20(11):1462-1474. https://doi.org/10.1093/neuonc/noy103

Author

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. / VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance. In: Neuro-Oncology. 2018 ; Vol. 20, No. 11. pp. 1462-1474.

Bibtex

@article{8f653a1200e3443080be22d961514630,
title = "VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance",
abstract = "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.",
author = "Michaelsen, {Signe R} and Mikkel Staberg and Henriette Pedersen and Jensen, {Kamilla E} and Wiktor Majewski and Helle Broholm and Nedergaard, {Mette K} and Christopher Meulengracht and Thomas Urup and Mette Villingsh{\o}j and Sl{\'a}vka Lukacova and Jane Skj{\o}th-Rasmussen and Jannick Brennum and Andreas Kj{\ae}r and Ulrik Lassen and Marie-Th{\'e}r{\'e}se Stockhausen and Poulsen, {Hans S} and Petra Hamerlik",
year = "2018",
doi = "10.1093/neuonc/noy103",
language = "English",
volume = "20",
pages = "1462--1474",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "11",

}

RIS

TY - JOUR

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

VL - 20

SP - 1462

EP - 1474

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 11

ER -

ID: 216511004