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Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

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Harvard

Hamerlik, P, Lathia, JD, Rasmussen, R, Wu, Q, Bartkova, J, Lee, M, Moudry, P, Bartek, J, Fischer, W, Lukas, J, Rich, JN & Bartek, J 2012, 'Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth' Journal of Experimental Medicine, bind 209, nr. 3, s. 507-20. https://doi.org/10.1084/jem.20111424

APA

Hamerlik, P., Lathia, J. D., Rasmussen, R., Wu, Q., Bartkova, J., Lee, M., ... Bartek, J. (2012). Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. Journal of Experimental Medicine, 209(3), 507-20. https://doi.org/10.1084/jem.20111424

CBE

MLA

Vancouver

Author

Hamerlik, Petra ; Lathia, Justin D ; Rasmussen, Rikke ; Wu, Qiulian ; Bartkova, Jirina ; Lee, MyungHee ; Moudry, Pavel ; Bartek, Jiri ; Fischer, Walter ; Lukas, Jiri ; Rich, Jeremy N ; Bartek, Jiri. / Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. I: Journal of Experimental Medicine. 2012 ; Bind 209, Nr. 3. s. 507-20.

Bibtex

@article{43e1685d899448619883d822974cf423,
title = "Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth",
abstract = "Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133(+) human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2-Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF-VEGFR2-NRP1, which is associated with VEGFR2-NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF-VEGFR2-NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach.",
keywords = "Antibodies, Monoclonal, Humanized, Autocrine Communication, Bevacizumab, Cell Proliferation, Cell Survival, Endosomes, Glioblastoma, Humans, In Vitro Techniques, Neoplastic Stem Cells, Neovascularization, Pathologic, Neuropilin-1, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",
author = "Petra Hamerlik and Lathia, {Justin D} and Rikke Rasmussen and Qiulian Wu and Jirina Bartkova and MyungHee Lee and Pavel Moudry and Jiri Bartek and Walter Fischer and Jiri Lukas and Rich, {Jeremy N} and Jiri Bartek",
year = "2012",
month = "3",
day = "12",
doi = "10.1084/jem.20111424",
language = "English",
volume = "209",
pages = "507--20",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "3",

}

RIS

TY - JOUR

T1 - Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

AU - Hamerlik, Petra

AU - Lathia, Justin D

AU - Rasmussen, Rikke

AU - Wu, Qiulian

AU - Bartkova, Jirina

AU - Lee, MyungHee

AU - Moudry, Pavel

AU - Bartek, Jiri

AU - Fischer, Walter

AU - Lukas, Jiri

AU - Rich, Jeremy N

AU - Bartek, Jiri

PY - 2012/3/12

Y1 - 2012/3/12

N2 - Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133(+) human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2-Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF-VEGFR2-NRP1, which is associated with VEGFR2-NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF-VEGFR2-NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach.

AB - Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133(+) human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2-Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF-VEGFR2-NRP1, which is associated with VEGFR2-NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF-VEGFR2-NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach.

KW - Antibodies, Monoclonal, Humanized

KW - Autocrine Communication

KW - Bevacizumab

KW - Cell Proliferation

KW - Cell Survival

KW - Endosomes

KW - Glioblastoma

KW - Humans

KW - In Vitro Techniques

KW - Neoplastic Stem Cells

KW - Neovascularization, Pathologic

KW - Neuropilin-1

KW - RNA, Small Interfering

KW - Vascular Endothelial Growth Factor A

KW - Vascular Endothelial Growth Factor Receptor-2

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1084/jem.20111424

DO - 10.1084/jem.20111424

M3 - Journal article

VL - 209

SP - 507

EP - 520

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 3

ER -

ID: 49729683