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Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositid...

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Autores principales: Stratman, Amber N., Farrelly, Olivia M., Mikelis, Constantinos M., Miller, Mayumi F., Wang, Zhiyong, Pham, Van N., Davis, Andrew E., Burns, Margaret C., Pezoa, Sofia A., Castranova, Daniel, Yano, Joseph J., Kilts, Tina M., Davis, George E., Gutkind, J. Silvio, Weinstein, Brant M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058007/
https://www.ncbi.nlm.nih.gov/pubmed/32139674
http://dx.doi.org/10.1038/s41467-020-14956-z
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author Stratman, Amber N.
Farrelly, Olivia M.
Mikelis, Constantinos M.
Miller, Mayumi F.
Wang, Zhiyong
Pham, Van N.
Davis, Andrew E.
Burns, Margaret C.
Pezoa, Sofia A.
Castranova, Daniel
Yano, Joseph J.
Kilts, Tina M.
Davis, George E.
Gutkind, J. Silvio
Weinstein, Brant M.
author_facet Stratman, Amber N.
Farrelly, Olivia M.
Mikelis, Constantinos M.
Miller, Mayumi F.
Wang, Zhiyong
Pham, Van N.
Davis, Andrew E.
Burns, Margaret C.
Pezoa, Sofia A.
Castranova, Daniel
Yano, Joseph J.
Kilts, Tina M.
Davis, George E.
Gutkind, J. Silvio
Weinstein, Brant M.
author_sort Stratman, Amber N.
collection PubMed
description Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositides consumed during intracellular transduction of pro-angiogenic signals in endothelial cells (EC), thus harnessing the tumor’s own production of excess stimulatory ligands to deplete adjacent ECs of the capacity to respond to these signals. Using zebrafish and human endothelial cells in vitro, we show ECs deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased vascular endothelial growth factor (VEGF) stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PIP2), resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling. Using murine tumor allograft models, we show that systemic or EC specific suppression of phosphoinositide recycling results in reduced tumor growth and tumor angiogenesis. Our results suggest inhibition of phosphoinositide recycling provides a useful anti-angiogenic approach.
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spelling pubmed-70580072020-03-06 Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling Stratman, Amber N. Farrelly, Olivia M. Mikelis, Constantinos M. Miller, Mayumi F. Wang, Zhiyong Pham, Van N. Davis, Andrew E. Burns, Margaret C. Pezoa, Sofia A. Castranova, Daniel Yano, Joseph J. Kilts, Tina M. Davis, George E. Gutkind, J. Silvio Weinstein, Brant M. Nat Commun Article Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositides consumed during intracellular transduction of pro-angiogenic signals in endothelial cells (EC), thus harnessing the tumor’s own production of excess stimulatory ligands to deplete adjacent ECs of the capacity to respond to these signals. Using zebrafish and human endothelial cells in vitro, we show ECs deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased vascular endothelial growth factor (VEGF) stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PIP2), resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling. Using murine tumor allograft models, we show that systemic or EC specific suppression of phosphoinositide recycling results in reduced tumor growth and tumor angiogenesis. Our results suggest inhibition of phosphoinositide recycling provides a useful anti-angiogenic approach. Nature Publishing Group UK 2020-03-05 /pmc/articles/PMC7058007/ /pubmed/32139674 http://dx.doi.org/10.1038/s41467-020-14956-z Text en © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Stratman, Amber N.
Farrelly, Olivia M.
Mikelis, Constantinos M.
Miller, Mayumi F.
Wang, Zhiyong
Pham, Van N.
Davis, Andrew E.
Burns, Margaret C.
Pezoa, Sofia A.
Castranova, Daniel
Yano, Joseph J.
Kilts, Tina M.
Davis, George E.
Gutkind, J. Silvio
Weinstein, Brant M.
Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
title Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
title_full Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
title_fullStr Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
title_full_unstemmed Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
title_short Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
title_sort anti-angiogenic effects of vegf stimulation on endothelium deficient in phosphoinositide recycling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058007/
https://www.ncbi.nlm.nih.gov/pubmed/32139674
http://dx.doi.org/10.1038/s41467-020-14956-z
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