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PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling

Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-depe...

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Autores principales: Egners, Antje, Rezaei, Maryam, Kuzmanov, Aleksandar, Poitz, David M., Streichert, Doreen, Müller-Reichert, Thomas, Wielockx, Ben, Breier, Georg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316346/
https://www.ncbi.nlm.nih.gov/pubmed/30563292
http://dx.doi.org/10.3390/cancers10120496
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author Egners, Antje
Rezaei, Maryam
Kuzmanov, Aleksandar
Poitz, David M.
Streichert, Doreen
Müller-Reichert, Thomas
Wielockx, Ben
Breier, Georg
author_facet Egners, Antje
Rezaei, Maryam
Kuzmanov, Aleksandar
Poitz, David M.
Streichert, Doreen
Müller-Reichert, Thomas
Wielockx, Ben
Breier, Georg
author_sort Egners, Antje
collection PubMed
description Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-dependent prolyl hydroxylase domain proteins (PHDs). However, the precise roles of these enzymes in tumor progression and their downstream signaling pathways are not fully characterized. Here, we study PHD3 function in murine experimental osteosarcoma. Unexpectedly, PHD3 silencing in LM8 cells affects neither HIF-1α protein levels, nor the expression of various HIF-1 target genes. Subcutaneous injection of PHD3-silenced tumor cells accelerated tumor progression and was accompanied by dramatic phenotypic changes in the tumor vasculature. Blood vessels in advanced PHD3-silenced tumors were enlarged whereas their density was greatly reduced. Examination of the molecular pathways underlying these alterations revealed that platelet-derived growth factor (PDGF)-C signaling is activated in the vasculature of PHD3-deficient tumors. Silencing of PDGF-C depleted tumor growth, increased vessel density and reduced vessel size. Our data show that PHD3 controls tumor growth and vessel architecture in LM8 osteosarcoma by regulating the PDGF-C pathway, and support the hypothesis that different members of the PHD family exert unique functions in tumors.
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spelling pubmed-63163462019-01-09 PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling Egners, Antje Rezaei, Maryam Kuzmanov, Aleksandar Poitz, David M. Streichert, Doreen Müller-Reichert, Thomas Wielockx, Ben Breier, Georg Cancers (Basel) Article Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-dependent prolyl hydroxylase domain proteins (PHDs). However, the precise roles of these enzymes in tumor progression and their downstream signaling pathways are not fully characterized. Here, we study PHD3 function in murine experimental osteosarcoma. Unexpectedly, PHD3 silencing in LM8 cells affects neither HIF-1α protein levels, nor the expression of various HIF-1 target genes. Subcutaneous injection of PHD3-silenced tumor cells accelerated tumor progression and was accompanied by dramatic phenotypic changes in the tumor vasculature. Blood vessels in advanced PHD3-silenced tumors were enlarged whereas their density was greatly reduced. Examination of the molecular pathways underlying these alterations revealed that platelet-derived growth factor (PDGF)-C signaling is activated in the vasculature of PHD3-deficient tumors. Silencing of PDGF-C depleted tumor growth, increased vessel density and reduced vessel size. Our data show that PHD3 controls tumor growth and vessel architecture in LM8 osteosarcoma by regulating the PDGF-C pathway, and support the hypothesis that different members of the PHD family exert unique functions in tumors. MDPI 2018-12-06 /pmc/articles/PMC6316346/ /pubmed/30563292 http://dx.doi.org/10.3390/cancers10120496 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Egners, Antje
Rezaei, Maryam
Kuzmanov, Aleksandar
Poitz, David M.
Streichert, Doreen
Müller-Reichert, Thomas
Wielockx, Ben
Breier, Georg
PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling
title PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling
title_full PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling
title_fullStr PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling
title_full_unstemmed PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling
title_short PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling
title_sort phd3 acts as tumor suppressor in mouse osteosarcoma and influences tumor vascularization via pdgf-c signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316346/
https://www.ncbi.nlm.nih.gov/pubmed/30563292
http://dx.doi.org/10.3390/cancers10120496
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