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Atypical E2Fs inhibit tumor angiogenesis

Atypical E2F transcription factors (E2F7 and E2F8) function as key regulators of cell cycle progression and their inactivation leads to spontaneous cancer formation in mice. However, the mechanism of the tumor suppressor functions of E2F7/8 remain obscure. In this study we discovered that atypical E...

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Autores principales: Weijts, B G M W, Westendorp, B, Hien, B T, Martínez-López, L M, Zijp, M, Thurlings, I, Thomas, R E, Schulte-Merker, S, Bakker, W J, de Bruin, A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770600/
https://www.ncbi.nlm.nih.gov/pubmed/28925392
http://dx.doi.org/10.1038/onc.2017.336
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author Weijts, B G M W
Westendorp, B
Hien, B T
Martínez-López, L M
Zijp, M
Thurlings, I
Thomas, R E
Schulte-Merker, S
Bakker, W J
de Bruin, A
author_facet Weijts, B G M W
Westendorp, B
Hien, B T
Martínez-López, L M
Zijp, M
Thurlings, I
Thomas, R E
Schulte-Merker, S
Bakker, W J
de Bruin, A
author_sort Weijts, B G M W
collection PubMed
description Atypical E2F transcription factors (E2F7 and E2F8) function as key regulators of cell cycle progression and their inactivation leads to spontaneous cancer formation in mice. However, the mechanism of the tumor suppressor functions of E2F7/8 remain obscure. In this study we discovered that atypical E2Fs control tumor angiogenesis, one of the hallmarks of cancer. We genetically inactivated atypical E2Fs in epithelial and mesenchymal neoplasm and analyzed blood vessel formation in three different animal models of cancer. Tumor formation was either induced by application of 7,12-Dimethylbenz(a)anthracene/12-O-Tetradecanoylphorbol-13-acetate or by Myc/Ras overexpression. To our surprise, atypical E2Fs suppressed tumor angiogenesis in all three cancer models, which is in a sharp contrast to previous findings showing that atypical E2Fs promote angiogenesis during fetal development in mice and zebrafish. Real-time imaging in zebrafish displayed that fluorescent-labeled blood vessels showed enhanced intratumoral branching in xenografted E2f7/8-deficient neoplasms compared with E2f7/8-proficient neoplasms. DLL4 expression, a key negative inhibitor of vascular branching, was decreased in E2f7/8-deficient neoplastic cells, indicating that E2F7/8 might inhibit intratumoral vessel branching via induction of DLL4.
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spelling pubmed-57706002018-01-22 Atypical E2Fs inhibit tumor angiogenesis Weijts, B G M W Westendorp, B Hien, B T Martínez-López, L M Zijp, M Thurlings, I Thomas, R E Schulte-Merker, S Bakker, W J de Bruin, A Oncogene Short Communication Atypical E2F transcription factors (E2F7 and E2F8) function as key regulators of cell cycle progression and their inactivation leads to spontaneous cancer formation in mice. However, the mechanism of the tumor suppressor functions of E2F7/8 remain obscure. In this study we discovered that atypical E2Fs control tumor angiogenesis, one of the hallmarks of cancer. We genetically inactivated atypical E2Fs in epithelial and mesenchymal neoplasm and analyzed blood vessel formation in three different animal models of cancer. Tumor formation was either induced by application of 7,12-Dimethylbenz(a)anthracene/12-O-Tetradecanoylphorbol-13-acetate or by Myc/Ras overexpression. To our surprise, atypical E2Fs suppressed tumor angiogenesis in all three cancer models, which is in a sharp contrast to previous findings showing that atypical E2Fs promote angiogenesis during fetal development in mice and zebrafish. Real-time imaging in zebrafish displayed that fluorescent-labeled blood vessels showed enhanced intratumoral branching in xenografted E2f7/8-deficient neoplasms compared with E2f7/8-proficient neoplasms. DLL4 expression, a key negative inhibitor of vascular branching, was decreased in E2f7/8-deficient neoplastic cells, indicating that E2F7/8 might inhibit intratumoral vessel branching via induction of DLL4. Nature Publishing Group 2018-01-11 2017-09-18 /pmc/articles/PMC5770600/ /pubmed/28925392 http://dx.doi.org/10.1038/onc.2017.336 Text en Copyright © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Short Communication
Weijts, B G M W
Westendorp, B
Hien, B T
Martínez-López, L M
Zijp, M
Thurlings, I
Thomas, R E
Schulte-Merker, S
Bakker, W J
de Bruin, A
Atypical E2Fs inhibit tumor angiogenesis
title Atypical E2Fs inhibit tumor angiogenesis
title_full Atypical E2Fs inhibit tumor angiogenesis
title_fullStr Atypical E2Fs inhibit tumor angiogenesis
title_full_unstemmed Atypical E2Fs inhibit tumor angiogenesis
title_short Atypical E2Fs inhibit tumor angiogenesis
title_sort atypical e2fs inhibit tumor angiogenesis
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770600/
https://www.ncbi.nlm.nih.gov/pubmed/28925392
http://dx.doi.org/10.1038/onc.2017.336
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