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Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis

Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes suc...

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Autores principales: Merk, Henriette, Zhang, Siwei, Lehr, Thorsten, Müller, Christoph, Ulrich, Melanie, Bibb, James A., Adams, Ralf H., Bracher, Franz, Zahler, Stefan, Vollmar, Angelika M., Liebl, Johanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868742/
https://www.ncbi.nlm.nih.gov/pubmed/26755662
http://dx.doi.org/10.18632/oncotarget.6842
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author Merk, Henriette
Zhang, Siwei
Lehr, Thorsten
Müller, Christoph
Ulrich, Melanie
Bibb, James A.
Adams, Ralf H.
Bracher, Franz
Zahler, Stefan
Vollmar, Angelika M.
Liebl, Johanna
author_facet Merk, Henriette
Zhang, Siwei
Lehr, Thorsten
Müller, Christoph
Ulrich, Melanie
Bibb, James A.
Adams, Ralf H.
Bracher, Franz
Zahler, Stefan
Vollmar, Angelika M.
Liebl, Johanna
author_sort Merk, Henriette
collection PubMed
description Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy.
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spelling pubmed-48687422016-05-20 Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis Merk, Henriette Zhang, Siwei Lehr, Thorsten Müller, Christoph Ulrich, Melanie Bibb, James A. Adams, Ralf H. Bracher, Franz Zahler, Stefan Vollmar, Angelika M. Liebl, Johanna Oncotarget Research Paper Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy. Impact Journals LLC 2016-01-08 /pmc/articles/PMC4868742/ /pubmed/26755662 http://dx.doi.org/10.18632/oncotarget.6842 Text en Copyright: © 2016 Merk et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Merk, Henriette
Zhang, Siwei
Lehr, Thorsten
Müller, Christoph
Ulrich, Melanie
Bibb, James A.
Adams, Ralf H.
Bracher, Franz
Zahler, Stefan
Vollmar, Angelika M.
Liebl, Johanna
Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis
title Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis
title_full Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis
title_fullStr Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis
title_full_unstemmed Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis
title_short Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis
title_sort inhibition of endothelial cdk5 reduces tumor growth by promoting non-productive angiogenesis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868742/
https://www.ncbi.nlm.nih.gov/pubmed/26755662
http://dx.doi.org/10.18632/oncotarget.6842
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