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Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines

Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte gr...

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Autores principales: Zomerman, Walderik W., Plasschaert, Sabine L. A., Diks, Sander H., Lourens, Harm-Jan, Meeuwsen-de Boer, Tiny, Hoving, Eelco W., den Dunnen, Wilfred F. A., de Bont, Eveline S. J. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619778/
https://www.ncbi.nlm.nih.gov/pubmed/26496080
http://dx.doi.org/10.1371/journal.pone.0141381
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author Zomerman, Walderik W.
Plasschaert, Sabine L. A.
Diks, Sander H.
Lourens, Harm-Jan
Meeuwsen-de Boer, Tiny
Hoving, Eelco W.
den Dunnen, Wilfred F. A.
de Bont, Eveline S. J. M.
author_facet Zomerman, Walderik W.
Plasschaert, Sabine L. A.
Diks, Sander H.
Lourens, Harm-Jan
Meeuwsen-de Boer, Tiny
Hoving, Eelco W.
den Dunnen, Wilfred F. A.
de Bont, Eveline S. J. M.
author_sort Zomerman, Walderik W.
collection PubMed
description Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor family (ErbB1-4) inhibition in medulloblastoma cell lines. Medulloblastoma cell lines were treated with tyrosine kinase inhibitors crizotinib or canertinib, targeting MET and ErbB1-4, respectively. Upon treatment, cells were stimulated with VEGF-A, PDGF-AB, HGF, FGF-2 or EGF. Subsequently, we measured cell viability and expression levels of growth factors and downstream signaling proteins. Addition of HGF or EGF phosphorylated MET or EGFR, respectively, and demonstrated phosphorylation of Akt and ERK1/2 as well as increased tumor cell viability. Crizotinib and canertinib both inhibited cell viability and phosphorylation of Akt and ERK1/2. Specifically targeting MET using shRNA’s resulted in decreased cell viability. Interestingly, addition of HGF to canertinib significantly enhanced cell viability as well as phosphorylation of Akt and ERK1/2. The HGF-induced bypass of canertinib was reversed by addition of crizotinib. HGF protein was hardly released by medulloblastoma cells itself. Addition of canertinib did not affect RTK cell surface or growth factor expression levels. This manuscript points to the bypassing capacity of exogenous HGF in medulloblastoma cell lines. It might be of great interest to anticipate on these results in developing novel clinical trials with a combination of MET and EGFR inhibitors in medulloblastoma.
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spelling pubmed-46197782015-10-29 Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines Zomerman, Walderik W. Plasschaert, Sabine L. A. Diks, Sander H. Lourens, Harm-Jan Meeuwsen-de Boer, Tiny Hoving, Eelco W. den Dunnen, Wilfred F. A. de Bont, Eveline S. J. M. PLoS One Research Article Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor family (ErbB1-4) inhibition in medulloblastoma cell lines. Medulloblastoma cell lines were treated with tyrosine kinase inhibitors crizotinib or canertinib, targeting MET and ErbB1-4, respectively. Upon treatment, cells were stimulated with VEGF-A, PDGF-AB, HGF, FGF-2 or EGF. Subsequently, we measured cell viability and expression levels of growth factors and downstream signaling proteins. Addition of HGF or EGF phosphorylated MET or EGFR, respectively, and demonstrated phosphorylation of Akt and ERK1/2 as well as increased tumor cell viability. Crizotinib and canertinib both inhibited cell viability and phosphorylation of Akt and ERK1/2. Specifically targeting MET using shRNA’s resulted in decreased cell viability. Interestingly, addition of HGF to canertinib significantly enhanced cell viability as well as phosphorylation of Akt and ERK1/2. The HGF-induced bypass of canertinib was reversed by addition of crizotinib. HGF protein was hardly released by medulloblastoma cells itself. Addition of canertinib did not affect RTK cell surface or growth factor expression levels. This manuscript points to the bypassing capacity of exogenous HGF in medulloblastoma cell lines. It might be of great interest to anticipate on these results in developing novel clinical trials with a combination of MET and EGFR inhibitors in medulloblastoma. Public Library of Science 2015-10-23 /pmc/articles/PMC4619778/ /pubmed/26496080 http://dx.doi.org/10.1371/journal.pone.0141381 Text en © 2015 Zomerman et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Zomerman, Walderik W.
Plasschaert, Sabine L. A.
Diks, Sander H.
Lourens, Harm-Jan
Meeuwsen-de Boer, Tiny
Hoving, Eelco W.
den Dunnen, Wilfred F. A.
de Bont, Eveline S. J. M.
Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines
title Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines
title_full Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines
title_fullStr Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines
title_full_unstemmed Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines
title_short Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines
title_sort exogenous hgf bypasses the effects of erbb inhibition on tumor cell viability in medulloblastoma cell lines
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619778/
https://www.ncbi.nlm.nih.gov/pubmed/26496080
http://dx.doi.org/10.1371/journal.pone.0141381
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