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Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma

Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplati...

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Autores principales: Steins, Anne, Ebbing, Eva A., Creemers, Aafke, van der Zalm, Amber P., Jibodh, Rajni A., Waasdorp, Cynthia, Meijer, Sybren L., van Delden, Otto M., Krishnadath, Kausilia K., Hulshof, Maarten C.C.M., Bennink, Roelof J., Punt, Cornelis J.A., Medema, Jan Paul, Bijlsma, Maarten F., van Laarhoven, Hanneke W.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767775/
https://www.ncbi.nlm.nih.gov/pubmed/31018252
http://dx.doi.org/10.1002/ijc.32364
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author Steins, Anne
Ebbing, Eva A.
Creemers, Aafke
van der Zalm, Amber P.
Jibodh, Rajni A.
Waasdorp, Cynthia
Meijer, Sybren L.
van Delden, Otto M.
Krishnadath, Kausilia K.
Hulshof, Maarten C.C.M.
Bennink, Roelof J.
Punt, Cornelis J.A.
Medema, Jan Paul
Bijlsma, Maarten F.
van Laarhoven, Hanneke W.M.
author_facet Steins, Anne
Ebbing, Eva A.
Creemers, Aafke
van der Zalm, Amber P.
Jibodh, Rajni A.
Waasdorp, Cynthia
Meijer, Sybren L.
van Delden, Otto M.
Krishnadath, Kausilia K.
Hulshof, Maarten C.C.M.
Bennink, Roelof J.
Punt, Cornelis J.A.
Medema, Jan Paul
Bijlsma, Maarten F.
van Laarhoven, Hanneke W.M.
author_sort Steins, Anne
collection PubMed
description Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplatin, paclitaxel and radiotherapy. We developed an in vitro approximation of this regimen and applied it to primary patient‐derived cultures. We observed a heterogeneous epithelial‐to‐mesenchymal (EMT) response to the high therapeutic pressure exerted by chemoradiation. We found EMT to be initiated by the autocrine production and response to transforming growth factor beta (TGF‐β) of EAC cells. Inhibition of TGF‐β ligands effectively abolished chemoradiation‐induced EMT. Assessment of TGF‐β serum levels in EAC patients revealed that high levels after neoadjuvant treatment predicted the presence of fluorodeoxyglucose uptake in lymph nodes on the post‐chemoradiation positron emission tomography‐scan. Our study shows that chemoradiation contributes to resistant metastatic disease in EAC patients by inducing EMT via autocrine TGF‐β production. Monitoring TGF‐β serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF‐β targeting therapy.
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spelling pubmed-67677752019-10-03 Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma Steins, Anne Ebbing, Eva A. Creemers, Aafke van der Zalm, Amber P. Jibodh, Rajni A. Waasdorp, Cynthia Meijer, Sybren L. van Delden, Otto M. Krishnadath, Kausilia K. Hulshof, Maarten C.C.M. Bennink, Roelof J. Punt, Cornelis J.A. Medema, Jan Paul Bijlsma, Maarten F. van Laarhoven, Hanneke W.M. Int J Cancer Molecular Cancer Biology Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplatin, paclitaxel and radiotherapy. We developed an in vitro approximation of this regimen and applied it to primary patient‐derived cultures. We observed a heterogeneous epithelial‐to‐mesenchymal (EMT) response to the high therapeutic pressure exerted by chemoradiation. We found EMT to be initiated by the autocrine production and response to transforming growth factor beta (TGF‐β) of EAC cells. Inhibition of TGF‐β ligands effectively abolished chemoradiation‐induced EMT. Assessment of TGF‐β serum levels in EAC patients revealed that high levels after neoadjuvant treatment predicted the presence of fluorodeoxyglucose uptake in lymph nodes on the post‐chemoradiation positron emission tomography‐scan. Our study shows that chemoradiation contributes to resistant metastatic disease in EAC patients by inducing EMT via autocrine TGF‐β production. Monitoring TGF‐β serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF‐β targeting therapy. John Wiley & Sons, Inc. 2019-05-07 2019-11-15 /pmc/articles/PMC6767775/ /pubmed/31018252 http://dx.doi.org/10.1002/ijc.32364 Text en © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Molecular Cancer Biology
Steins, Anne
Ebbing, Eva A.
Creemers, Aafke
van der Zalm, Amber P.
Jibodh, Rajni A.
Waasdorp, Cynthia
Meijer, Sybren L.
van Delden, Otto M.
Krishnadath, Kausilia K.
Hulshof, Maarten C.C.M.
Bennink, Roelof J.
Punt, Cornelis J.A.
Medema, Jan Paul
Bijlsma, Maarten F.
van Laarhoven, Hanneke W.M.
Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma
title Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma
title_full Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma
title_fullStr Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma
title_full_unstemmed Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma
title_short Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma
title_sort chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma
topic Molecular Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767775/
https://www.ncbi.nlm.nih.gov/pubmed/31018252
http://dx.doi.org/10.1002/ijc.32364
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