Chemoradiation induces epithelial-to-mesenchymal transition in esophageal adenocarcinoma

Anne Steins, Eva A. Ebbing, Aafke Creemers, Amber P. van der Zalm, Rajni A. Jibodh, Cynthia Waasdorp, Sybren L. Meijer, Otto M. van Delden, Kausilia K. Krishnadath, Maarten C. C. M. Hulshof, Roelof J. Bennink, Cornelis J. A. Punt, Jan Paul Medema, Maarten F. Bijlsma, Hanneke W. M. van Laarhoven

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)2792-2803
JournalInternational Journal of Cancer
Volume145
Issue number10
DOIs
Publication statusPublished - 2019

Cite this

Steins, A., Ebbing, E. A., Creemers, A., van der Zalm, A. P., Jibodh, R. A., Waasdorp, C., ... van Laarhoven, H. W. M. (2019). Chemoradiation induces epithelial-to-mesenchymal transition in esophageal adenocarcinoma. International Journal of Cancer, 145(10), 2792-2803. https://doi.org/10.1002/ijc.32364
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. In: International Journal of Cancer. 2019 ; Vol. 145, No. 10. pp. 2792-2803.
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title = "Chemoradiation induces epithelial-to-mesenchymal transition in esophageal adenocarcinoma",
abstract = "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.",
author = "Anne Steins and Ebbing, {Eva A.} and Aafke Creemers and {van der Zalm}, {Amber P.} and Jibodh, {Rajni A.} and Cynthia Waasdorp and Meijer, {Sybren L.} and {van Delden}, {Otto M.} and Krishnadath, {Kausilia K.} and Hulshof, {Maarten C. C. M.} and Bennink, {Roelof J.} and Punt, {Cornelis J. A.} and Medema, {Jan Paul} and Bijlsma, {Maarten F.} and {van Laarhoven}, {Hanneke W. M.}",
year = "2019",
doi = "10.1002/ijc.32364",
language = "English",
volume = "145",
pages = "2792--2803",
journal = "International Journal of Cancer",
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Steins, A, Ebbing, EA, Creemers, A, van der Zalm, AP, Jibodh, RA, Waasdorp, C, Meijer, SL, van Delden, OM, Krishnadath, KK, Hulshof, MCCM, Bennink, RJ, Punt, CJA, Medema, JP, Bijlsma, MF & van Laarhoven, HWM 2019, 'Chemoradiation induces epithelial-to-mesenchymal transition in esophageal adenocarcinoma' International Journal of Cancer, vol. 145, no. 10, pp. 2792-2803. https://doi.org/10.1002/ijc.32364

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.

In: International Journal of Cancer, Vol. 145, No. 10, 2019, p. 2792-2803.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Chemoradiation induces epithelial-to-mesenchymal transition in esophageal adenocarcinoma

AU - Steins, Anne

AU - Ebbing, Eva A.

AU - Creemers, Aafke

AU - van der Zalm, Amber P.

AU - Jibodh, Rajni A.

AU - Waasdorp, Cynthia

AU - Meijer, Sybren L.

AU - van Delden, Otto M.

AU - Krishnadath, Kausilia K.

AU - Hulshof, Maarten C. C. M.

AU - Bennink, Roelof J.

AU - Punt, Cornelis J. A.

AU - Medema, Jan Paul

AU - Bijlsma, Maarten F.

AU - van Laarhoven, Hanneke W. M.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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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UR - https://www.ncbi.nlm.nih.gov/pubmed/31018252

U2 - 10.1002/ijc.32364

DO - 10.1002/ijc.32364

M3 - Article

VL - 145

SP - 2792

EP - 2803

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

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Steins A, Ebbing EA, Creemers A, van der Zalm AP, Jibodh RA, Waasdorp C et al. Chemoradiation induces epithelial-to-mesenchymal transition in esophageal adenocarcinoma. International Journal of Cancer. 2019;145(10):2792-2803. https://doi.org/10.1002/ijc.32364