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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-?) of EAC cells. Inhibition of TGF-? ligands effectively abolished chemoradiation-induced EMT. Assessment of TGF-? 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-? production. Monitoring TGF-? serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF-? targeting therapy.

SUBMITTER: Steins A

PROVIDER: S-EPMC6767775 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Steins Anne A Ebbing Eva A EA Creemers Aafke A van der Zalm Amber P AP Jibodh Rajni A RA Waasdorp Cynthia C Meijer Sybren L SL van Delden Otto M OM Krishnadath Kausilia K KK Hulshof Maarten C C M MCCM Bennink Roelof J RJ Punt Cornelis J A CJA Medema Jan Paul JP Bijlsma Maarten F MF van Laarhoven Hanneke W M HWM

International journal of cancer 20190507 10

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) r ...[more]

PMID: 31018252

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Project description:BackgroundLung cancer is the most common and lethal malignancy worldwide. TCTP is highly expressed in various cancers including lung cancer. Epithelial-mesenchymal transition (EMT) could increase cancer cell invasion. Whether TCTP's expression is associated with EMT in lung adenocarcinoma is largely unknown.MethodsSeveral Gene Expression Omnibus datasets were used to analyze the correlation between TCTP expression and overall survival of lung adenocarcinoma patients by Kaplan-Meier survival analysis. Then, 24 surgically removed fresh lung adenocarcinoma tissue samples and paired paracancer tissue samples were used to analyze the correlation between TCTP expression and tumor stage by immunohistochemical analysis. Furthermore, stable cell lines were generated using lentiviral transduction systems to knock down or overexpress TCTP in A549 cells. Cell migration and invasion were measured by scratch and transwell assays, and EMT marker proteins such as α-SMA, ZEB1, and E-cadherin were quantitated by Western blot. The expression levels of miR-200a, miR-141, and miR-429 were determined by real-time quantitative PCR, and their target genes were predicted by an online database miRTarBase. The interaction between TCTP and these genes was analyzed by String database and visualized by Cytoscape.ResultsTCTP was highly expressed in tumor tissues compared to paracancer tissues. The expression of TCTP was associated with shorter overall survival. TCTP knockdown experiment in A549 cells suggested that TCTP knockdown could decrease the migration and invasion of lung cancer cells, and the expression level of ZEB1 and α-SMA, but increase the expression of E-cadherin and p53. Vice versa, overexpression of TCTP could increase the migration and invasion of cancer cells, and the expression level of ZEB1 and α-SMA, but decrease the expression of E-cadherin and p53. Furthermore, we found the expression of miR-200a, miR-141, and miR-429 was associated with TCTP expression.ConclusionTCTP promotes EMT in lung adenocarcinoma, and this effect may be associated with miR-200 family members like miR-200a, miR-141, and miR-429.

Dataset Information

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

Publications

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

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