Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2020; 26(23): 3236-3248
Published online Jun 21, 2020. doi: 10.3748/wjg.v26.i23.3236
Neoadjuvant chemoradiation changes podoplanin expression in esophageal cancer patients
Ute Warnecke-Eberz, Patrick Plum, Viola Schweinsberg, Uta Drebber, Christiane J Bruns, Dolores T Müller, Arnulf H Hölscher, Elfriede Bollschweiler
Ute Warnecke-Eberz, Patrick Plum, Christiane J Bruns, Dolores T Müller, Elfriede Bollschweiler, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne 50937, Germany
Viola Schweinsberg, Department of Dermatology, University Hospital of Cologne, Cologne 50937, Germany
Uta Drebber, Institute of Pathology, University Hospital of Cologne, Cologne 50937, Germany
Arnulf H Hölscher, Agaplesion Markus Hospital, Frankfurt 60431, Germany
Author contributions: Warnecke-Eberz U, Bollschweiler E designed the study; Warnecke-Eberz U, Hölscher AH coordinated the study; Schweinsberg V performed the experiments; Warnecke-Eberz U, Bollschweiler E acquired, analysed and interpreted the data; Drebber U did the pathological evaluation and scoring of protein staining; Warnecke-Eberz U, Bollschweiler E, Plum P wrote the manuscript; Müller DT supported writing of manuscript; Bruns CJ supported data interpretation.
Institutional review board statement: The use of human tissue samples and clinical data was approved by the ethics commitee of the University Hospital of Cologne (Germany), all patients provided signed informed consent, and the research was carried out in accordance with the Helsinki Declaration.
Conflict-of-interest statement: The authors disclose any conflicts of interests.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ute Warnecke-Eberz, PhD, Professor, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, Kerpener Str. 62, Cologne 50937, Germany. ute.warnecke-eberz@uk-koeln.de
Received: December 30, 2019
Peer-review started: December 30, 2019
First decision: January 19, 2020
Revised: April 20, 2020
Accepted: May 30, 2020
Article in press: May 30, 2020
Published online: June 21, 2020
Processing time: 174 Days and 0.7 Hours
ARTICLE HIGHLIGHTS
Research background

Patients with locally advanced esophageal carcinoma have a poor prognosis. Additionally, only 40%-50% of the patients profit by improved survival from neoadjuvant therapies after the burden of chemoradiation.

Research motivation

We urgently need markers for diagnosis of earlier tumor stages, for prediction of therapy response and prognosis, as well as targets for novel therapies.

Research objectives

Our aim was to evaluate the predictive impact of podoplanin expression for therapy response and prognosis and a potential association with post-transcriptional regulation by miR-363 as one mechanism of deregulation in cancer. Podoplanin protein expression has been related to clinical parameters (histological tumor type, histopathologic response classification, survival rate, clinical tumor category), with regard to a potential benefit for personalization of neoadjuvant treatment.

Research methods

Podoplanin has been visualized by immunohistochemistry in resection-specimen of 195 patients: 90 squamous cell carcinomas of the esophagus (ESCC), 105 adenocarcinomas of the esophagus (EAC) with clinical T2-3, Nx, M0. RNA was extracted from paraffin-embedded tissue, miRNA-363 quantified by real-time TaqMan-real-time-PCR.

Research results

We confirmed high podoplanin expression (HPE) in ESCC patients and its absence in EAC. We detected lower podoplanin expression in resection-specimen of 58 ESCC patients after neoadjuvant (RTx/CTx) treatment, only 11% with HPE of > 5%, compared to 32 non-pretreated primary surgery patients with 50% HPE, P = 0.0001. This novel finding of a lower podoplanin expression in the pretreated patient cohort was confirmed by the comparison of corresponding surgical specimens after neoadjuvant treatment with the individual matching pretherapeutic biopsies of 56 patients, P < 0.001. Podoplanin, however, is no predictive marker for response to neoadjuvant chemoradiation. Due to the small number of cT1-T2 patients we were only able to show a trend of association with podoplanin protein expression. We were able to demonstrate a prognostic impact of podoplanin, as well as for miR-336, a posttranscriptional regulator of this protein.

Research conclusions

Direct surgery ESCC patients with a low podoplanin expression have a better prognosis. Chemoradiation results in reduction of expression of podoplanin protein in patients with ESCC. Podoplanin expression seems to be, among others, controlled by miR-363.

Research perspectives

The decrease of podoplanin expression might become a therapeutic option.