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
Abstract
BACKGROUND

Locally advanced adenocarcinoma of the esophagus (EAC) and squamous cell carcinoma (ESCC) result in a worse prognosis. Neoadjuvant treatment improves survival, however, only for responders. The transmembrane glycoprotein podoplanin is overexpressed in squamous cell carcinomas, miRNA-363 is associated to its regulation in head and neck cancer.

AIM

To predict therapy response and prognosis markers, and targets for novel therapies would individualize treatments leading to more favourable outcomes.

METHODS

Expression of podoplanin protein has been visualized by immunohistochemistry in surgical specimens of 195 esophageal cancer patients who underwent transthoracic esophagectomy: 90 ESCC and 105 EAC with clinical T2-3, Nx, M0. One hundred and six patients received neoadjuvant chemoradiation. RNA was extracted from paraffin-embedded tissue, and miRNA-363 quantified by real-time TaqMan-real-time-PCR. D2-40 mab staining of > 5% was scored as high podoplanin expression (HPE). We related podoplanin and miRNA-363 expression to histopathologic response after neoadjuvant treatment and clinicopathological characteristics, such as histological tumor type, survival rate or clinical tumor category.

RESULTS

We confirmed expression of membrane-bound podoplanin in 90 ESCC patients. 26% showed HPE of > 5%. In addition, absence in EAC patients (only 2% with HPE) was shown. Lower podoplanin expression has been detected in resection-specimen of 58 ESCC patients after neoadjuvant (RTx/CTx) treatment, only 11% with HPE, compared to 50% HPE of 32 non-pretreated primary surgery patients, P = 0.0001. This difference of podoplanin expression was confirmed comparing pre-treatment biopsies with matching post-treatment surgical specimens, P < 0.001. Podoplanin has been identified as a prognostic marker in 32 patients that underwent primary surgery without neoadjuvant treatment. Low (0-5%) podoplanin expression was associated with better prognosis compared to patients with HPE, P = 0.013. Podoplanin expression has been associated with post-transcriptional regulation by miRNA-363. At a cut-off value of miR-363 < 7, lower miR-363 expression correlated with HPE in surgical tissue specimens of primary surgery patients, P = 0.013. Therefore, ESCC patients with miRNA-363 expression < 7 had a worse prognosis than patients expressing miRNA-363 ≥ 7, P = 0.049.

CONCLUSION

Analysis of the molecular process that leads to decrease in podoplanin expression during neoadjuvant treatment and its regulation may provide novel markers and targets to improve targeted therapy of ESCC.

Keywords: Esophageal cancer, Response prediction, Prognosis, D2-40, Posttranscriptional regulation, miRNA-363

Core tip: Podoplanin is an oncofetal membrane protein, re-expressed in squamous cell carcinoma of the esophagus. Podoplanin expression seems to be, among others, controlled by miR-363. Chemoradiation results in reduction of podoplanin protein expression, and furthermore, podoplanin is a prognostic factor for survival. This implicates that a decrease of podoplanin might become a therapeutic option.