Int. J. Mol. Sci. 2016, 17(2), 209; https://doi.org/10.3390/ijms17020209
Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis
Roland S. Croner 1,†,*
, Müzeyyen Sevim 2,†, Metodi V. Metodiev 3, Peter Jo 4, Michael Ghadimi 4, Vera Schellerer 1, Maximillian Brunner 1, Carol Geppert 5, Tilman Rau 5
, Michael Stürzl 6, Elisabeth Naschberger 6, Klaus E. Matzel 1, Werner Hohenberger 1, Friedrich Lottspeich 2 and Josef Kellermann 2
, Michael Stürzl 6, Elisabeth Naschberger 6, Klaus E. Matzel 1, Werner Hohenberger 1, Friedrich Lottspeich 2 and Josef Kellermann 21
Department of Surgery, University Hospital Erlangen, Erlangen 91054, Germany
2
Max-Planck-Institute of Biochemistry, Martinsried 82152, Germany
3
School of Biological Sciences/Proteomics Unit, University of Essex; Wivenhoe Park, Colchester, Essex CO4 3SQ, UK
4
Department of Surgery, University Hospital Göttingen, Göttingen 37075, Germany
5
Department of Pathology, University Hospital Erlangen, Erlangen 91054, Germany
6
Division of Molecular and Experimental Surgery, University Hospital Erlangen, Erlangen 91054, Germany
†
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Stephen A. Bustin and David Sheehan
Received: 29 October 2015 / Revised: 20 January 2016 / Accepted: 25 January 2016 / Published: 4 February 2016
(This article belongs to the Section Biochemistry)
Abstract
Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%–15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients’ informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL™) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort. View Full-TextKeywords:
rectal cancer; chemoradiation; proteomic; ICPL
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Croner, R.S.; Sevim, M.; Metodiev, M.V.; Jo, P.; Ghadimi, M.; Schellerer, V.; Brunner, M.; Geppert, C.; Rau, T.; Stürzl, M.; Naschberger, E.; Matzel, K.E.; Hohenberger, W.; Lottspeich, F.; Kellermann, J. Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis. Int. J. Mol. Sci. 2016, 17, 209.
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