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Journal of Cancer Research and Clinical Oncology

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Open Access 01-01-2019 | Original Article – Cancer Research

FGF8 induces therapy resistance in neoadjuvantly radiated rectal cancer

Authors: Felix Harpain, Mohamed A. Ahmed, Xenia Hudec, Gerald Timelthaler, Gerd Jomrich, Leonhard Müllauer, Edgar Selzer, Wolfgang Dörr, Michael Bergmann, Klaus Holzmann, Bettina Grasl-Kraupp, Michael Grusch, Walter Berger, Brigitte Marian, Gerd R. Silberhumer

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2019

Abstract

Purpose

Therapy response to neoadjuvant radiochemotherapy (nRCT) of locally advanced rectal cancer varies widely so that markers predicting response are urgently needed. Fibroblast growth factor (FGF) and FGF receptor (FGFR) signaling is involved in pro-survival signaling and thereby may result in radiation resistance.

Methods

In a cohort of 43 rectal cancer patients, who received nRCT, we analyzed protein levels of FGF 8 and its downstream target Survivin by immunohistochemistry to assess their impact on nRCT response. In vitro resistance models were created by exposing colorectal cancer cell lines to fractionated irradiation and selecting long-term survivors.

Results

Our findings revealed significantly higher FGF8 and Survivin staining scores in pre-treatment biopsies as well as in surgical specimens of non-responsive compared to responsive patients. Functional studies demonstrated dose-dependent induction of FGF8 mRNA expression in mismatch-incompetent DLD1 cells already after one dose of irradiation. Surviving clones after one or two series of radiation were more resistant to an additional radiation fraction than non-irradiated controls and showed a significant increase in expression of the FGF8 receptor FGFR3 and of Survivin on both the RNA and the protein levels.

Conclusion

The results of this study suggest that FGF8 and Survivin contribute to radiation resistance in rectal cancer and may serve as markers to select patients who may not benefit from neoadjuvant radiotherapy.

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Title: FGF8 induces therapy resistance in neoadjuvantly radiated rectal cancer
Authors: Felix Harpain
Mohamed A. Ahmed
Xenia Hudec
Gerald Timelthaler
Gerd Jomrich
Leonhard Müllauer
Edgar Selzer
Wolfgang Dörr
Michael Bergmann
Klaus Holzmann
Bettina Grasl-Kraupp
Michael Grusch
Walter Berger
Brigitte Marian
Gerd R. Silberhumer
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-018-2757-7

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