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Title: Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells

Abstract

Crosstalk between carcinoma associated fibroblasts (CAFs) and oral squamous cell carcinoma (OSCC) cells is suggested to mediate phenotype transition of cancer cells as a prerequisite for tumour progression, to predict patients’ outcome, and to influence the efficacy of EGFR inhibitor therapies. Here we investigate the influence of activated fibroblasts as a model for CAFs on phenotype and EGFR signalling in OSCC cells in vitro. For this, immortalised hTERT-BJ1 fibroblasts were activated with TGFβ1 and PDGFAB to generate a myofibroblast or proliferative phenotype, respectively. Conditioned media (FCM{sub TGF}, FCM{sub PDGF}) were used to stimulate PE/CA-PJ15 OSCC cells. Results were compared to the effect of conditioned media of non-stimulated fibroblasts (FCM{sub B}). FCM{sub TGF} stimulation leads to an up-regulation of vimentin in the OSCC cells and an enhancement of invasive behaviour, indicating EMT-like effects. Similarly, FCM{sub TGF}≫FCM{sub PDGF} induced up-regulation of EGFR, but not of ErbB2/ErbB3. In addition, we detected an increase in basal activities of ERK, PI3K/Akt and Stat3 (FCM{sub TGF}>FCM{sub PDGF}) accompanied by protein interaction of vimentin with pERK. These effects are correlated with an increased proliferation. In summary, our results suggest that the activated myofibroblast phenotype provides soluble factors which are able to induce EMT-like phenomena and to increasemore » EGFR signalling as well as cell proliferation in OSCC cells. Our results indicate a possible influence of activated myofibroblasts on EGFR-inhibitor therapy. Therefore, CAFs may serve as promising novel targets for combined therapy strategies. - Highlights: • A cell culture model for cancer associated fibroblasts is described. • The mutual interaction with OSCC cells leads to up-regulation of EGFR in tumour cells. • mCAF induces EGFR downstream signalling with increased proliferation in OSCC. • Erk activation is associated with protein interaction with vimentin as sign of EMT. • Results qualify CAF as promising new therapeutic targets in OSCC.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [3];  [2]
  1. Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena (Germany)
  2. Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07740 Jena (Germany)
  3. Clinic of Internal Medicine I, Jena University Hospital, 07740 Jena (Germany)
Publication Date:
OSTI Identifier:
22395881
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 322; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOMAS; CELL CULTURES; CELL PROLIFERATION; COMBINED THERAPY; FIBROBLASTS; GROWTH FACTORS; IN VITRO; PHENOTYPE; RECEPTORS; TRANSCRIPTION

Citation Formats

Berndt, Alexander, Büttner, Robert, Gühne, Stefanie, Gleinig, Anna, Richter, Petra, Chen, Yuan, Franz, Marcus, and Liebmann, Claus. Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells. United States: N. p., 2014. Web. doi:10.1016/J.YEXCR.2013.12.024.
Berndt, Alexander, Büttner, Robert, Gühne, Stefanie, Gleinig, Anna, Richter, Petra, Chen, Yuan, Franz, Marcus, & Liebmann, Claus. Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells. United States. doi:10.1016/J.YEXCR.2013.12.024.
Berndt, Alexander, Büttner, Robert, Gühne, Stefanie, Gleinig, Anna, Richter, Petra, Chen, Yuan, Franz, Marcus, and Liebmann, Claus. Tue . "Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells". United States. doi:10.1016/J.YEXCR.2013.12.024.
@article{osti_22395881,
title = {Effects of activated fibroblasts on phenotype modulation, EGFR signalling and cell cycle regulation in OSCC cells},
author = {Berndt, Alexander and Büttner, Robert and Gühne, Stefanie and Gleinig, Anna and Richter, Petra and Chen, Yuan and Franz, Marcus and Liebmann, Claus},
abstractNote = {Crosstalk between carcinoma associated fibroblasts (CAFs) and oral squamous cell carcinoma (OSCC) cells is suggested to mediate phenotype transition of cancer cells as a prerequisite for tumour progression, to predict patients’ outcome, and to influence the efficacy of EGFR inhibitor therapies. Here we investigate the influence of activated fibroblasts as a model for CAFs on phenotype and EGFR signalling in OSCC cells in vitro. For this, immortalised hTERT-BJ1 fibroblasts were activated with TGFβ1 and PDGFAB to generate a myofibroblast or proliferative phenotype, respectively. Conditioned media (FCM{sub TGF}, FCM{sub PDGF}) were used to stimulate PE/CA-PJ15 OSCC cells. Results were compared to the effect of conditioned media of non-stimulated fibroblasts (FCM{sub B}). FCM{sub TGF} stimulation leads to an up-regulation of vimentin in the OSCC cells and an enhancement of invasive behaviour, indicating EMT-like effects. Similarly, FCM{sub TGF}≫FCM{sub PDGF} induced up-regulation of EGFR, but not of ErbB2/ErbB3. In addition, we detected an increase in basal activities of ERK, PI3K/Akt and Stat3 (FCM{sub TGF}>FCM{sub PDGF}) accompanied by protein interaction of vimentin with pERK. These effects are correlated with an increased proliferation. In summary, our results suggest that the activated myofibroblast phenotype provides soluble factors which are able to induce EMT-like phenomena and to increase EGFR signalling as well as cell proliferation in OSCC cells. Our results indicate a possible influence of activated myofibroblasts on EGFR-inhibitor therapy. Therefore, CAFs may serve as promising novel targets for combined therapy strategies. - Highlights: • A cell culture model for cancer associated fibroblasts is described. • The mutual interaction with OSCC cells leads to up-regulation of EGFR in tumour cells. • mCAF induces EGFR downstream signalling with increased proliferation in OSCC. • Erk activation is associated with protein interaction with vimentin as sign of EMT. • Results qualify CAF as promising new therapeutic targets in OSCC.},
doi = {10.1016/J.YEXCR.2013.12.024},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 2,
volume = 322,
place = {United States},
year = {2014},
month = {4}
}