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 (FCMTGF, FCMPDGF) were used to stimulate PE/CA-PJ15 OSCC cells. Results were compared to the effect of conditioned media of non-stimulated fibroblasts (FCMB). FCMTGF stimulation leads to an up-regulation of vimentin in the OSCC cells and an enhancement of invasive behaviour, indicating EMT-like effects. Similarly, FCMTGF≫FCMPDGF 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 (FCMTGF>FCMPDGF) 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.
authors.affiliation: Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena, Germany. Electronic address: alexander.berndt@med.uni-jena.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
authors.affiliation: Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07740 Jena, Germany. Electronic address: Robert-Buettner@gmx.net.
authors.forename: Robert
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena, Germany. Electronic address: stefanie_guehne@gmx.net.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gühne
authors.affiliation: Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena, Germany. Electronic address: annagleinig@yahoo.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Gleinig
authors.affiliation: Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena, Germany. Electronic address: P.Richter@med.uni-jena.de.
authors.forename: Petra
authors.initials: P
authors.lastname: Richter
authors.affiliation: Center for Molecular Biomedicine, Institute of Pathology, Jena University Hospital, 07740 Jena, Germany. Electronic address: Yuan.Chen@med.uni-jena.de.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Clinic of Internal Medicine I, Jena University Hospital, 07740 Jena, Germany. Electronic address: Marcus.Franz@med.uni-jena.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Franz
authors.affiliation: Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07740 Jena, Germany. Electronic address: Claus.Liebmann@uni-jena.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Liebmann
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C075278:platelet-derived growth factor A; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: Cell cycle; EGFR signaling; EMT; OSCC; Tumour associated fibroblasts