title: Myofibroblasts have an impact on expression, dimerization and signaling of different ErbB receptors in OSCC cells.
abstract: BACKGROUND
  Receptors of the ErbB family belong to the key players in cancer development and are targets of several therapeutic approaches. Their functional dependency on the tumor microenvironment, especially on CAFs is albeit still poorly understood. Our objective was to investigate the impact of CAF secretome on ErbB receptor expression and signaling behavior in OSCC.
  
  
  METHODS
  Stimulation of PE/CA-PJ15 OSCC cells with conditioned media of TGF-β1-activated fibroblasts was used as model system for CAF to cancer cell communication. Thereby costimulation with inhibitors against matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), MAPK/ERK kinase (MEK), phosphoinositide-3 kinase (PI3-K), signal transducer and activator of transcription 3 (Stat3) or knockdown of Her3 by siRNA was utilized for detailed investigation of the expression, dimerization and signaling pattern of ErbB in western blot and coimmunoprecipitation.
  
  
  RESULTS
  Our results show that soluble factors in activated fibroblast secretome stimulate metalloproteinase activity in the membrane of cancer cells. Thereby ligands are released that activate EGFR and subsequently upregulates EGFR expression via the STAT3 pathway. Simultaneously, the expression of PKCɛ was enhanced via a PI3-kinase/Akt-mediated pathway and a negative feedback regulation loop on EGFR downstream signaling generated. Furthermore, the activated fibroblasts secretome stimulated the highly oncogenic hetero-dimerization between HER3 and p95HER2. That protein association is inversely dependent on the expression level of HER3.
  
  
  CONCLUSIONS
  Our results demonstrate that the activated fibroblasts secretome can induce a counterbalanced regulation of protein expression, downstream signaling and the dimerization patterns of different ErbB receptor subtypes in the cancer cell. Thus, the combinatorial targeting of CAFs and selective ErbB receptor subtype inhibitors may provide a useful approach in cancer therapy.
authors.affiliation: a Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena , Jena , Germany.|b Leibniz Institute on Aging - Fritz Lipmann Institute , >Jena > , Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Büttner
authors.affiliation: c Institute of Pathology, Jena University Hospital , Jena , Germany , and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
authors.affiliation: b Leibniz Institute on Aging - Fritz Lipmann Institute , >Jena > , Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Valkova
authors.affiliation: c Institute of Pathology, Jena University Hospital , Jena , Germany , and.
authors.forename: Petra
authors.initials: P
authors.lastname: Richter
authors.affiliation: a Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena , Jena , Germany.|d Institute for Medical Physics and Biophysics, Leipzig University Hospital , Leipzig , Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Korn
authors.affiliation: a Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena , Jena , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kosan
authors.affiliation: a Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena , Jena , Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Liebmann
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D055503:Protein Multimerization; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: ErbB receptor subtypes; OSCC cells; PKCɛ; cancer-associated fibroblasts; p95HER2