title: CD4+T cells potently induce epithelial-mesenchymal-transition in premalignant and malignant pancreatic ductal epithelial cells-novel implications of CD4+T cells in pancreatic cancer development.
abstract: Chronic pancreatitis (CP) is a risk factor of pancreatic ductal adenocarcinoma (PDAC) and characterized by a pronounced desmoplastic reaction with CD4+T cells accounting for the majority of the stromal T cell infiltrate. Epithelial-mesenchymal-transition (EMT) is a critical process for metastasis by which epithelial/carcinoma cells become enabled to disseminate probably prior to tumor formation. To investigate whether CD4+T cells induce EMT in human pancreatic ductal epithelial cells, premalignant H6c7 cells were mono- or co-cultured with human CD4+CD25+CD127-CD49d-regulatory T cells (T-regs) or CD4+CD25-T-effector cells (T-effs) being isolated by negative magnetic bead separation from blood of healthy donors. Particularly in the presence of activated T-effs, H6c7 cells acquired a spindle-shaped morphology, reduced E-cadherin expression, and elevated expression of the mesenchymal proteins vimentin, L1CAM, and ZEB-1. This was accompanied by an increased invasive behavior. Moreover, activated T-effs exerted similar effects in the PDAC cell line T3M4. Blocking of TNF-α and IL-6 being released at greater amounts into supernatants during co-cultures with activated T-effs attenuated the EMT-associated alterations in H6c7 cells. Supporting these findings, EMT-associated alterations (exemplified by reduced E-cadherin expression and enhanced expression of vimentin and L1CAM) were predominantly detected in ductal epithelium of CP tissues surrounded by a dense stroma enriched with CD4+T cells. Overall this study points to a novel role of CD4+T cells beyond their immune function in pancreatic tumorigenesis and underscores the view that EMT induction in pancreatic ductal epithelial cells represents an early event in PDAC development being essentially promoted by inflammatory processes.
authors.affiliation: Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Goebel
authors.affiliation: Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Grage-Griebenow
authors.affiliation: Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany.
authors.forename: Artur
authors.initials: A
authors.lastname: Gorys
authors.affiliation: Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Helm
authors.affiliation: Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany.
authors.forename: Geeske
authors.initials: G
authors.lastname: Genrich
authors.affiliation: Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany.
authors.forename: Lennart
authors.initials: L
authors.lastname: Lenk
authors.affiliation: Institute of Immunology; Christian-Albrechts-University and UKSH Campus Kiel ; Kiel, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
authors.affiliation: First Department of Medicine; UKSH Campus Lübeck ; Lübeck, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ungefroren
authors.affiliation: Institute of Medical Informatics and Statistics; UKSH Campus Kiel ; Kiel, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Freitag-Wolf
authors.affiliation: Department of Pathology and Neuropathology; University Hospital Tübingen ; Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Institute of Pathology; UKSH Campus Kiel ; Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Laboratory of Molecular Gastroenterology & Hepatology; Department of Internal Medicine I; UKSH Campus Kiel ; Kiel, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
authors.affiliation: Group Inflammatory Carcinogenesis; Institute for Experimental Medicine; Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel ; Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Sebens
keywords: AUC, area under the curve; CP, chronic pancreatitis; E-cadherin; EMT, epithelial-mesenchymal-transition; L1CAM; PBMC, peripheral blood mononuclear cells; PDAC, pancreatic ductal adenocarcinoma; PanIN, pancreatic intraepithelial neoplasia; SD, standard deviation; T-effs, CD4+CD25− T-effector cells; T-regs, CD4+CD25+CD127−CD49d− regulatory T cells; cell invasion; chronic pancreatitis; pancreatic cancer precursor lesion; tumor stroma