title: Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: the role of neutrophils and neutrophil-derived elastase.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n = 115) were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and-by implication-to tumor progression is possible.
authors.affiliation: Institut für Immunologie, Universität Heidelberg, Germany. t.grosse-steffen@web.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Grosse-Steffen
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Nathalia
authors.initials: N
authors.lastname: Giese
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: G Maria
authors.initials: GM
authors.lastname: Hänsch
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy / Q000379:methods; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099254:Organic Cation Transporter 3
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D007633:Keratins; D019272:Leukocyte Elastase; D009687:Nuclear Proteins; D027701:Organic Cation Transport Proteins; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; D000099254:Organic Cation Transporter 3; C103173:TWIST1 protein, human; C486307:ZEB1 protein, human