title: Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase-mediated degradation of E-cadherin in pancreatic tumors.
abstract: Pancreatic ductal adenocarcinoma (PDAC) presenting with a micropapillary growth pattern is frequently associated with a prominent neutrophil infiltration into the tumor. The relevance of neutrophil infiltrates for tumor progression, however, is still debated. To gain insight into the role of polymorphonuclear neutrophils (PMNs) in PDAC, we assessed their effect on pancreatic tumor cells grown in vitro as monolayers. Time-lapse video microscopy showed a PMN-induced dyshesion of the tumor cells, and subsequent experiments revealed that this dyshesion was due to PMN elastase-mediated degradation of E-cadherin, an adhesion molecule that mediates the intercellular contact of the tumor cells. E-cadherin degradation by elastase or--(for comparison) down-modulation by specific siRNA, significantly increased the migratory capacity of the pancreatic tumor cells, leading to the hypothesis that PMNs could contribute to the invasive tumor growth. To address this issue, biopsies of patients with PDAC (n = 112) were analyzed. We found that E-cadherin expression correlated negatively with PMN infiltration, compatible with the notion that E-cadherin is cleaved by PMN-derived elastase, which in turn could result in the dispersal of the tumor cells, enhanced migratory capacity and thus invasive tumor growth.
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
authors.forename: Thomas Große
authors.initials: TG
authors.lastname: Steffen
authors.forename: Frank
authors.initials: F
authors.lastname: Günther
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.forename: Klaus
authors.initials: K
authors.lastname: Felix
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Gertrud M
authors.initials: GM
authors.lastname: Hänsch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000096:biosynthesis / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D019272:Leukocyte Elastase / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis
chemical_list: D015820:Cadherins; D009363:Neoplasm Proteins; D019272:Leukocyte Elastase