title: Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration.
abstract: BACKGROUND
  Ovarian cancer (OvCa) is a highly aggressive malignoma with a tumor-promoting microenvironment. Infiltration of polymorphonuclear neutrophils (PMN) is frequently seen, raising the question of their impact on tumor development. In that context, effects of PMN on human ovarian cancer cells were assessed.
  
  
  METHODS
  Human epithelial ovarian cancer cells were incubated with human PMN, lysate of PMN, or neutrophil elastase. Morphological alterations were observed by time-lapse video-microscopy, and the underlying molecular mechanism was analyzed by flow cytometry and Western blotting. Functional alternations were assessed by an in vitro wound healing assay. In parallel, a large cohort of n=334 primary OvCa tissue samples of various histological subtypes was histologically evaluated.
  
  
  RESULTS
  Co-cultivation of cancer cells with either PMN or PMN lysate causes a change of the polygonal epithelial phenotype of the cells towards a spindle shaped morphology, causing a cribriform cell growth. The PMN-induced alteration could be attributed to elastase, a major protease of PMN. Elastase-induced shape change was most likely due to the degradation of membranous E-cadherin, which results in loss of cell contacts and polarity. Moreover, in response to elastase, epithelial cytokeratins were downmodulated, in parallel with a nuclear translocation of β-catenin. These PMN-elastase induced alterations of cells are compatible with an epithelial-to-mesenchymal transition (EMT) of the cancer cells. Following EMT, the cells displayed a more migratory phenotype. In human biopsies, neutrophil infiltration was seen in 72% of the cases. PMN infiltrates were detected preferentially in areas with low E-cadherin expression.
  
  
  CONCLUSIONS
  PMN in the microenvironment of OvCa can alter tumor cells towards a mesenchymal and migratory phenotype.
authors.affiliation: 1. Department of Gynecology and Obstetrics, University Hospital Heidelberg, Germany;
authors.forename: Christine
authors.initials: C
authors.lastname: Mayer
authors.affiliation: 2. Institute of Pathology, Charité, University Hospital Berlin, Germany;; 3. Tumorbank Ovarian Cancer Network (TOC), Berlin, Germany;
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.affiliation: 4. Institute of Pathology, University Hospital Heidelberg, Germany;
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Meyer
authors.affiliation: 5. BioQuant, COS Heidelberg, University Heidelberg, Germany;
authors.forename: Katrin
authors.initials: K
authors.lastname: Hübner
authors.affiliation: 1. Department of Gynecology and Obstetrics, University Hospital Heidelberg, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Rom
authors.affiliation: 1. Department of Gynecology and Obstetrics, University Hospital Heidelberg, Germany;
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.affiliation: 3. Tumorbank Ovarian Cancer Network (TOC), Berlin, Germany;; 6. Department of Gynecology, Charité University Hospital Berlin, Germany;
authors.forename: Ioana
authors.initials: I
authors.lastname: Braicu
authors.affiliation: 3. Tumorbank Ovarian Cancer Network (TOC), Berlin, Germany;; 6. Department of Gynecology, Charité University Hospital Berlin, Germany;
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: 7. Institute of Immunology, University Hospital Heidelberg, Germany.
authors.forename: G Maria
authors.initials: GM
authors.lastname: Hänsch
authors.affiliation: 4. Institute of Pathology, University Hospital Heidelberg, Germany;
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
keywords: Ovarian cancer; epithelial to mesenchymal transition; migration.; neutrophil elastase; neutrophils; tumor microenvironment