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Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration

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...

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Autores principales: Mayer, Christine, Darb-Esfahani, Silvia, Meyer, Anne-Sophie, Hübner, Katrin, Rom, Joachim, Sohn, Christof, Braicu, Ioana, Sehouli, Jalid, Hänsch, G. Maria, Gaida, Matthias M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2016
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820731/
https://www.ncbi.nlm.nih.gov/pubmed/27053953
http://dx.doi.org/10.7150/jca.14169
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author Mayer, Christine
Darb-Esfahani, Silvia
Meyer, Anne-Sophie
Hübner, Katrin
Rom, Joachim
Sohn, Christof
Braicu, Ioana
Sehouli, Jalid
Hänsch, G. Maria
Gaida, Matthias M.
author_facet Mayer, Christine
Darb-Esfahani, Silvia
Meyer, Anne-Sophie
Hübner, Katrin
Rom, Joachim
Sohn, Christof
Braicu, Ioana
Sehouli, Jalid
Hänsch, G. Maria
Gaida, Matthias M.
author_sort Mayer, Christine
collection PubMed
description 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. Conclusion: PMN in the microenvironment of OvCa can alter tumor cells towards a mesenchymal and migratory phenotype.
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spelling pubmed-48207312016-04-06 Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration Mayer, Christine Darb-Esfahani, Silvia Meyer, Anne-Sophie Hübner, Katrin Rom, Joachim Sohn, Christof Braicu, Ioana Sehouli, Jalid Hänsch, G. Maria Gaida, Matthias M. J Cancer Research Paper 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. Conclusion: PMN in the microenvironment of OvCa can alter tumor cells towards a mesenchymal and migratory phenotype. Ivyspring International Publisher 2016-03-10 /pmc/articles/PMC4820731/ /pubmed/27053953 http://dx.doi.org/10.7150/jca.14169 Text en © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.
spellingShingle Research Paper
Mayer, Christine
Darb-Esfahani, Silvia
Meyer, Anne-Sophie
Hübner, Katrin
Rom, Joachim
Sohn, Christof
Braicu, Ioana
Sehouli, Jalid
Hänsch, G. Maria
Gaida, Matthias M.
Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration
title Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration
title_full Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration
title_fullStr Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration
title_full_unstemmed Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration
title_short Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration
title_sort neutrophil granulocytes in ovarian cancer - induction of epithelial-to-mesenchymal-transition and tumor cell migration
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820731/
https://www.ncbi.nlm.nih.gov/pubmed/27053953
http://dx.doi.org/10.7150/jca.14169
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