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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Cancer
2016 ; 7
(5
): 546-54
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Neutrophil Granulocytes in Ovarian Cancer - Induction of
Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration
#MMPMID27053953
Mayer C
; Darb-Esfahani S
; Meyer AS
; Hübner K
; Rom J
; Sohn C
; Braicu I
; Sehouli J
; Hänsch GM
; Gaida MM
J Cancer
2016[]; 7
(5
): 546-54
PMID27053953
show ga
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 ?-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.