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
