Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration.
Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration.
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DOI：
10.7150/jca.14169
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发表时间：
2016
影响因子：
3.9
通讯作者：
Gaida MM
中科院分区：
文献类型：
--
作者：
Mayer C;Darb-Esfahani S;Meyer AS;Hübner K;Rom J;Sohn C;Braicu I;Sehouli J;Hänsch GM;Gaida MM
背景：卵巢癌（OvCa）是一种高度侵袭性的恶性肿瘤，具有促肿瘤微环境。多形核中性粒细胞（PMN）的浸润是常见的，提出了它们对肿瘤发展的影响的问题。在此背景下，评估了PMN对人卵巢癌细胞的影响。方法：将人卵巢癌细胞与人中性粒细胞（PMN）、PMN裂解物或中性粒细胞弹性蛋白酶共同孵育。通过延时视频显微镜观察形态学变化，并通过流式细胞术和Western印迹分析潜在的分子机制。通过体外伤口愈合试验评估功能改变。同时，对一个大型队列的n=334份不同组织学亚型的原发性OvCa组织样本进行了组织学评价。结果如下：癌细胞与PMN或PMN裂解物的共培养导致细胞的多边形上皮表型向纺锤形形态的变化，导致筛状细胞生长。中性粒细胞引起的变化可能归因于弹性蛋白酶，中性粒细胞的主要蛋白酶。弹性蛋白酶诱导的形状变化最有可能是由于膜E-钙粘蛋白的降解，这导致细胞接触和极性的丧失。此外，响应弹性蛋白酶，上皮细胞角蛋白下调，与β-连环蛋白的核转位平行。这些PMN-弹性蛋白酶诱导的细胞改变与癌细胞的上皮-间充质转化（EMT）相容。EMT后，细胞表现出更多的迁移表型。在人类活检中，72%的病例中观察到中性粒细胞浸润。中性粒细胞浸润检测优先在E-cadherin表达低的地区。结论：OvCa微环境中的PMN可使肿瘤细胞向间质和迁移表型转变。
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.