Ascites-induced shift along epithelial-mesenchymal spectrum in ovarian cancer cells: enhancement of their invasive behavior partly dependant on αv integrins
Ascites-induced shift along epithelial-mesenchymal spectrum in ovarian cancer cells: enhancement of their invasive behavior partly dependant on αv integrins
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DOI：
10.1007/s10585-014-9658-1
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发表时间：
2014-08-01
影响因子：
4
通讯作者：
Kellouche, S.
中科院分区：
文献类型：
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作者：
Carduner, L.;Leroy-Dudal, J.;Kellouche, S.
至少三分之一的上皮性卵巢癌(OC)患者在确诊时出现腹水，几乎所有患者在复发时都有腹水。腹水是活性分子和细胞成分的动态储存库，腹水的存在与OC的腹膜转移相关，并与不良预后相关。由于上皮-间充质转化(EMT)涉及OC进展的不同阶段，我们研究了独特的腹水肿瘤微环境对EMT状态和OC细胞行为的影响。三种OC细胞系暴露在腹水中会导致细胞形态的改变。在腹水中，最初具有中间上皮表型的OC细胞的特征是明显的上皮标志物错位(E-钙粘蛋白，ZO-1染色)，而最初具有中间间质表型的OC细胞的间质标志物(N-钙粘附素，波形蛋白)增强。腹水通过允许具有初始上皮中间表型的细胞的增殖和球体的形成以及集落的扩展，或者有利于具有间充质中间表型的细胞的迁移，不同地触发与初始细胞特征相关的播散性表型。在腹水微环境中，观察到αv整合素重新进入细胞，腹水诱导的两种不同侵袭性表型(即球体形成或迁移)的增加与αv整合素有关。因此，腹水诱导向上皮-间充质光谱的不稳定中间状态转变，并赋予更具侵略性的细胞行为，该行为基于最初的上皮-间充质细胞特征而采取不同的途径。
At least one-third of patients with epithelial ovarian cancer (OC) present ascites at diagnosis and almost all have ascites at recurrence. The presence of ascites, which acts as a dynamic reservoir of active molecules and cellular components, correlates with the OC peritoneal metastasis and is associated with poor prognosis. Since epithelial-mesenchymal transition (EMT) is involved in different phases of OC progression, we have investigated the effect of the unique ascitic tumor microenvironment on the EMT status and the behavior of OC cells. The exposure of three OC cell lines to ascites leads to changes in cellular morphologies. Within ascites, OC cells harboring an initial intermediate epithelial phenotype are characterized by marked dislocation of epithelial markers (E-cadherin, ZO-1 staining) while OC cells initially harboring an intermediate mesenchymal phenotype strengthen their mesenchymal markers (N-cadherin, vimentin). Ascites differentially triggers a dissemination phenotype related to the initial cell features by either allowing the proliferation and the formation of spheroids and the extension of colonies for cells that present an initial epithelial intermediate phenotype, or favoring the migration of cells with a mesenchymal intermediate phenotype. In an ascitic microenvironment, a redeployment of alpha v integrins into cells was observed and the ascites-induced accentuation of the two different invasive phenotypes (i.e. spheroids formation or migration) was shown to involve alpha v integrins. Thus, ascites induces a shift toward an unstable intermediate state of the epithelial-mesenchymal spectrum and confers a more aggressive cell behavior that takes on a different pathway based on the initial epithelial-mesenchymal cell features.