Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity.
Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity.
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卵巢癌中上皮和间充质标记的分析揭示了表型异质性和可塑性。
DOI：
10.1371/journal.pone.0016186
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发表时间：
2011-01-14
期刊：
影响因子：
3.7
通讯作者：
Lieber A
中科院分区：
文献类型：
--
作者：
Strauss R;Li ZY;Liu Y;Beyer I;Persson J;Sova P;Möller T;Pesonen S;Hemminki A;Hamerlik P;Drescher C;Urban N;Bartek J;Lieber A
在我们对卵巢癌细胞的研究中，我们已经确定了处于短暂E/M杂交阶段的细胞亚群，即同时表达上皮和间充质标记的细胞。E/M细胞不是同质的，但在体外和体内都含有亚群，可以根据许多表型特征来区分，包括E-cadherin的亚细胞定位，以及Tie2、CD133和CD44的表达水平。一个细胞亚群（E/M-MP）（膜E-cadherinlow/细胞质E-cadherinhigh/CD133high， CD44high, Tie2low）在肿瘤形成细胞中高度富集，并表现出通常与癌症干细胞相关的特征。我们的数据表明，E/M-MP细胞能够在一定条件下分化成不同的谱系，并具有自我更新的能力，即在分化过程中维持一个未分化的E/M-MP细胞子集。E/M-MP细胞向间充质或上皮细胞的反分化与干细胞标记物的缺失和致瘤性相关。体内异种移植物肿瘤的生长是由E/M-MP细胞驱动的，这些细胞产生上皮性卵巢癌细胞。相反，在体外，我们发现E/M-MP细胞分化为间充质细胞，这一过程涉及到与上皮细胞到间充质细胞转化相关的途径。我们还发现表型可塑性依赖于外部因素，如饥饿或与上皮细胞或间充质细胞共培养产生的压力。我们的研究为卵巢癌的表型复杂性提供了更好的理解，并对卵巢癌的治疗具有指导意义。
In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherinlow/cytoplasmic E-cadherinhigh/CD133high, CD44high, Tie2low) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy.
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