Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress.
Stemness and chemoresistance in epithelial ovarian carcinoma cells under shear stress.
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DOI：
10.1038/srep26788
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发表时间：
2016-06-01
影响因子：
4.6
通讯作者：
Wong AS
中科院分区：
文献类型：
--
作者：
Ip CK;Li SS;Tang MY;Sy SK;Ren Y;Shum HC;Wong AS
成功治疗癌症的最大挑战之一是耐药性。一种令人兴奋的方法是根除癌症干细胞(CSCs)。然而，对调控CSCs形成和扩展的关键信号知之甚少。此外，缺乏可靠的临床前预测模型一直是发现新的抗癌药物和预测其临床活性的主要障碍。在这里，在卵巢癌中，一种迅速致命的高度耐药的肿瘤，我们使用可定制的微流体平台和最接近于肿瘤行为的三维球体，提供了第一个证据来证明机械刺激在CSC表型中的因果参与。我们发现，卵巢癌细胞在流体切应力下生长时，显著获得了上皮向间充质转化和CSC标记的表达，并对临床相关剂量的一线化疗药物顺铂和紫杉醇产生了显著的化疗耐药，这与恶性腹水中的生理水平相吻合，但在静态条件下不能。此外，我们还发现了在切应力诱导的CSC富集中，microRNA-199a-3p、磷脂酰肌醇3-激酶/Akt和多药转运体激活的一个新的联系。我们的发现揭示了流体动力学在癌症进展中的重要性，强调了在治疗学的发展中需要一个流动信息框架。
One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics.