The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer.
The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer.
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DOI：
10.18632/oncotarget.17871
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发表时间：
2017-07-04
期刊：
影响因子：
--
通讯作者：
Katabuchi H
中科院分区：
文献类型：
--
作者：
Tayama S;Motohara T;Narantuya D;Li C;Fujimoto K;Sakaguchi I;Tashiro H;Saya H;Nagano O;Katabuchi H
上皮性卵巢癌是一种高度致命的恶性肿瘤。此外，克服化疗耐药性是治疗卵巢癌患者的主要挑战。癌症干细胞 (CSC) 假说认为 CSC 是导致肿瘤发生、转移和对常规治疗产生耐药性的罪魁祸首。尽管越来越多的证据表明 CSC 与化疗耐药有关，但 CSC 标志物 EpCAM 对化疗耐药的贡献仍未解决。在这里，我们证明了含有高水平 EpCAM 的卵巢癌在一线化疗后实现总体反应率的可能性显着降低。此外，多变量分析显示EpCAM表达是化疗耐药的独立危险因素，表明EpCAM表达是化疗反应的预测生物标志物。与这些临床观察一致，在体外测定中，我们发现与 EpCAM 阴性细胞相比，EpCAM 阳性卵巢癌细胞亚群通过阻止化疗诱导的细胞凋亡（受 EpCAM-Bcl-2 轴调节）对顺铂治疗做出反应，显示出显着更高的生存能力。此外，在体内小鼠模型中，与 EpCAM 阳性细胞相比，铂类药物优先消除 EpCAM 阴性细胞，这表明 EpCAM 阳性细胞的剩余亚群有助于化疗后肿瘤复发。最后，我们还发现 EpCAM 表达增加与卵巢癌患者预后不良相关。我们的研究结果强调了 EpCAM 在化疗耐药中的临床意义，并为 EpCAM 靶向治疗改善化疗耐药性提供了理论依据。靶向 EpCAM 应该是有效根除作为卵巢癌推定根源的 CSC 的一种有前途的方法。
Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved. Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAM-positive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapy-induced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis in ovarian cancer patients. Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer.
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影响因子：
11.2
作者：
Jaeger, Michael;Schoberth, Alexandra;Lindhofer, Horst
通讯作者：
Lindhofer, Horst
影响因子：
168.9
作者：
Gastl, G;Spizzo, G;Mikuz, G
通讯作者：
Mikuz, G
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1111/igc.0b013e3181a8331f
发表时间：
2009-07-01
影响因子：
4.8
作者：
Bellone, Stefania;Siegel, Eric R.;Santin, Alessandro D.
通讯作者：
Santin, Alessandro D.