Depleting ovarian cancer stem cells with calcitriol.
Depleting ovarian cancer stem cells with calcitriol.
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DOI：
10.18632/oncotarget.24520
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发表时间：
2018-03-06
期刊：
影响因子：
--
通讯作者：
Wang QE
中科院分区：
文献类型：
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作者：
Srivastava AK;Rizvi A;Cui T;Han C;Banerjee A;Naseem I;Zheng Y;Wani AA;Wang QE
癌症干细胞（CSC）是包括卵巢癌在内的许多实体瘤的根源。根除 CSC 代表了一种新的癌症治疗策略。骨化三醇，也称为 1,25-二羟基维生素 D3 [1,25(OH)2D3]，是维生素 D 的活性代谢物，是一种有效的类固醇激素。骨化三醇通过调节多种信号通路在多种癌症中显示出抗肿瘤作用。据报道，骨化三醇可以调节正常干细胞和癌症干细胞的特性。然而，骨化三醇对卵巢癌生长和卵巢CSC的影响仍不清楚。在这里，通过使用用人卵巢癌细胞生成的小鼠皮下异种移植模型，我们证明了骨化三醇的施用能够显着延迟肿瘤生长。骨化三醇治疗还可消除以 ALDH+ 和 CD44+CD117+ 为特征的卵巢 CSC 群体；通过体内有限稀释分析评估，降低了它们在 CSC 培养条件下形成球体的能力，并降低了肿瘤起始细胞的频率。机制研究表明，骨化三醇通过核维生素 D 受体 (VDR) 介导的 Wnt 通路抑制来消耗 CSC。此外，尽管 VDR 的表达水平相当，但卵巢 CSC 中 VDR 途径的激活比非 CSC 中的骨化三醇更敏感。综上所述，我们的数据表明骨化三醇能够通过抑制 Wnt 信号通路来消耗卵巢 CSC 群，从而阻碍异种移植肿瘤的生长。
Cancer stem cells (CSCs) represent the root of many solid tumors including ovarian cancer. Eradication of CSCs represents a novel cancer therapeutic strategy. Calcitriol, also known as 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is an active metabolite of vitamin D, functioning as a potent steroid hormone. Calcitriol has shown anti-tumor effects in various cancers by regulating multiple signaling pathways. It has been reported that calcitriol can regulate the properties of normal and CSCs. However, the effect of calcitriol on the ovarian cancer growth and ovarian CSCs is still unclear. Here, by using a mouse subcutaneous xenograft model generated with human ovarian cancer cells, we have demonstrated that administration of calcitriol is able to strikingly delay the tumor growth. Calcitriol treatment can also deplete the ovarian CSC population characterized by ALDH+ and CD44+CD117+; decrease their capacity to form sphere under the CSC culture condition, and reduce the frequency of tumor-initiating cells, as evaluated by in vivo limiting dilution analysis. Mechanistic investigation revealed that calcitriol depletes CSCs via the nuclear vitamin D receptor (VDR)-mediated inhibition of the Wnt pathway. Furthermore, the activation of VDR pathway is more sensitive to calcitriol in ovarian CSCs than in non-CSCs, although the expression levels of VDR are comparable. Taken together, our data indicate that calcitriol is able to deplete the ovarian CSC population by inhibiting their Wnt signaling pathway, consequently, impeding the growth of xenograft tumors.