Reversal of epithelial-mesenchymal transition and inhibition of tumor stemness of breast cancer cells through advanced combined chemotherapy
Reversal of epithelial-mesenchymal transition and inhibition of tumor stemness of breast cancer cells through advanced combined chemotherapy
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DOI：
10.1016/j.actbio.2022.08.024
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发表时间：
2022-10-12
影响因子：
9.7
通讯作者：
Fan, Yujiang
中科院分区：
文献类型：
--
作者：
Cui, Yani;Zhao, Mingda;Fan, Yujiang
Wnt/β 3-catenin信号通路的异常激活和耐药肿瘤细胞和癌症干细胞（cancer stem cells，CSC）中的上皮-间质转化（epithelial-mesenchymal transition，EMT）刺激肿瘤转移和复发。在这里，盐霉素（SL）和阿霉素（DOX）的一个有前途的组合化疗策略，通过靶向的共同递送纳米系统特异性抑制肿瘤干细胞，以克服这种异常的进展。这种策略可能是有益的药物，可以有效地渗透和浸润到3D培养的乳腺癌干细胞（BCSC）的球体中。Wnt/β 3-连环蛋白信号通路相关基因（β 3-连环蛋白、LRP 6、LEF 1和TCF 12）和靶基因（细胞周期蛋白D1、Cmyc和纤连蛋白）以及CSC干细胞相关基因（Oct 4、Nanog和Hes 1）的表达被修饰有作为活性靶向部分的寡聚透明质酸的氧化还原敏感性共递送胶束下调。体外EMT相关基因（E-cadherin和Vimentin）表达的变化表明EMT过程也被有效逆转。该策略在体内对4 T1荷瘤小鼠的实体瘤生长具有较强的抑制作用，有效降低了肿瘤转移的风险，并有效减轻了恶性肿瘤引起的脾肿大。E-cadherin、Vimentin和β-catenin的免疫组织化学染色分析证实，实体瘤中也实现了EMT的倒置。这些结果突出了SL和DOX联合化疗策略消除乳腺癌的潜力。
The abnormal activation of the Wnt/ j3-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in drug-resistant tumor cells and cancer stem cells (CSCs) stimulate tumor metastasis and recurrence. Here, a promising combined chemotherapeutic strategy of salinomycin (SL) and doxorubicin (DOX) with specific inhibition of tumor stemness by a targeted co-delivery nanosystem was developed to overcome this abnormal progression. This strategy could be benefit drugs to effectively penetrate and infiltrate into spheres of 3D-cultured breast cancer stem cells (BCSCs). The expression of the Wnt/ j3-catenin signaling pathway-related genes ( j3-catenin, LRP6, LEF1 , and TCF12 ) and target genes ( Cyclin D1, Cmyc , and Fibronectin ) as well as CSC stemness-related genes ( Oct4, Nanog , and Hes1 ) was downregulated by redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety. The changes in EMT-associated gene expression ( E-cadherin and Vimentin ) in vitro showed that the EMT process was also effectively inverted. This strategy achieved a strong inhibitory effect on solid tumor growth and an effective reduction in the risk of tumor metastasis in 4T1 tumor-bearing mice in vivo and effectively alleviated splenomegaly caused by the malignant tumor. Immunohistochemical staining analysis of E-cadherin, Vimentin, and j3-catenin confirmed that the inversion of the EMT was also achieved in solid tumors. These results highlight the potential of SL and DOX combined chemotherapeutic strategy for eliminating breast carcinoma.