A CFH peptide-decorated liposomal oxymatrine inactivates cancer-associated fibroblasts of hepatocellular carcinoma through epithelial-mesenchymal transition reversion.
A CFH peptide-decorated liposomal oxymatrine inactivates cancer-associated fibroblasts of hepatocellular carcinoma through epithelial-mesenchymal transition reversion.
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CFH 肽修饰的脂质体氧化苦参碱通过上皮-间质转化逆转灭活肝细胞癌的癌症相关成纤维细胞
DOI：
10.1186/s12951-022-01311-1
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发表时间：
2022-03-05
影响因子：
10.2
通讯作者：
Chen Y
中科院分区：
文献类型：
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作者：
Guo J;Zeng H;Shi X;Han T;Liu Y;Liu Y;Liu C;Qu D;Chen Y
癌症相关成纤维细胞（CAF）恶化肿瘤微环境（TME）并阻碍肿瘤内药物递送。直接消耗CAFs存在不可预测的肿瘤转移风险。上皮-间质转化（EMT）是肝星状细胞转化为CAFs的关键过程，但逆转EMT对抗肝癌的可行性尚未得到全面研究。在这项研究中，我们报告了一种CFH肽（CFHKHKSPALSPVGGG）修饰的脂质体氧化苦参碱（CFH/OM-L），具有高亲和力的Tenascin-C通过逆转EMT靶向灭活CAFs，这是通过体内和体外上调E-cadherin和下调波形蛋白，N-cadherin和snail蛋白来验证的。CFH/OM-L与负载阿糖胞苷的脂质复合物组合后，在3D肿瘤球体和富含基质的肿瘤裸鼠移植瘤模型中均明显增强综合抗癌功效。联合治疗不仅有效地逆转了体内EMT过程，而且还显著降低了胶原蛋白，为纳米颗粒的深度渗透创造了有利条件。更重要的是，CFH/OM-L不杀死但灭活CAF，不仅导致肿瘤转移的低风险，还导致重编程TME，如M1肿瘤相关巨噬细胞极化和自然杀伤细胞活化。这种策略为在不消耗CAF的情况下重塑TME铺平了温和的道路，并为设计联合肝细胞癌治疗策略提供了强有力的工具。在线版本包含补充材料，可通过10.1186/s12951-022-01311-1获得。
Cancer-associated fibroblasts (CAFs) deteriorate tumor microenvironment (TME) and hinder intra-tumoral drug delivery. Direct depleting CAFs exists unpredictable risks of tumor metastasis. Epithelial–mesenchymal transition (EMT) is a critical process of CAFs converted from hepatic stellate cells during hepatocellular tumorigenesis; however, until now the feasibility of reversing EMT to battle hepatocellular carcinoma has not been comprehensively explored. In this study, we report a CFH peptide (CFHKHKSPALSPVGGG)-decorated liposomal oxymatrine (CFH/OM-L) with a high affinity to Tenascin-C for targeted inactivating CAFs through reversing EMT, which is verified by the upregulation of E-cadherin and downregulation of vimentin, N-cadherin, and snail protein in vivo and in vitro. After the combination with icaritin-loaded lipid complex, CFH/OM-L obviously boosts the comprehensive anticancer efficacy in both 3D tumor spheroids and stromal-rich tumor xenograft nude mouse models. The combinational therapy not only effectively reversed the in vivo EMT process but also significantly lowered the collagen, creating favorable conditions for deep penetration of nanoparticles. More importantly, CFH/OM-L does not kill but inactivates CAFs, resulting in not only a low risk of tumor metastasis but also a reprogramming TME, such as M1 tumor-associated macrophages polarization and natural killer cells activation. Such strategy paves a moderate way to remold TME without depleting CAFs and provides a powerful tool to design strategies of combinational hepatocellular carcinoma therapy. The online version contains supplementary material available at 10.1186/s12951-022-01311-1.
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影响因子：
11.5
作者：
Kyle, Alastair H.;Huxham, Lynsey A.;Minchinton, Andrew I.
通讯作者：
Minchinton, Andrew I.
影响因子：
7.2
作者：
Chiquet-Ehrismann, Ruth;Tucker, Richard P.
通讯作者：
Tucker, Richard P.
癌症相关成纤维细胞靶向脂质体全面启动肿瘤微环境，与癌细胞靶向化疗药物递送系统联合治疗
影响因子：
10.8
作者：
Chen, Binlong;Dai, Wenbing;Zhang, Qiang
通讯作者：
Zhang, Qiang
影响因子：
17.1
作者：
Lang, Jiayan;Zhao, Xiao;Nie, Guangjun
通讯作者：
Nie, Guangjun
DOI：
10.1146/annurev-pathol-052016-100322
发表时间：
2017-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
Affo S;Yu LX;Schwabe RF
通讯作者：
Schwabe RF