Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
Clinical Research Unit, Changhai Hospital, Naval Medical University, 168 Changhai Road, 200433, Shanghai, China.
J Nanobiotechnology. 2022 Feb 14;20(1):79. doi: 10.1186/s12951-022-01280-5.
The malignant transformation of normal resident hepatic stem/progenitor cells has a critical role in hepatocarcinogenesis and the recurrence of hepatocellular carcinoma (HCC). We defined such hepatic progenitor cells as hepatoma-initiating cells. An efficient strategy is required to target and kill the hepatoma-initiating cells. We isolated extracellular microparticles (MPs) derived from apoptotic hepatic progenitor cells (HPCs) and tested their ability to inhibit hepatocarcinogenesis. Extracellular MPs were isolated from HPCs, hepatocytes and liver tumor cells. Their effects on tumor growth were investigated in rat primary HCC models, in which hepatocarcinogenesis is induced by diethylnitrosamine (DEN). The extracellular MPs derived from apoptotic HPCs, apoptotic hepatocytes and apoptotic liver tumor cells were similar in morphology, diameter and zeta potential. However, they had different antitumor effects. In DEN-exposed rats, only the MPs derived from apoptotic HPCs effectively inhibit hepatocarcinogenesis. In vitro and in vivo analyses confirmed that HPCs preferentially take up MPs derived from apoptotic HPCs compared to MPs from other liver cell types. Proteomic analysis of MPs from apoptotic HPCs showed enrichment of proteins involved in cell death pathways. Thus, HPC-derived MPs contain a death signal to induce the killing of hepatoma-initiating cells. Our findings provide evidence that a death signal encapsulated in HPC-derived extracellular microparticles can efficiently clear hepatoma-initiating cells and prevent hepatocarcinogenesis.
正常驻留的肝干细胞/祖细胞的恶性转化在肝癌发生和肝细胞癌（HCC）复发中起关键作用。我们将这种肝祖细胞定义为肝癌起始细胞。需要一种有效的策略来靶向和杀死肝癌起始细胞。我们分离了来自凋亡肝祖细胞（HPC）的细胞外微颗粒（MPs），并测试了它们抑制肝癌发生的能力。从 HPC、肝细胞和肝癌细胞中分离细胞外 MPs。在大鼠原发性 HCC 模型中研究了它们对肿瘤生长的影响，其中肝癌发生是由二乙基亚硝胺（DEN）诱导的。凋亡 HPC、凋亡肝细胞和凋亡肝癌细胞衍生的细胞外 MPs 在形态、直径和 ζ 电位方面相似，但它们具有不同的抗肿瘤作用。在 DEN 暴露的大鼠中，只有来自凋亡 HPC 的 MPs 能有效抑制肝癌发生。体外和体内分析证实，与来自其他肝细胞类型的 MPs 相比，HPC 优先摄取来自凋亡 HPC 的 MPs。凋亡 HPC 衍生的 MPs 的蛋白质组学分析显示，细胞死亡途径相关蛋白富集。因此，HPC 衍生的 MPs 包含诱导肝癌起始细胞杀伤的死亡信号。我们的研究结果提供了证据，表明封装在 HPC 衍生的细胞外微颗粒中的死亡信号可以有效地清除肝癌起始细胞并预防肝癌发生。
