Delivery of human natural killer cell-derived exosomes for liver cancer therapy: an in vivo study in subcutaneous and orthotopic animal models.
Delivery of human natural killer cell-derived exosomes for liver cancer therapy: an in vivo study in subcutaneous and orthotopic animal models.
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用于肝癌治疗的人类自然杀伤细胞衍生的外泌体的递送：皮下和原位动物模型的体内研究。
DOI：
10.1080/10717544.2022.2118898
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发表时间：
2022-12
期刊：
影响因子：
6
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中科院分区：
文献类型：
--
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外泌体是由各种细胞类型分泌的纳米级细胞外囊泡，包括免疫系统的细胞，如自然杀伤（NK）细胞。它们通过在细胞之间运输信号分子而在细胞间通讯中发挥作用。最近的研究报道，NK细胞来源的外泌体（NK-exo）含有细胞毒性蛋白诱导的细胞死亡。然而，NK-exo的特性和潜在的功能，特别是对肝癌的了解甚少。在这项研究中，我们使用原位和皮下肿瘤模型研究了NK-exo在原发性肝癌、肝细胞癌（HCC）中的抗肿瘤作用。我们发现NK-exo表达典型的外泌体标记物（例如，CD 63、CD 81和阿利克斯）和细胞毒性蛋白（例如，穿孔素、颗粒酶B、FasL和TRAIL）。NK-exo被HCC细胞（例如Hep 3B、HepG 2和Huh 7）选择性摄取。有趣的是，与HepG 2和Huh 7细胞相比，Hep 3B细胞诱导的细胞毒性最高，并显着增强NK-exo的细胞凋亡。此外，我们证明NK-exo抑制丝氨酸/苏氨酸蛋白激酶（例如AKT和ERK 1/2）的磷酸化，并增强Hep 3B细胞中特异性凋亡标志物（例如caspase-3、-7、-8、-9和PARP）的活化。NK-exo在原位和皮下HCC小鼠模型中也表现出主动靶向能力和有效的治疗效果。总的来说，这些结果表明，NK-exo在HCC中显示出强的抗肿瘤作用，这是由涉及丝氨酸/苏氨酸激酶途径相关的细胞增殖和半胱天冬酶活化途径相关的细胞凋亡的新的调节机制介导的。
Exosomes are nanosized extracellular vesicles secreted by various cell types, including those of the immune system, such as natural killer (NK) cells. They play a role in intercellular communication by transporting signal molecules between the cells. Recent studies have reported that NK cell-derived exosomes (NK-exo) contain cytotoxic proteins-induced cell death. However, the characteristics and potential functions of NK-exo, especially for the liver cancer are poorly understood. In this study, we investigated the anti-tumor effects of NK-exo in the primary liver cancer, hepatocellular carcinoma (HCC), using the orthotopic and subcutaneous tumor model. We found that NK-exo expressed both typical exosomal markers (e.g. CD63, CD81, and Alix) and cytotoxic proteins (e.g. perforin, granzyme B, FasL, and TRAIL). NK-exo were selectively taken up by HCC cells (e.g. Hep3B, HepG2, and Huh 7). Interestingly, Hep3B cells induced the highest cytotoxicity compared with HepG2 and Huh7 cells, and substantially enhanced the apoptosis by NK-exo. Furthermore, we demonstrated that NK-exo inhibited the phosphorylation of serine/threonine protein kinases (e.g. AKT and ERK1/2), and enhanced the activation of specific apoptosis markers (e.g. caspase-3, -7, -8, -9, and PARP) in Hep3B cells. NK-exo also exhibit the active targeting ability and potent therapeutic effects in both orthotopic and subcutaneous HCC mouse models. Overall, these results suggest that NK-exo indicate strong anti-tumor effects in HCC, which are mediated by novel regulatory mechanisms involved in serine/threonine kinase pathway-associated cell proliferation and caspase activation pathway-associated apoptosis.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
4.1
作者：
Liu P;Chen L;Zhang H
通讯作者：
Zhang H
影响因子：
5.2
作者：
Di Pace, Anna Laura;Tumino, Nicola;Moretta, Lorenzo
通讯作者：
Moretta, Lorenzo
DOI：
10.1159/000099265
发表时间：
2007-01-01
期刊：
Chemical immunology and allergy
影响因子：
--
作者：
Ferguson, Thomas A;Griffith, Thomas S
通讯作者：
Griffith, Thomas S
PI3K/Akt/GSK-3 beta/ROS/eIF2B 通路通过抑制 NK 细胞的细胞毒性和肿瘤细胞易感性促进乳腺癌生长和转移
影响因子：
5.5
作者：
Jin, Fengjiao;Wu, Zhaozhen;Wang, Yue
通讯作者：
Wang, Yue