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肿瘤微环境与肝癌干细胞相互作用对肝细胞癌发生发展的影响
DOI: 10.3969/j.issn.1001-5256.2023.03.032
利益冲突声明：所有作者均声明不存在利益冲突。
作者贡献声明：田堰鑫负责文献阅读及综述撰写；李娜、高雷、武佳负责提供修改意见；朱英负责课题设计拟定写作思路，指导撰写、修改文章并最后定稿。
Influence of the interaction between tumor microenvironment and liver cancer stem cells on the development and progression of hepatocellular carcinoma
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摘要: 近几年，肝癌干细胞(LCSC)被认为是肝细胞癌(HCC)治疗失败和复发的主要原因之一。许多研究已经表明LCSC是肝癌肿瘤中具有自我更新、分化和致瘤能力的一小部分细胞，它能启动HCC的发生，并影响其增殖、侵袭、转移、复发和耐药。最近以肿瘤微环境(TME)为基础的治疗已经开展，许多研究发现靶向TME的相关元素比靶向肿瘤细胞本身更具治疗价值。TME是LCSC和肝癌细胞生长的微环境，它与LCSC相互作用，发挥协同效应，对HCC的发生发展起着积极作用。本文介绍了TME中的各种细胞成分和非细胞成分如何与LCSC相互作用，调节肝癌的发生、发展。此外，还描述了TME中主要成分与LCSC相关联的一些分子靶点及治疗方法或药物，以期能在它们的基础上寻求更安全、更有效的HCC靶向治疗方法。Abstract: In recent years, liver cancer stem cells (LCSC) have been considered one of the main causes of treatment failure and recurrence of hepatocellular carcinoma (HCC). Many studies have shown that LCSC are a small fraction of cells with the abilities of self-renewal, differentiation, and tumorigenesis in HCC tumor, which can initiate the onset of HCC and affect its proliferation, invasion, metastasis, recurrence, and drug resistance. Therapies based on tumor microenvironment (TME) have been developed recently, and a number of studies have found that targeting the relevant elements of TME has a higher therapeutic value than targeting tumor cells themselves. TME is the microenvironment for the growth of LCSC and HCC cells, and it interacts with LCSC and has a synergistic effect, thereby playing a positive role in the development and progression of HCC. This article introduces how various cellular components and non-cellular components in TME interact with LCSC to regulate the development and progression of the HCC. In addition, this article also describes the molecular targets, therapies, and drugs associated with the main components of TME and LCSCs, in order to seek safer and more effective targeted therapies for HCC.
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Key words:
- Carcinoma, Hepatocellular /
- Neoplastic Stem Cells /
- Tumor Microenvironment
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注：COMP，软骨寡聚基质蛋白。
图 1 肿瘤微环境与肝癌干细胞相互作用而影响肝细胞癌的发生和发展
Figure 1. Tumor microenvironment interacts with the liver cancer stem cells to influence the occurrence and development of hepatocellular carcinoma
表 1 肿瘤微环境的细胞成分和非细胞成分与肝癌干细胞的作用机制及对HCC的影响
Table 1. The mechanism of cellular and non-cellular components of tumor microenvironment with the liver cancer stem cells and their effect on HCC
分类 作用机制 功能 非细胞成分 ECM (1)ECM重塑和HA增加LCSC干性标志物CD44、CD133的表达[5-7]
(2)FN影响LCSC细胞间通讯[7]促HCC的增殖、侵袭、转移、耐药 细胞外调控分子 (1)HIF：协同ECM重塑、肿瘤新生血管网和EMT激活Notch信号通路，促LCSC生成、维持、干性特点、化学抗性和治疗抵抗[2, 8-13]
(2)TGFβ：BMP4、BMP9和EMT激活TGFβ信号通路，促进CD133和EPCAM的表达，改变LCSC恶性表型，促其分化[12, 14-17]
(3)其他细胞外调控分子：a, OSM激活STAT3信号通路，介导LCSC分化[12, 18]；b, MMP-2和MMP-9增强LCSC的自我更新和化学抗性[19-20]促HCC的发生、侵袭、转移和耐药 EV (1)miR-125b、miR-130、miR-155、Kras mRNA参与CSC重编程；miRNA-181激活Wnt/β-catenin信号通路，增加miRNA-130b和lncTCF7的表达，促LCSC自我更新、分化、干性、恶性表型转化[22-27]
(2)Gankyrin激活PI3K/AKT信号通路，促LCSC增殖和化疗抗性[16, 28]
(3)递送治疗药物，miR-21和miR-9-3p作为HCC诊断和预后判断标准[22, 25]促HCC的发生、增殖、凋亡、耐药 其他环境因素 通过LCSC发挥促瘤作用[29] 细胞成分 内皮细胞与血管网络 分泌IL-17A上调PD-L1，分泌HIF、VEGF和TGFβ增加LOXL2的表达，诱导EMT和VM的形成，协同ECM重塑，促LCSC自我更新、干性和化学抗性[5, 31-33] 促HCC发生、转移 免疫细胞 (1)TAM释放VEGF、MMP、分泌蛋白S100A9、TGFβ和TNF，激活IL-6/STAT3信号通路，与肿瘤新生血管协同，改变LCSC表型和功能[2, 6, 12, 36]
(2)TAN分泌BMP2和TGFβ来诱导LCSC的产生[37]
(3)树突状细胞和T淋巴细胞促LCSC的维持和免疫逃逸[6, 12]促HCC的发生、侵袭、转移 CAF 分泌多种因子，介导ECM重塑，激活TGFβ、Hedgehog、STAT3等信号通路，促进LCSC干性、恶性表型转化[6, 29] 促HCC侵袭、转移 其他细胞 通过LCSC发挥促瘤作用[6, 38-41] 注：HIF，缺氧诱导因子；BMP，骨形态发生蛋白；MMP，基质金属蛋白酶；lncTCF7, 长链非编码转录因子7；PD-L1, 程序性死亡受体-配体1；TAM，肿瘤相关巨噬细胞；TAN，肿瘤相关中性粒细胞。 
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表 2 肿瘤微环境各成分和LCSC相关联的分子靶点、治疗方法或药物
Table 2. Molecular targets, therapeutic methods or drugs associated with various components of the tumor microenvironment and the LCSC
分子靶点 治疗方法或药物 TME各成分靶点对LCSC的作用 ECM 胶原蛋白参与ECM重塑导致LCSC干性标志物CD44、CD133表达的增加；FN影响LCSC细胞间通讯[5-7, 42-43] 胶原蛋白 吡格列酮 CD44 抗CD44抗体; miR-199a-3p CD133 MV-141.7;MV-AC133 FNR 抗整合素α4β1抗体 HIF 内皮细胞分泌HIF-1α对LCSC的恶性改变起支持作用；Akt/HIF-1α/PDGF自分泌环增强LCSC的化学抗性[2, 5, 8-13, 44-45] HIF-1α HDAC6特异性抑制剂 PDGFR 索拉非尼; 仑伐替尼; 瑞戈非尼 TGFβ siRNA; 吡非尼酮; 氟非尼酮 TGFβ和BMP导致LCSC干性标志物CD133、EPCAM表达的增加[12, 14-17, 42, 46-48] BMP DMH1 EpCAM VB4-845;Edrecolomab; RNAi 其他细胞外调控分子 IL-6、MMP和TIMP对LCSC的恶性改变起支持作用[12, 18-20, 42] IL-6 阿司匹林 MMP FR(EtOH) TIMP 常山酮 EV 载药RBC-EV EV、Wnt/β-catenin信号和lncTCF7对LCSC的恶性改变起支持作用[22-27, 42-43] Wnt/β-catenin siRNA lncTCF7 - 其他环境因素 缺氧、氧化应激和自噬LCSC的恶性改变起支持作用[29, 42-43, 49-50] 缺氧 Evofosfamide (TH-302);DS-PLGA 氧化应激 Oroxylin A; 甲基阿魏酸 自噬 3-甲基腺嘌呤; 巴弗洛霉素A1 内皮细胞/血管 阿替利珠单抗 内皮细胞通过PD-L1、HIF-1α、VEGF和LOXL2对LCSC的恶性改变起支持作用[5, 31-33, 42, 44-47] PD-L1 HDAC6特异性抑制剂 HIF-1α VEGF 贝伐珠单抗 VEGFR 索拉非尼; 仑伐替尼; 瑞戈非尼; 卡博替尼 LOXL2 辛妥珠单抗 TGFβ siRNA; 吡非尼酮; 氟非尼酮 免疫细胞 TAM通过分泌VEGF、MMP、TGFβ和TNF激活IL-6/STAT3信号通路对LCSC的恶性改变起支持作用；而TAN通过BMP2和TGFβ对LCSC的恶性改变起支持作用[2, 6, 12, 36-37, 42, 45-49] TAM 索拉非尼 VEGF 贝伐珠单抗 MMP FR(EtOH) TGFβ siRNA; 吡非尼酮; 氟非尼酮 TNF 阿司匹林 IL-6 阿司匹林 STAT 利匹韦林 BMP DMH1 CAF CAF分泌胶原蛋白、TGFβ、CCL2、CCL5和IL6参激活TGFβ和STAT3信号通路对LCSC的恶性改变起支持作用[6, 42, 46-47, 51] TGFβ 吡非尼酮; 氟非尼酮 STAT 利匹韦林 胶原蛋白 吡格列酮 CCR2/5 Cenicriviroc CCR5 Met-CCL5 IL-6 阿司匹林 注：FNR，纤连蛋白受体；HIF，缺氧诱导因子；PDGF/PDGFR，血小板衍生生长因子及受体；RNAi，RNA干扰；siRNA，小干扰RNA；TIMP，金属蛋白酶组织抑制剂；RBC-EV，红细胞释放的细胞外囊泡；VEGF /VEGFR，血管内皮生长因子及受体；CCR2/5，CCL2/5的受体。
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