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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

田堰鑫 李娜 高雷 武佳 朱英

引用本文:
Citation:

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
基金项目: 

国家自然科学基金 (82274260)

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。
详细信息
    通信作者:

    朱英,zhuyingsh52@126.com (ORCID: 0000-0002-0624-7974)

Influence of the interaction between tumor microenvironment and liver cancer stem cells on the development and progression of hepatocellular carcinoma

Research funding: 

National Natural Science Foundation of China (82274260)

More Information
  • 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。

     

  • 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

    注:COMP,软骨寡聚基质蛋白。

    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。
    下载: 导出CSV

    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。
    下载: 导出CSV
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