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外泌体在肝内胆管癌中的作用
DOI: 10.12449/JCH240130
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：唐晋元负责课题设计与论文撰写；杨陈凤麟、梁冬乐负责绘制表格与图片；罗雨豪负责思路设计，文章修改和最后定稿。
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摘要: 肝内胆管癌（ICC）是一种特殊类型的肝癌，其早期临床症状不典型，大多数患者初诊时已处于中晚期。由于缺乏有效的分子标志物和治疗手段，ICC患者5年生存率极低。外泌体是一种细胞分泌的囊泡，包含蛋白质、RNA、脂质等，是细胞间通讯的重要载体。近期研究显示外泌体在ICC发生发展过程中扮演重要角色，本文就外泌体在ICC中的诊断、治疗作用及其机制进行综述，并展望外泌体的治疗前景与潜在的临床应用。Abstract: Intrahepatic cholangiocarcinoma （ICC） is a special type of liver cancer with atypical clinical symptoms in the early stage， and most patients are already in the advanced stage at the time of initial diagnosis. Due to a lack of effective molecular markers and treatment options， ICC patients tend to have an extremely low five-year survival rate. Exosomes are vesicles secreted by cells that contain proteins， RNA， and lipids， and they are important carriers of intercellular communication. Recent studies have shown that exosomes play a crucial role in the development and progression of ICC， and this article reviews the role and mechanism of exosomes in the diagnosis and treatment of ICC and looks into the future treatment prospect and potential clinical application of exosomes.
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Key words:
- Cholangiocarcinoma /
- Exosomes /
- Diagnosis /
- Therapeutics
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急性失代偿期肝硬化(AD)定义为肝硬化患者的腹水、肝性脑病或静脉曲张出血的急性发展/恶化。以严重的全身炎症和器官衰竭为特征的AD亚组，这些特征是慢加急性肝衰竭(ACLF)的标志，这是一种独特的临床综合征，与极高的短期死亡风险相关。
AD的高凝和低纤溶可能与疾病进展和凝血相关并发症有关。来自意大利阿齐安达·奥斯佩代尔大学的Zanetto等进行了一项前瞻性研究，目的是描述AD患者的凝血改变; 评估这些改变是否可以预测ACLF和出血/血栓形成。
前瞻性招募在院的AD患者，并进行广泛的凝血分析，包括凝血因子、凝血调节蛋白修饰的凝血酶生成试验，并评估内源性凝血酶生成能力[血浆高凝性标记]、纤溶因子和纤溶酶-抗纤溶酶复合物(纤溶激活标记)。用C反应蛋白(CRP)评估炎症严重程度。在研究的第1部分，比较了AD患者与对照组(稳定失代偿和代偿性肝硬化)的凝血情况。在研究的第二部分，前瞻性地随访了AD患者1年，并调查了ACLF和出血/血栓形成的预测因子。
此研究共招募了169例AD患者(终末期肝病模型中位数评分20分；CLIF-C AD中位数评分54分)。与对照组相比，AD与更明显的高凝相关(P＜0.0001)，纤溶激活无差异。在随访中，55例发展为ACLF。CLIF-CAD、CRP和Child-Pugh与ACLF独立相关。结合这些变量的预测模型(Padua模型)准确地识别出ACLF高风险个体(AUC=0.857，95%CI：0.798~0.915，敏感度74.5%，特异度83.3%)。值得注意的是，CRP和进展为ACLF(而非基线凝血障碍)与出血有关(n=11)；CRP和抗纤溶因子PAI-1＞50 ng/mL与血栓形成有关(n=14)。Padua模型的预后价值在一个独立的双中心欧洲队列(n=301)中得到验证。
总之，在一个前瞻性的AD住院患者队列中，发现凝血和纤溶改变与ACLF的发展之间没有联系。因此，与最近的假说相反，高凝和低纤溶状态不太可能直接参与AD的进展，不能作为治疗位点。全身炎症的严重程度和肝脏失代偿是ACLF最强的独立预测因素。结合血浆CRP水平、CLIF-C AD评分和Child分级的预测模型准确地识别了随后发展为ACLF的AD患者。如果得到进一步证实，Padua AD模型可能成为一个额外的手段，以改进对考虑新的疾病改善疗法的AD患者的识别，并加快肝移植的评估。
摘译自：ZANETTO A, PELIZZARO F, CAMPELLO E, et al. Severity of systemic inflammation is the main predictor of ACLF and bleeding in individuals with acutely decompensated cirrhosis[J]. J Hepatol, 2022. DOI: 10.1016/j.jhep.2022.09.005. [Online ahead of print].
(吉林大学第一医院 肝胆胰内科 许珉 辛桂杰 报道)
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注： EVCOX，环加氧酶；CTLA-4，细胞毒性T淋巴细胞抗原4；CXCL，C-X-C基序趋化因子配体；EGF，表皮生长因子；ERK，细胞外信号调节激酶；Hh，刺猬通路；IDH，异柠檬酸脱氢酶；iNOS，诱导氮氧化物合酶；MMP，基质金属蛋白酶；NF-κB，核因子κB；PDGF，血小板衍生生长因子；PD-1，程序性死亡蛋白1；PD-L1，程序性死亡配体1；PGE，前列腺素E；PI3K，磷脂酰肌醇3-激酶；STAT3，信号传导和转录因子3；TAM，肿瘤相关巨噬细胞；TAN，肿瘤相关性中性粒细胞。
图 2 ICC的分子发病机制
Figure 2. Molecular pathogenesis of cholangiocarcinoma
图 3 ICC源性外泌体调节肿瘤进展的机制
Figure 3. ICC derived exosomes can regulate tumor progression through a variety of mechanisms
图 4 外泌体在ICC与CAF细胞通信中的作用
Figure 4. Effects of exosomes on the interaction between ICC and CAF cells
表 1 外泌体与其他传统细胞外囊泡的区别
Table 1. Differences between exosomes and other traditional extracellular vesicles
特征 直径（nm） 密度（g/mL） 形状 组成 标志物 细胞内起源 外泌体 40～100 1.13～1.19 杯状 胆固醇，鞘磷脂，神经酰胺，脂筏，暴露PPS CD63，CD9，Alix， TSG101 内部隔室 （核内体） 微泡 100～1 000 不规则形状 暴露PPS 整合素，选择素 和CD40配体 质膜 核外颗粒体 50～200 双圆形 胆固醇，二酰基甘油，PPS CR1和蛋白水解酶 质膜 膜颗粒 50～80 1.04～1.07 圆形 CD133 质膜 外泌体样颗粒 20～50 1.1 不规则形状 无脂筏 TNFR I 凋亡小泡 50～500 1.16～1.28 异形 组蛋白 
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