胆管细胞癌(cholangiocarcinoma,CCA)于1840年首次被报道,然而当时这一疾病并没有受到人们的重视,直到100年后才有系统的综述介绍CCA[1-2]。CCA可以起源于胆道的任何位置,临床上多数按解剖学位置将其分为肝内胆管癌(intrahepatic cholangiocarcinoma,iCCA)、肝门部胆管癌(perihilar cholangiocarcinoma,pCCA)和远端胆管癌(distal cholangiocarcinoma,dCCA),60%的CCA都发生在肝胆管分叉处[3]。大多数CCA患者早期无明显症状,有些患者直到晚期发生了胆道梗阻才来就诊,目前常规超声筛查难以发现早期的小病灶,确诊时间较晚也是导致CCA总体5年生存率小于10%的原因之一。因此,寻找特异的生物学标志物,早期筛查出CCA已成为目前临床关注的重点[4]。
外泌体是由内涵体分泌产生的直径在30~150 nm的胞外囊泡(extracellular vesicle,EV),根据大小、功能、运输方式等不同,胞外囊泡还包括微泡(microvesicles)、凋亡小体(apoptosis bodies)等[5]。细胞分泌外泌体这一现象最早是在1983年由Johnstone等[6]在培养绵羊网织红细胞时发现,但是当时认为其只是细胞处理代谢废物的一种途径,在1987年的后续研究[7]中将这种特殊的囊泡命名为外泌体。目前已知外泌体参与的生理过程有器官发育、抗原呈递和免疫反应、神经元通信及控制和细胞增殖等过程[8]。由于外泌体不但能够在体液中稳定广泛存在,而且能够携带有细胞的特异分子,这就为探究外泌体相关肿瘤标记物、载药治疗技术提供了可能。
随着分子生物学技术的进步,不同外泌体携带的组分逐渐被鉴定出来。尽管外泌体的来源细胞特性高度影响外泌体成分的表达,但一些蛋白诸如四次跨膜蛋白(CD9、CD26、CD58)、Rab蛋白家族、热休克蛋白家族(Hsp70、Hsp90)、核内体相关蛋白(Alix、TSG101)等都是常见的共同表达成分[9]。外泌体中的核酸分子无论是DNA还是编码的mRNA和非编码RNA(miRNA、lncRNA、circRNA)都没有缺席,这丰富了外泌体对于靶细胞表达调控的机制。此外,外泌体的膜上还能检测到多种丰富的脂质,如磷脂酰丝氨酸和胆固醇[10]。
外泌体中的核酸分子在CCA中的作用
环状RNA 环状RNA(circular RNA,circRNA)是非编码长链RNA的一种,共价闭环的结构是它的特征,由于没有极性和polyA尾部结构,具有相对无干扰的结构框架;并且circRNA在真核转录组中表达具有高度特异性,这使得circRNA在一些疾病中扮演分子标志物的角色[11-12]。
研究发现,circ-0000284在胆管癌细胞系分泌的外泌体中表达增多,并具有明显的促进迁移、侵袭的能力[13]。该团队也发现circ-0000284能够作为miRNA海绵与miR-637结合抑制其作用,同时在结肠癌中发现其与miR-7也有类似机制[14]。有研究发现circ-0000284在肝癌细胞中显著上调,促进肿瘤细胞增殖;而另有研究发现该分子也可以抑制膀胱癌的生长和转移[15-16]。circ-0000284究竟是致癌还是抑癌分子还需要更深入的研究。
circ-CCAC1是新发现的在CCA组织和胆汁外泌体中都过表达的circRNA,发挥功能时circ-CCAC1主要通过海绵作用结合miR-514a-5p上调阴阳蛋白1(Yin-Yang 1,yy1)表达,进一步激活钙调亲环蛋白配体(calcium signal-modulating cyclophilin ligand,CAMLG)来促进CCA进展,这也是首次证明circ-CCAC1/miR-514a-5p/yy1/CAMLG轴在CCA中的重要性,而且CCA分泌的携带circ-CCAC1的外泌体还有促进血管内皮细胞生成的作用,因此CCA组织和胆汁的外泌体中都上调的circ-CCAC1被认为可能是一种CCA潜在标记物[17-18]。
在CCA患者中高表达的circDNM3OS与肿瘤的大小、TNM分期和淋巴结浸润有关,这一现象是circDNM3OS通过海绵作用于miR-145-5p后上调致癌基因MORC2,促进了CCA细胞的恶性转化和谷氨酰胺代谢[19-20]。不过该分子在外泌体中的表达情况还未有实验验证。
miRNA miRNA(microRNA)因为具有靶向mRNA的能力而在转录后调控中扮演重要角色,并参与各种生理、病理过程[21]。研究发现血浆或胆汁中都存在核糖核酸酶(ribonuclease,RNase),并且外源性miRNA会被降解以维持机体稳态,内源性miRNA能够稳定发挥作用的机制目前尚未完全确定,但外泌体作为miRNA的主要载体保护其不被分解已经得到验证[22-24]。外泌体miRNA的功能中,与CCA相关的研究主要是作为生物标记物的功能[25]。
有研究比较CCA细胞系来源的外泌体中miRNA与胆管上皮细胞的差异,在CCA中miR-205-5p上调最明显,miR-199a-5p下调最明显,通过京都基因和基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)富集分析发现这些差异miRNA与癌症相关的途径有显著的关联[26]。随后在CCA患者血清中检测外泌体来源miRNA,筛选出5个有显著差异的miRNA分子,其中MiR-200家族中有4个microRNA(miR-141-3p、miR-200a-3p、miR-200b-3p和miR-200C-3p)的AUC高于CA19-9(0.78),miR-200a/c-3p不仅是诊断CCA的生物标志物,且浓度与CCA分期成正相关,这使其成为反映疾病进展的指标[27]。
治疗方面,在CCA及其基质中下调的外泌体中的miR-195能够抑制CCA的生长和侵袭能力,CCA小鼠模型中注入包裹miR-195的外泌体后也观察到同样的现象,但是具体机制还不清楚[28]。有关miRNA的实验室研究较多,而临床试验相对较少,因此还需要更多的临床数据验证实验室结果[29]。
mRNA 早在2007年研究者就观察到,将鼠源的外泌体与人肥大细胞体外共培养后,肥大细胞表达鼠源特异性蛋白,便推测外泌体中mRNA有能够到靶细胞翻译的功能。目前基于外泌体携带功能性mRNA的核酸疗法备受关注,通过外泌体的载体特性可能更好地解决mRNA无法有效递送至目标组织或细胞的问题[30-31]。
Haga等[32]将CCA细胞系提取出来的外泌体与骨髓间充质干细胞共培养后,增强了间充质干细胞的迁移能力和α-平滑肌肌动蛋白mRNA的表达,以及CXCL-1、CCL2和IL-6 mRNA的表达和释放,通过将外泌体与胆管癌细胞中mRNA比较,发现外泌体中相关mRNA显著上调,因此推测是CCA外泌体携带的mRNA释放到间充质细胞中发挥了作用[32]。随着分子生物学技术的进步,有多篇文献报道了运用多组学技术检测CCA患者血清及尿液分子中可用作标记物的mRNA,但筛选出多个特异分子而未进行深入的临床及分子机制研究,距离用于临床解决实际问题还有较远距离[33]。
外泌体中的蛋白质分子在CCA中的研究 外泌体所携带的蛋白质一般分成非特异性和特异性两大类:非特异性蛋白包括细胞骨架蛋白、与转运有关的四跨膜蛋白家族成员(CD9、CD63、CD81和CD82)、热休克蛋白、整合素等,在研究中主要作为外泌体鉴定的标志物;特异性蛋白主要与分泌细胞有关,随着疾病的进展,含量和定位会有明显变化[34-35]。目前外泌体相关文献中,对于蛋白质的研究只占了小部分,但是随着蛋白质组学技术的发展,对于蛋白质在外泌体功能方面的关注越来越多,外泌体蛋白质的研究不仅能增加对其生物学作用机制的认识,还可能发现新的生物标志物[36]。当前对于CCA相关外泌体中蛋白质的鉴定方法以蛋白质质谱为主,而外泌体来源有多种方式,包括患者血浆提取、体外培养的CCA细胞上清液提取、动物原位CCA模型的血浆提取以及直接从人CCA组织提取,由于外泌体来源和质谱的参数不同,得到的差异蛋白的种类和数量也不同[37-39]。
有研究对比了CCA患者与健康人血清中外泌体蛋白质谱,试图找出具有诊断意义的差异蛋白,在其中AUC值与敏感性最高的是氨肽酶N(aminopeptidase N,APN),APN用于筛查CCA的敏感性超过常用指标CA199,但特异性略低[38]。APN是一种可以裂解蛋白质N端氨基酸的锌酶,属于M1锌金属肽酶家族成员,在多种肿瘤及其周围血管组织都有发现[40]。APN关注焦点是作为检测肝细胞肝癌干细胞的标记物,而CCA中癌症干细胞的比例远高于大多数实体瘤,因此推测血清中外泌体APN的升高与CCA的进展存在关联,其中具体机制还需要进一步的探索[41-42]。
除了血清,胆汁也是重要的胆管癌外泌体来源之一。最近有研究使用组学分析比较了CCA患者和胆结石患者胆汁中外泌体携带的蛋白质,发现Claudin-3具有作为CCA生物标记物的潜力,因为其表达升高显著,敏感性和差异性都高达0.875[39]。Claudin-3具有不依赖钙离子的细胞黏附活性,在紧密连接细胞、消除细胞间隙、细胞旁运输以及细胞增殖迁移中起重要作用,在结肠癌中Claudin-3的表达上调会破坏紧密连接的稳定性,导致大分子的细胞旁通量增加,促使细胞迁移和集落形成的诱导,不过这一现象还未在CCA中得到验证[43-44]。
通过对CCA细胞系与正常人胆管上皮细胞系H69培养后分离出的外泌体蛋白质质谱组学分析,筛选出38种差异表达蛋白,差异最大的是半乳糖凝集素3结合蛋白(lectin galactoside binding soluble 3 binding protein,LG3BP),也被称为MAC2BP、M2BP[37]。将CCA细胞分离出的外泌体与H69细胞系共培养,发现CCA细胞系的外泌体增强了H69细胞的转移和侵袭能力,而对其增殖能力影响不大,但该研究样本数量较少,有待进一步验证。LG3BP为一种分泌蛋白,广泛存在于细胞外基质中,在正常人的肝组织中表达量较低,参与调节Wnt蛋白的胞外扩散,提示其在肿瘤的免疫逃逸中有重要作用[45]。研究发现,LG3BP在高复发风险的子宫内膜癌患者血清外泌体中富集,在人类大肠癌和前列腺癌的细胞外基质中表达升高[46-47]。LG3BP曾经被认为是一种用于诊断非酒精性肝硬化及丙型肝炎等慢性肝病的标志物,然而最近有研究对其诊断效能产生了质疑,借助外泌体来提高LG3BP的诊断效能可能成为一个新的突破点[48-49]。
成纤维细胞生长因子(fibroblast growth factor,FGF)及其下游的信号通路参与调节多种生物学功能,包括细胞增殖、分化、组织修复、血管生成等,成纤维细胞生长因子受体(fibroblast growth factor receptor,FGFR)轴的异常激活是肿瘤发生的重要因素[50]。最近的研究发现,iCCA中几种不同的FGFR2基因有较高的概率发生融合,但是pCCA/dCCA中几乎没有融合,这提示发生在不同位置的CCA可能在起源上存在差异[51-52]。FGFR2融合蛋白通过激活丝裂原活化蛋白激酶来激活FGFR相关通路,并促进非锚位生长;存在FGFR异位的肿瘤中FGFR的结合配体介导低聚化和相应的FGFR激酶的激活,这些基因融合现象的发现为靶向治疗提供帮助,首个针对膀胱癌FGFR突变位点的靶向药物厄达替尼在2019年4月被FDA批准上市[53-54]。FGF2被骨髓基质细胞分泌到外泌体中,携带FGF2的外泌体被白血病细胞摄取后能够逃脱化疗药物的攻击,但关于CCA进展中是否存在外泌体相关FGF家族的现象还需要进一步研究[55]。
胞质异戊柠檬酸脱氢酶1(isocitrate dehydrogenase [NADP] cytoplasmic,IDH1)是一种能催化异柠檬酸还原型NADP生成α酮戊二酸的酶,IDH1基因突变现象在多种肿瘤中都有发现,IDH1突变通过抑制其正常催化的反应来起到负性调节作用[56]。研究发现IDH1突变的胆管癌细胞系中外泌体分泌量明显减少,通过通路分析推测可能是一种ATP受体P2RX7高表达导致的,与P2RX7共表达的基因多与外泌体的释放和定位相关,该发现是IDH1突变的CCA在外泌体研究中的首次尝试[57]。
结语 CCA作为肝胆系统第二高发的癌症,近年来发病率和死亡率都有上升的趋势,临床工作中应对该疾病有足够的重视,当务之急是开发出高效的早期诊断手段。外泌体是近年来新发现的细胞间信息交流信使,分布广泛且稳定性好,拥有疾病诊断和靶向治疗的潜能是外泌体目前广受关注的重要原因。当前限制外泌体领域进展的一大因素是外泌体富集和纯化技术,目前尚无实现高通量、高纯度、高速率的外泌体提取方法。总体来说,外泌体应用于CCA的诊疗研究数量较少,这可能与CCA的患者基数较小有关,虽然已有几个基于外泌体的组学研究筛选出的潜在标记物,但尚无后续的深入研究能够得到可靠的依据。外泌体应用于诊断还处于早期阶段,随着研究深入,外泌体应用于CCA这一类高度恶性肿瘤的早期诊断具有深远的临床意义。
作者贡献声明 慈鸿飞 文献检索,论文设计和撰写。贾户亮 论文构思和修订。
利益冲突声明 所有作者均声明不存在利益冲突。
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