中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Efficacy of endoscopic ultrasound-guided coil placement combined with tissue adhesive injection in treatment of gastric varices with spontaneous shunt

DOI: 10.12449/JCH240416
Research funding:

Science and Technology Project of Hubei Provincial Health Commission (WJ2021F066)

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  • Corresponding author: GAO Shan, 860792677@qq.com (ORCID: 0000-0002-8232-4234)
  • Received Date: 2023-06-28
  • Accepted Date: 2023-08-04
  • Published Date: 2024-04-25
  •   Objective  To investigate the efficacy, safety, and cost-effectiveness of endoscopic ultrasound (EUS)-guided coil placement combined with tissue adhesive injection in the treatment of gastric varices with spontaneous shunt.  Methods  A retrospective analysis was performed for the patients with acute gastric variceal bleeding and spontaneous portosystemic shunt who were hospitalized and received balloon-occluded retrograde transvenous obliteration (BRTO) combined with endoscopic tissue adhesive injection or EUS-guided coil placement combined with tissue adhesive injection in Xiangyang Central Hospital from March 2019 to September 2022. The two surgical procedures were compared in terms of efficacy (technical success rate, 5-day rebleeding rate, 1-year rebleeding rate, and time to rebleeding), safety (the incidence rate of ectopic embolism, the amount of tissue adhesive used, and the amount of lauromacrogol used), and cost-effectiveness (hospital costs and length of hospital stay). The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. The Kaplan-Meier method was used to estimate the rebleeding. The chi-square test was used for comparison of categorical data between two groups.  Results  A total of 25 patients received successful EUS-guided coil placement and tissue adhesive injection, with a technical success rate of 100%, a median amount of 2.5 mL tissue adhesive used, a median amount of 11.0 mL lauromacrogol used, a mean length of hospital stay of 14.88±3.21 days, a mean hospital cost of 32 660.00±4 602.07 yuan, and a 5-day rebleeding rate of 0%; among these patients, 2 were lost to follow-up, and 23 patients with complete follow-up data had an incidence rate of ectopic embolism of 0% and a median time to rebleeding of 689 days. A total of 14 patients underwent modified BRTO combined with endoscopic tissue adhesive injection, with a technical success rate of 100%; a median amount of 5.0 mL tissue adhesive used during surgery, which was significantly higher than that used in EUS (U=39.000, P<0.001); a median amount of 10.5 mL lauromacrogol used during surgery; a mean length of hospital stay of 15.38±4.94 days; a mean hospital cost of 57 583.47±18 955.40 yuan, which was significantly higher than that used in EUS (t=-6.310, P<0.001); a 5-day rebleeding rate of 0%. No patient was lost to follow-up, and all 14 patients had an incidence rate of ectopic embolism of 0% and a median time to rebleeding of 244.50 days, with no significant difference between the two groups (χ2=1.448, P=0.229).  Conclusion  EUS-guided coil placement combined with tissue adhesive injection is a relatively safe and effective technique for the treatment of gastric variceal bleeding and has a high technical success rate, a low incidence rate of serious adverse events, and similar efficacy to BRTO, with higher safety and cost-effectiveness.

     

  • 肝细胞癌(HCC)是全球范围内最常见的恶性肿瘤之一。我国HCC的发病率及死亡率居高不下,给国家以及社会带来了巨大的经济负担1。由于HCC的起病隐匿,大多数患者确诊时已处于疾病晚期,故HCC的治疗效果不佳,预后普遍很差。随着研究的不断深入,科学家不仅研究突变的癌细胞本身,还研究癌细胞周围环境以及它们之间的功能串扰。越来越多的证据2-3表明肿瘤微环境(tumor microenvironment,TME)对肿瘤发展起到十分重要的作用,通过重塑TME来调控肿瘤进展成为新的研究热点。Hedgehog(Hh)通路是一种有效的致癌驱动信号,可促进肿瘤的增殖、存活、血管生成、侵袭转移、代谢重组及上皮间质转换等多种癌症特征4,但其在抗肿瘤免疫反应调节中的作用在近年的研究中才逐渐得到关注5。Hh信号通路在HCC发生和HCC的TME中起重要作用。Hh信号的异常激活可能加速了肝癌的生长。Hh信号和TME之间的相互串扰影响肿瘤生长、免疫耐受、炎症和耐药6。本文就Hh信号异常激活在肝癌和肝癌TME中的作用及机制的研究现状与潜在的治疗意义作一综述。

    1980年Nüsslein-Volhard等7学者在果蝇中发现的Hh信号分子,是一种由信号细胞所分泌的局域性蛋白质配体。Hh基因能使果蝇的幼虫虫体长出许多刺突,形似刺猬,故名“刺猬通路”。在哺乳动物体内Hh通路主要由3个Hh家族成员[音速刺猬(Sonic Hedgehog,SHH)、印度刺猬(Indian Hedgehog,IHH)、沙漠刺猬(Desert Hedgehog,DHH)]、2个跨膜受体[Pathed (Ptch)和Smoothened(Smo)]、3个Gli蛋白(Gli1、Gli2和Gli3),以及下游的靶基因等组成8。3个Hh同源基因,编码3种SHH、IHH、DHH的蛋白配体,它们均由具有信号活性功能的氨基端(Hh-N)和有自身蛋白水解酶活性及胆固醇转移酶功能的羧基端(Hh-C)组成。Ptch蛋白家族成员都是含12次跨膜结构域的膜蛋白,能与Hh结合,对Hh信号通路起负调控作用。Smo是一种7次跨膜受体,是Hh信号传递所必需的受体8-9。当没有Hh配体蛋白时,Ptch能释放抑制Smo活性的蛋白,从而阻滞Smo的激活,使得Hh信号通路关闭。而当Hh配体蛋白(SHH、IHH或DHH)与Ptch结合后,Ptch停止分泌,Smo解除抑制,Hh信号系统被激活,最终导致Gli转录因子成员的激活、向细胞核转移,上调Hh通路下游靶基因如VEGF、Myc、Cyclin D等,从而促进肿瘤增殖、侵袭、转移、血管生成等10

    Hh信号通路在胚胎发育过程中发挥着十分重要的作用,可以诱导内胚祖细胞向肝细胞分化11,当胚胎成熟时,这一途径就会失活。健康成年人的肝细胞几乎不表达Hh配体,因此Hh信号通路并不活跃。当各种急、慢性肝损伤发生时,如乙型或丙型肝炎、酒精性肝病、非酒精性脂肪性肝病、胆汁淤积性肝损伤、肝大部分切除等,Hh信号显著重新激活12-13。虽然Hh通路的瞬时激活有助于急性损伤后的肝再生,但是旁分泌Hh信号的持续诱导会使肝上皮细胞和邻近间质细胞之间平衡改变,促进肝纤维化、肝硬化和肝癌的发生14

    在HCC中,Hh通路的激活支持了肿瘤细胞的生长,并且使得肝癌发展不同阶段的凋亡减少15。在肝癌组织和肝癌细胞系中,Hh信号通路中的重要成分表达增高,通常与肝癌的恶性程度、淋巴结转移等密切相关16-17。Chen等18研究表明靶向抑制Gli1,不仅可以通过抑制Hh信号抑制肝癌的生长,还可以通过下调基质金属蛋白酶2(MMP-2)、MMP-9,阻断上皮间质转化来抑制HCC的迁移和侵袭。因此,抑制或干扰Gli1表达可以抑制肿瘤的进展。He等19研究结果显示,LINC01093能与胰岛素样生长因子2 mRNA结合蛋1(IGF2BP1)结合,干扰IGF2BP1与胶质瘤相关癌基因同源物1(Gli1 mRNA)之间的相互作用,其结果是导致Gli1 mRNA的降解,而LINC01093过表达可显著抑制肝癌细胞的增殖和转移。相反,它的敲除促进了HCC的进展。Huang等20研究表明,在切除的肝癌组织中Smo和miR-338-3p的表达呈负相关,miR-338-3p的表达缺失与HCC的临床侵袭性有关,Smo的激活导致c-MYC的过表达,促进肝癌的发生发展,miR338-3p可通过抑制Smo介导的MMP-9的表达来抑制肝癌细胞的体外侵袭。以上研究结果均表明,Hh的异常激活与肝癌的发生发展密切相关,抑制Hh通路相关因子可以延缓肝癌的进展。近年来随着TME研究的深入,发现激活的Hh信号可以通过影响肿瘤干细胞(cancer stem cell,CSC)干性等调节肿瘤耐药,而且阻断Hh信号通路能够逆转肿瘤耐药21。Gu等22学者的研究发现,环状RNA CircIPO11激活Hh信号能驱动CSC的自我更新,促进肝癌的生长。究其本质原因可能是CircIPO11能将TOP1招募到Gli1启动子上,触发其转录,导致Hh的激活。

    总之Hh信号通路在进化上是保守的,与胚胎发育、正常组织修复、上皮间质转化、CSC干性维持以及肝癌的发生进展密切相关23

    TME是一个复杂的、不断进化的实体,是指肿瘤在其发生发展过程中所处的内环境,作为肿瘤免疫效应阶段的执行场所,TME参与肝癌的免疫耐受和应答,影响肝癌的发展和预后24。在肝癌生长的早期,肝癌细胞及支持其存活、侵袭、转移的TME成分之间形成了一种动态和相互作用的关系。为了克服低氧和酸性的微环境,TME协调促进血管生成的过程,以恢复氧气和营养供应,并清除代谢废物。在此期间,肿瘤被各种适应性免疫细胞和先天免疫细胞侵染,根据环境的不同,这些细胞既可以执行抗肿瘤功能,抑制肿瘤进展,还可以促进肿瘤生长25图1)。

    注: 当没有Hh配体蛋白时,Ptch能释放抑制Smo活性的蛋白,从而阻滞Smo的激活,使得Hh信号通路关闭。而当Hh配体蛋白(SHH、IHH或DHH)与Ptch结合后,Ptch停止分泌,Smo解除抑制,Hh信号系统被激活,最终导致Gli转录因子成员的激活、向细胞核转移,上调Hh通路下游靶基因如VEGF、Myc、Cyclin D等,从而促进肿瘤增殖、侵袭、转移等;细胞中的Hh信号能驱动肿瘤间质中肿瘤相关巨噬细胞(TAM)的M2极化,抑制CD8+T淋巴细胞功能,从而促进肿瘤的生长;细胞中异常激活的Hh信号和肿瘤相关成纤维细胞(CAF)相互作用并协同促进肿瘤的发展。
    图  1  肝癌TME中的Hh信号转导
    Figure  1.  Hh signal transduction in TME of hepatocellular carcinoma

    CAF是TME中最重要的间质成分之一26。活化的CAF在细胞外基质重塑、癌细胞增殖、代谢重编程、侵袭、干性和其他恶性行为,以及在肿瘤血管生成、转移、免疫抑制和治疗耐药等方面发挥重要调节作用27-28。Hh信号通路是上述过程中的关键参与者之一4。CAF不仅是TME中Hh配体的潜在来源,而且还通过激活Gli1来响应Hh信号。

    CAF在细胞来源、表型和功能等方面表现出生物异质性29。但它们都表达某些间充质标志物,包括α-SMA、Vimentin和FSP-1。大多数CAF亚群通常表现出促癌作用,通过不同的途径参与肿瘤发展的多个阶段930-31。CAF不仅可以促进肿瘤的增殖,而且诱导癌细胞的免疫逃避32-34。此外,CAF还能够通过释放MMP来降解细胞外基质,同时合成新的基质蛋白,为肿瘤侵袭和血管生成提供结构支持35-36。异常激活的Hh信号和CAF相互作用并协同促进肿瘤的发展37,比如,在肺部肿瘤中Hh信号的激活增加了CAF中Forkhead Box F1的表达,调节了这些成纤维细胞的收缩能力以及肝细胞生长因子(hepatocyte growth factor,HGF)和成纤维细胞生长因子2(fibroblast growth factor 2,FGF2)的产生,从而刺激肺癌细胞的迁移38。在乳腺癌中的CSC可以分泌SHH作为旁分泌信使,激活CAF中的Hh信号,从而产生CSC自我更新的因子,加速CSC扩增39。乳腺癌细胞产生的Hh配体能使CAF重新编程,提供支持CSC的免疫微环境,还能通过表达FGF5和产生纤维状胶原导致化疗耐药40。肝脏肿瘤多由肝纤维化或肝硬变发展而来,肝癌细胞始终嵌入在富含CAF的微环境中。CAF能够增加肝癌细胞的增殖和侵袭性41,CAF来源的外切体已被报道参与调节HCC的TME。Liu等42研究表明,CAF来源的CCL2、CCL5、CCL7和CXCL16通过诱导肝癌细胞中Hh和转化生长因子-β通路的激活而促进肝癌转移。因此可以推论:CAF与肿瘤之间通过异常激活Hh信号相互串扰是促进肿瘤发展的重要因素之一。通过抑制Hh信号通路进而抑制肿瘤进展,以期为肝癌治疗提供新的方法。

    研究43-45表明,从包括基底细胞癌、乳腺癌、肝癌、结直肠癌和胰腺癌在内的一系列癌症中分泌的Hh配体可以调节间质细胞,创造促进癌症进展的有利环境。然而,Hh配体如何作用于TME内的间质细胞以促进肿瘤生长以及参与这一过程的细胞类型仍有待阐明。TAM是TME的重要组成部分,在某些实体肿瘤中,TAM可占TME的50%46。TAM功能可塑性极强,并能够快速适应微环境的变化,通过为恶性细胞提供营养支持来促进肿瘤疾病的进展、免疫逃逸和耐药47-48。此外,TAM具有空间异质性,可以根据其所占据的TME的特定区域获得特殊的功能状态。在TME中,TAM通常表现为抗炎的M2样表型,以促进肿瘤生长。TME的缺氧区和坏死区富含M2样TAM,尽管其抗原提呈能力有限,流动性低,但是会分泌大量的肿瘤支持因子以促进肿瘤生长,而血管周围区域的TAM亚群具有强大的促血管生成功能和免疫抑制特性49。CD8+T淋巴细胞是肿瘤浸润淋巴细胞中的主要抗瘤细胞,可以通过细胞接触的方式释放穿孔素、颗粒酶B、IFN-γ、TNF等细胞因子杀伤靶细胞50。十分遗憾的是,TME中CD8+T淋巴细胞常常表现为耗竭状态,这也是促进肿瘤生长和发生免疫逃逸的重要机制之一51。而且有研究5表明,TAM向M2型转化,在肝癌中介导了CD8+T淋巴细胞的耗竭。Petty等5学者通过肝癌小鼠模型发现,髓系细胞中的Hh信号能驱动肿瘤间质中TAM的M2极化,从而促进肿瘤的生长,深入研究表明,肿瘤来源的SHH主要是通过转录因子Krüppel样因子4直接作用于TAM,促进M2极化。肿瘤细胞和TAM之间Hh通信的缺失会干扰TAM M2极化,导致肿瘤生长受阻。此外,Hh诱导的TAM产生CXCL9和CXCL10来抑制CD8+T淋巴细胞向TME的募集。该团队另一项研究52还发现,Hh能诱导TAM上的细胞程序性死亡配体1(PD-L1)表达,进而抑制肿瘤浸润性CD8+T淋巴细胞杀伤能力和细胞毒性。Tan等53学者也得出了同样的结论,他们观察到,在临床上HCC患者经肝动脉化疗栓塞术(TACE)治疗后,TME中CD8+T淋巴细胞的数量减少且抗肿瘤的功能下降。究其具体原因可能是因为TACE治疗后肿瘤组织中TREM2+TAM数量增加,分泌CXCL9的水平降低,Gal-1释放增加,Gal-1可以上调血管内皮细胞的PD-L1,从而抑制CD8+T淋巴细胞向肿瘤组织中募集,还抑制CD8+T淋巴细胞的杀伤功能。抑制TREM2能增强抗PD-L1药物对HCC的治疗效果。

    因此,在TME中,Hh信号和TAM共同影响CD8+T淋巴细胞的功能,进而促进肿瘤免疫耐受。通过靶向Hh信号通路,还可能成为调节间质细胞与浸润性免疫细胞之间直接和间接相互作用的关键,可为肝脏肿瘤治疗提供新的思路。

    Hh信号成分的表达水平与包括HCC在内的人类恶性肿瘤的发生发展密切相关。Jeng等17在一项前瞻性研究中纳入2006—2010年的50例肝癌根治性切除术后患者。检测SHH、Ptch-1和Gli1在肝癌组织和配对的非癌肝组织中的mRNA表达并比较复发组与未复发组的临床病理特征及复发率。结果显示Ptch-1 mRNA及Gli1 mRNA与血清甲胎蛋白水平、肿瘤大小、肿瘤分期显著相关。Gli1基因在肿瘤及癌旁肝组织中的同时阳性表达与临床预后显著相关18。这些数据均表明Hh通路的激活在肝癌的发展中必不可少,Gli1可作为肝癌预后的一个预测指标,也可作为一个强大的激活剂来介导和放大Hh反应54-55。Chen等56还发现Gli1的过度表达与HCC的包膜侵犯、晚期肿瘤分期、血管侵犯和肝内转移有关。综上,Hh信号成分的表达水平是肝癌预后的有用标志物,Hh通路可能是HCC潜在的治疗靶点。

    目前学者们已经致力于Hh抑制剂的研发,美国食品药物监督管理局已批准三种针对Smo的药物。但是Smo突变或Smo非依赖的Hh途径激活增加了对新型Hh抑制剂的需求。下游效应子Gli抑制剂是克服耐药的主要策略。目前抑制Hh信号转导的药物包括5E1(抗SHH)、环多巴胺、Vismodegib、Sonidegib(抗Smo)、ATO、Gant-58、Gant-61(抗Gli1/Gli2转录因子)等57。GDC-0449(Vismodegib)作为获批上市的口服全身性刺激素拮抗剂,可以与Smo结合发挥作用,已证实在基底细胞癌和髓母细胞瘤的治疗中取得了令人鼓舞的结果58-60。在肝癌的治疗中,Pinter等61证实,Hh途径抑制剂GDC-0449通过抑制Hh通路相关蛋白,在体外下调肿瘤血管内皮生长因子的产生,并抑制大鼠肝癌模型中肿瘤组织的血管生成和肿瘤生长。GANT61作为Gli1和Gli2的小分子抑制剂,能诱导体外培养的肝癌细胞自噬和凋亡。在小鼠异种移植肿瘤模型中,GANT61则表现为抑制肿瘤生长62。而且还有一些证据23-25表明,旁分泌的SHH信号的传递,能强烈影响TME的间质细胞。肿瘤来源的SHH,不仅可以直接作用于TAM促进M2极化,诱导TAM上的PD-L1表达,而且还可以抑制TAM产生CXCL9和CXCL10来抑制CD8+T淋巴细胞向TME的募集5,进而抑制肿瘤浸润性CD8+T淋巴细胞杀伤能力和细胞毒性,加速肿瘤进展。通过抑制Hh通路来改善免疫抑制微环境可能是一种新的治疗肿瘤的方法。

    Hh通路作为HCC潜在的治疗靶点,更深入地了解其作用机制以及Hh与TME的串扰,有望为肝脏肿瘤的治疗策略提供新的见解。

    Hh信号通路的异常激活在肝脏肿瘤的发生进展中发挥着重要作用。事实上,Hh信号的异常激活不仅导致肿瘤细胞的增殖,增加肿瘤侵袭、转移、血管复建等恶性表型,Hh还直接调控肿瘤干细胞表型特征的表达介导肿瘤耐药。Hh配体通过调节巨噬细胞和T淋巴细胞的免疫反应以及肿瘤相关炎症因子的表达,促进抑制型肿瘤免疫微环境的建立。因此Hh不仅是肿瘤增殖的促进剂,而且是导致免疫抑制微环境形成、T淋巴细胞耗竭以及肿瘤免疫逃逸的关键,故通过抑制Hh信号来治疗肝脏肿瘤有望成为HCC行之有效的新的治疗方法。

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