Research progress of tumor necrosis factor-α in hepatocellular carcinoma
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摘要:
肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)是一种多功能炎性细胞因子,在肿瘤发生和发展中具有双向调节作用,对肝细胞癌(hepatocellular carcinoma,HCC)的发生、发展调节途径多样,机制尚不完全清楚。血管内皮生长因子(vascular endothelial growth factor,VEGF)分子信号通路和核因子κB(nuclear factor kappa B,NF-κB)信号通路在HCC发生和发展中扮演着重要的角色。外周血TNF-α浓度和肿瘤组织中TNF-α浓度对HCC患者接受一些治疗后的预后表现出了较好的预测价值,但对接受精确放疗的HCC患者预后预测价值,需要被进一步明确。
Abstract:Tumor necrosis factor-α (TNF-α) is a multifunctional inflammatory cytokine that has a bidirectional regulatory role in the occurrence and development of tumors. TNF-α participates in various regulatory pathways for the occurrence and development of hepatocellular carcinoma (HCC), but the mechanisms are not fully clear. Vascular endothelial growth factor (VEGF) and nuclear factor kappa B (NF-κB) signal pathways are considered as important roles in the occurrence and development of HCC. Peripheral blood TNF-α concentration and tumor tissue TNF-α concentration have shown good predictive values for the prognosis of HCC patients after receiving some treatments. The prognostic predictive value of TNF-α for HCC patients receiving precise radiotherapy needs to be further clarified.
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Keywords:
- tumor necrosis factor-α /
- hepatocellular carcinoma /
- radiotherapy /
- prognosis
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1975年,Carswell等发现了血清中的肿瘤坏死因子(tumor necrosis factor,TNF),这种细胞因子可以导致肿瘤组织发生出血、坏死[1]。TNF家族2个核心成员分别是TNF-α和TNF-β[2-3]。TNF-α主要由活化的巨噬细胞、T淋巴细胞、B淋巴细胞等分泌产生[4]。TNF-α是一种炎性细胞因子,生物学活性极其广泛,除了具有促炎、抗病毒和免疫调节的功能之外,还能杀灭肿瘤细胞[3, 5]。有趣的是,随着研究的深入,TNF-α在肿瘤的发生和发展中表现出了抑瘤和促瘤的双重功能[6-7]。
肝细胞癌(hepatocellular carcinoma,HCC)是目前世界上最常见的恶性肿瘤之一,其发病率和死亡率居高不下,严重威胁着人类的健康[8-9]。在中国,乙型肝炎病毒和丙型肝炎病毒慢性感染是导致HCC发生的主要危险因素,尤其是乙型肝炎病毒的持续感染,导致肝硬化的发生,继而发生HCC[10-12]。根据病期不同,HCC目前的治疗手段主要有手术切除(含肝移植)、消融治疗、经导管动脉化疗栓塞、放射治疗以及靶向和免疫等全身系统治疗[13-15]。
1. TNF-α在HCC发生过程中的机制
HCC是一种慢性炎症相关性疾病,主要是由肝脏长期病毒感染损伤和纤维化导致[16-17]。Hammam等[18]揭示在HCC的发生过程中,血清TNF-α的表达明显增加;伴有肝硬化的HCC患者与不伴有肝硬化的HCC患者相比,肝脏组织的TNF-α表达明显增加;肝脏炎症程度较高或纤维化分期较高的患者中,血清TNF-α表达也明显增加。另外,该研究还进一步揭示了TNF-α诱导血管生成在肝炎到肝硬化再发展成为HCC过程中可能扮演着重要角色;在该进程中,血管内皮生长因子(vascular endothelial growth factor,VEGF)分子信号通路可能是一条重要的信号通路[18-19]。
肝前体细胞(hepatic progenitor cells,HPCs)具有多向分化功能,在长期的慢性炎症微环境中,HPCs的扩增和分化可能会发生异常,进而导致HCC的发生[20-21]。有学者[22]利用单细胞转录组测序揭示TNF-α在诱导HPCs向肿瘤细胞转化过程中TNFR2至关重要,TNFR2-hnRNPK-YAP信号轴发挥的作用很关键。也有研究[23]报道,脂多糖(lipopolysaccharide,LPS)可以诱导HPCs向肌成纤维细胞分化,形成肝脏促瘤的炎症微环境、肝脏纤维化,HPCs分化形成的肌成纤维细胞分泌白介素-6和TNF-α,进而导致Ras信号通路的激活和p53信号通路的失活,最终促进HPCs向HCC细胞分化。
TNF-α基因启动子区域存在多态性位点,TNF-α基因变异与HCC之间的关系尚不完全清楚。有研究[24]报道,特定的TNF-α多态性可能与HCC易感性有关。TNF-α-308G/A多态性与HCC易感性增加显著相关,在亚洲人群中,有研究报道TNF-α-238G/A多态性与HCC风险没有显著相关性,但是TNF-α-238 G/A多态性与HCC易感性之间的关系仍然存在争议[25-29]。亚洲人群中,TNF-α-863C/A的多态性也被认为与HCC发生有关,而TNF-α-857C/T和TNF-α-1031T/C的多态性与HCC的发生风险则无关[29]。垂体肿瘤转化基因1(pituitary tumor transforming gene 1,PTTG1)是HCC中潜在的炎症相关癌基因,TNF-α诱导PTTG1表达,PTTG1上调c-myc,参与HCC的发生[30]。
2. TNF-α在HCC进展过程中的机制
TNF-α诱导的信号传导通过激活核因子κB(nuclear factor kappa B,NF-κB)、c-Jun N-末端激酶(c-Jun N-terminal kinase,JNK)途径,促进HCC的进展[31-33]。另外,STAT3炎性转录因子也可以被TNF-α激活,通过下游通路促进HCC的疾病进展[34-35]。TNF-α可以促进HCC的转移,A20蛋白是NF-κB信号通路的负调控因子,A20蛋白对TNF-α诱导的HCC细胞运动具有负调控作用,对于微血管侵犯(microvascular invasions,MVI)细胞的HCC患者,A20的表达下调[36]。肿瘤微环境中的TNF-α还可以通过NF-κB途径诱导HCC细胞中肌腱蛋白C的表达,从而促进HCC细胞的迁移,进而促进HCC的转移[37]。TNF-α通过激活Erk1/2-NF-κB途径,明显增强HepG2细胞中MMP-13/MMP-3的表达并促进细胞迁移;TIPE2能够通过抑制Erk1/2和NF-κB的激活来抑制TNF-α诱导的HCC转移[38]。蛋白激酶D(protein kinase D,PKD)对TNF-α诱导的HCC上皮-间质转移和HCC转移中也被发现具有正向调节作用[39]。
3. TNF-α对HCC治疗预后的影响
手术切除是HCC治疗的主要方式[40-41]。Nakazaki等[42]曾发现HCC复发患者的血清TNF-α浓度要明显高于无复发的患者(P<0.01)。Cai等[43]回顾性分析了157例经病理证实的HCC手术切除患者临床资料后发现,HCC患者术前血清TNF-α浓度越高,患者的无复发生存率越低,HCC患者术前血清TNF-α浓度是术后无复发生存的独立预后因素;该研究中,血清TNF-α的最佳截断值是14.9 pg/mL。Li等[44]采用免疫组织化学染色方法检测HCC(BCLC-0-B)患者肿瘤组织中TNF-α和NF-κB的表达,通过分析发现TNF-α和NF-κB均高表达的HCC患者生存时间明显延长(P<0.05);HCC肿瘤组织中,TNF-α和NF-κB的高表达反而是预测HCC患者术后生存率和复发的独立预后因素(P<0.05)。
除手术切除外,HCC的另一项根治性治疗手段是射频消融治疗(radiofrequency ablation,RFA)[45-47]。Guo等[48]通过前瞻性研究共纳入22例行RFA治疗的HCC患者,在RFA前(基线水平)、RFA后1周、RFA后4周时分别检测了患者外周血中的TNF-α浓度,结果发现RFA后第4周时TNF-α浓度低(低于20.4 pg/mL)的患者更容易复发,RFA后第4周时外周血TNF-α的浓度可以预测肿瘤的复发。
放射治疗在HCC治疗中同样扮演着重要的角色。对于小肝癌,立体定向放射治疗(stereotactic body radiation therapy,SBRT)同样可以取得与手术切除或RFA相类似的根治性效果,是不宜手术切除或RFA患者的替代治疗手段[49-51]。Cha等[52]对接受常规放射治疗的51例HCC患者放疗前血清炎性因子进行研究,暂未发现放疗前血清TNF-α浓度对患者的预后具有预测价值。
对于中晚期HCC,系统治疗如靶向治疗在HCC的治疗中发挥重要作用[53-54]。Iida-Ueno等[55]对无法手术切除的100例HCC患者血浆进行了分析,其中27例患者有治疗开始后的血浆TNF-α浓度变化随访,发现血浆TNF-α浓度在索拉非尼治疗的前5~10 d的变化可以预测HCC患者对索拉非尼治疗的反应,血浆TNF-α浓度出现上升的患者,肿瘤更容易进展。
4. 抗TNF-α治疗在HCC治疗中的作用
研究[56-57]报道,在较低区间内的高浓度TNF-α在HCC生长中具有促瘤作用。Li等[58]报道,TNF-α在HCC组织以及HCC细胞系HepG2和Hep3B中高表达。在体外研究中,抗TNF-α抗体(英夫利昔单抗和依那西普)通过抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性的作用,可以降低HCC细胞活力,英夫利昔单抗治疗可以显著增加HepG2和Hep3B细胞的凋亡;在体内实验[58]中,抗TNF-α治疗延迟了小鼠HCC的进展。
综上所述,TNF-α是一种炎性细胞因子,可以通过多条途径影响HCC的发生和发展。TNF-α的表达水平对HCC患者的治疗预后具有较好的预测价值。但是,对接受传统放疗的HCC患者,TNF-α的表达水平与预后关系不密切;精准放疗时代,特别是SBRT技术治疗HCC时,对机体免疫的影响尚不完全清楚,TNF-α对HCC接受精准放疗患者的复发、转移影响机制以及对患者预后的“指示剂”功能尚待进一步探索。抗TNF-α治疗和TNF-α高浓度灌注治疗也值得进一步研究。
伦理声明 无。利益冲突 所有作者声明不存在利益冲突。作者贡献 胡永:阅读文献、整理文献、论文写作;陈一兴和杜世锁:对论文写作进行指导;曾昭冲:对论文进行选题和框架搭建,指导论文写作,审核论文。 -
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