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通讯作者:

胡海(1975-),男,北京人,博士生导师,主要从事肿瘤代谢重编程和肿瘤代谢转化研究。E-mail:huhai@mail.sysu.edu.cn

中图分类号:R734.2

文献标识码:A

文章编号:2096-8965(2020)01-0079-07

DOI:10.12287/j.issn.2096-8965.20200113

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目录contents

    摘要

    转化医学促进了分子生物学等基础医学发展,改变了医学模式。其目的是将医学的基础研究成果快速有效的转化为用于临床的技术和药物,为医学知识服务临床铺平道路。随着肿瘤分子生物学的研究进展,越来越多的分子生物标志物被发现并用于肺癌的诊断、治疗、预后和疗效监测。本文将肺癌分子标志物的研究进展和在转化方面的应用进行综述。

    Abstract

    The translational medicine has improved the development of basic medicine such as molecular biology and has changed the medical model. The aim of translational medicine is to translate the basic research achievement of medical biology into technologies and drugs for application quickly and effectively. With the research progress of molecular biology of lung cancer, more molecular biomarkers have been found and used for tumor diagnosis, treatment, prognosis and curative effect surveillance. The research and application of lung cancer molecular markers are summarized as follows.

    关键词

    肺癌分子标志物转化医学

  • 转化医学(Translational Medicine)又称转化研究(Translational Research)。Choi[1] 1992年在Science杂志上发表论文首次提出“bench to bedside”的概念,之后Geraghty[2] 在Lancet杂志发表论文首次使用“translational medicine”一词。转化医学核心内容是将医学生物学基础研究成果快速有效的转化为可以在临床应用的理论、技术、方法和药物,将基础研究成果“转化”为对疾病的预防、诊断、治疗及预后,实现从基础研究到临床转化的转变。近年来,细胞分子生物学、免疫学等基础学科迅猛发展,但是其研究成果未能在临床应用中得到充分体现,迫切需要转化医学参与其中,发挥重要桥梁作用。

  • 肿瘤分子标志物(Tumor Marker,TM) 是在恶性肿瘤发生和增殖过程中,肿瘤细胞相关基因表达差异或机体对肿瘤反应发生改变的基因或蛋白[3]。 近年来,新的肿瘤分子标志物随着生物技术的快速发展不断被发现。理想的肿瘤分子标志物必须具备敏感性高、特异性好、检测方便、预测可靠等特点。现如今尚未找到一种肿瘤特异的分子标志物。广泛应用的肿瘤分子标志物确切的应为肿瘤相关分子标志物。肿瘤分子标志物的筛选方法随着蛋白质组学的发展和质谱技术的应用也不断革新,新的标志物不断深入研究,推动了肿瘤研究的进展。现如今肿瘤分子标志物筛选方法包括以差异基因表达产物作为分子标志物的筛选[4] 和以肿瘤抗原作为分子标志物的筛选[5]

  • 肺癌的死亡率居我国所有恶性肿瘤之首,5年生存率为10%~15%,严重威胁人类健康。肺癌主要分为两大类,小细胞肺癌(Small Cell Lung Carcinoma,SCLC) 和非小细胞肺癌(Non-small Cell Lung Carcinoma,NSCLC),两种类型的肺癌分别占肺癌患者总数的15%和85%,两者的致病方式和治疗原则有区别[6, 7]。肺癌起病隐匿,早期缺乏特异性症状,70%患者确诊时已经属于晚期甚至存在远端转移(ⅢB/Ⅳ期),失去了最佳的治疗时机[8]。肺癌的早发现、早诊断、早治疗是提高患者生存率的关键。临床上常应用于肺癌监测的肿瘤分子标志物包括癌胚抗原、神经元特异性烯醇化酶、鳞状细胞癌抗原等,同时随着肺癌致癌驱动基因的相继确定, 靶向药物改善和延长了携带相应驱动基因的肺癌患者的预后和生存,相关基因产物成为肺癌的肿瘤分子标志物。另外肺癌的免疫治疗是目前肺癌研究热点,免疫检测点抑制剂程序死亡受体-1/配体-L1是目前选择免疫治疗患者的最佳的分子标志物。本文将对其中广泛应用于临床的肺癌分子标志物的研究进展和临床应用进行综述。

  • 1 肺癌分子标志物的研究进展

  • 1.1 癌胚抗原(Carcinoembryonic Antigen,CEA)

  • CEA是从胚胎结肠黏膜上皮细胞和结肠癌细胞中发现的一类多糖蛋白,肺癌患者血清CEA水平可增高,CEA在肺腺癌中的阳性率可以高达70%, 且TNM分期越晚表达水平越高[9]。CEA作为肺腺癌肿瘤分子标志物对诊断意义重大,临床上CEA常与其他肿瘤分子标志物联合检测提高肺癌的检出效率。Grunnet等[9] 证实CEA是NSCLC复发和死亡风险的独立预测因子。Okamura等[10] 也通过回归性分析证实NSCLC患者CEA水平增高,Ⅲ期和Ⅳ期肺癌患者血清CEA水平明显高于Ⅰ期和Ⅱ期患者, 血清CEA水平直接与NSCLC患者的预后相关。

  • 1.2 神经元特异性烯醇化酶(Neuron Specific Enolase,NSE)

  • NSE参与糖酵解途径,催化2-磷酸甘油酸裂解为磷酸烯醇式丙酮酸,细胞破裂时释放入血。感染等良性疾病也会出现NSE一过性增高。SCLC可以高频生成NSE,因此NSE可以作为SCLC的肿瘤分子标志物,其主要对广泛期患者有较好的诊断作用,但是对局限期间肺癌的灵敏度仅有20%[11]。 NSE升高与NSCLC患者生存期呈负相关,可以作为NSCLC患者生存期的独立预测因子。研究发现SCLC患者中NSE/CEA比值显著高于鳞癌和大细胞肺癌,NSE/CEA比值诊断肺癌的灵敏度、特异性和符合率高于NSE和CEA单独检测,提示联合检测的重要性[12]

  • 1.3 鳞状细胞癌抗原(Squamous Cell Carcinoma Antigen,SCC-Ag)

  • SCC-Ag是从子宫组织中提取的一种糖蛋白, 血清SCC-Ag可以对肺癌的组织病理学类型进行鉴别, 并且与肺癌的严重程度相关。 SCC-Ag对NSCLC和SCLC的诊断价值不同,其对NSCLC的诊断敏感度相对较高,对肺鳞癌的敏感度为33%~78%,特异性为89%~100%,而对SCLC的诊断敏感度仅为15.5%。当血清SCC-Ag浓度大于2 ng/mL的时候,存在NSCLC的可能性为95%,此为肺鳞癌的可能性为80%,因此SCC-Ag对肺癌有好的诊断价值并有助于组织学分型,特别是对肺鳞癌有很强的诊断价值。SCC-Ag对无临床症状的早期肺癌患者诊断意义不大,但是对晚期肺癌患者有很好的相关性,因此可以用于治疗的监控[13]。Chu等[14] 发现肺癌患者SCC-Ag水平较肺部良性疾病患者显著增加,晚期肺癌患者血清SCC-Ag水平与早期肺癌患者SCC-Ag水平显著提高,血清SCC-Ag水平与肺鳞癌患者的预后相关。同时Yu等[15] 也证明SCCAg水平高的肺癌患者生存期缩短。

  • 1.4 细胞角蛋白19 片段抗原(Cytokeratin 19 Fragment Antigen,CYFRA21-1)

  • 细胞角蛋白在上皮细胞中起到支架作用,角蛋白19 广泛分布于鳞状上皮细胞表面。恶性上皮肿瘤细胞中蛋白酶被激活,大量可溶性的角蛋白19 片段被释放,造成血清中细胞角蛋白浓度增加。 CYFRA21-1 是从癌症患者血清中发现的细胞角蛋白19 片段,能被BMI19-21 和KS19-1 两种特异性单克隆抗体识别,其血清浓度与肺癌组织类型密切相关[10]。CYFRA21-1 对肺癌的分期有一定的参考价值,也可作为预后观察指标。Matsuoka等[16] 发现术前CYFRA21-1 水平升高的NSCLC患者5 年生存期比术前CYFRA21-1 正常患者显著降低,晚期NSCLC患者血清CYFRA21-1水平升高提示预后不良。Holdenrieder等[17] 发现,CYFRA21-1 是复发性NSCLC二线化疗疗效的独立预测因子,但是CYFRA21-1 单独检测在肺癌早期诊断中敏感度不高, 且缺乏器官或部位特异性。

  • 1.5 胃泌素释放肽前体(Pro-gastrin Releasing Peptide,Pro-GRP)

  • 胃泌素释放肽(Gastrin Releasing Peptide,GRP) 只在神经组织和肺内的神经内分泌细胞中低水平表达,可以作为SCLC的自分泌生长因子,促进SCLC快速生长。Pro-GRP是GRP稳定的前体结构,在血浆中含量稳定,可反映血液中GRP的表达水平,因此,可以作为临床上评价肺癌的指标。 国际多中心临床研究发现Pro-GRP在SCLC和肺部良性疾病患者中存在显著性差异,如果血清ProGRP升高,则发生SCLC的可能性较大,肺鳞癌患者Pro-GRP水平比肺腺癌患者增高更明显[18]。另外肾脏功能对Pro-GRP在体内的含量有较大影响,临床上肺癌患者检测Pro-GRP水平时需要同时检查患者的肾功能,排除肾小球滤过率降低造成机体ProGRP水平的增加。

  • 1.6 微核糖核酸(Micro Ribonucleic Acid,miRNA)

  • miRNA是一大类内源性非编码单链小分子RNA,参与调控多个肿瘤相关信号通路,在转录后水平调控靶基因的表达,涉及细胞增殖、凋亡等多个过程。Larzabal等[19] 发现NSCLC细胞中的miR205可以引起细胞周期停滞,抑制细胞生长,其作用的靶基因为整合素 α5。miRNA也参与肺癌细胞上皮-间充质转化,影响肿瘤细胞的侵袭、迁移和耐药。Kitamura等[20] 发现TGF-β1 可以在肺癌细胞中诱导miR-134、miR-487b、miR-655的过表达,其中miR-134、miR-487b的过表达促进了肺癌上皮-间充质转变(Epithelial-mesenchymal Transition,EMT) 和对吉非替尼的耐药性,这些miRNA的敲除抑制了EMT过程并逆转TGF-β1 诱导的对吉非替尼的耐药性。研究表明miR-134、miR-487b、miR-655 可以通过靶向MAGI2 促进TGF-β1 诱导的EMT现象并影响对吉非替尼的耐药性,其抑制作用导致了肺癌PTEN稳定性丧失,miR-134、miR-487b、 miR-655 可以成为晚期肺腺癌治疗的新靶点。另外,研究证明miR-141作用于肺癌细胞中趋化因子1(CXCL1),从而调节T细胞迁移到恶性胸水中,与有恶性胸腔积液的NSCLC患者生存相关,miR-141 低表达促进肿瘤免疫逃逸。循环miR-944 在肺鳞癌中显著增加,可以通过miR-944 区分肺腺癌和肺鳞癌[21]。值得注意的是在肿瘤临床症状出现之前, miRNA已经出现在血液中并可被检测到,可以通过组学测定找寻多种体现肺癌标志的miRNAs[22],研究发现miRNA152-3p、miRNA199a-5、miRNA20a-5p与肺腺癌患者复发相关,miRNA1155-5p、miRNA233-3p、miRNA126-3p升高提示肺癌进展风险高[23]

  • 1.7 肺癌上皮-间充质转化(EMT)相关分子标志物

  • 肺癌侵袭和转移过程中有EMT发生,抑制肺癌的转移可以通过阻断肺癌细胞的EMT细胞通路实现,TGF-β1可以造成肺癌细胞发生EMT,上皮标志分子E-cadherin表达下降,而间充质分子Vimentin和Snail升高,这些分子也可以作为肺癌的标志物体现EMT的水平。

  • E-cadherin可以维持上皮细胞极性和完整性, 参与了肺癌的发生发展,检测E-cadherin可以作为肺癌治疗和预后的判断。肺癌时,E-cadherin表达下降,肿瘤细胞间黏附作用减弱,方便肺癌侵袭性生长。人参皂苷Rg3 可以增加E-cadherin表达,减少N-cadherin、Snail和Vimentin表达,同时下调FUT4表达,可以通过EMT对肺癌致病机制进行深入研究[24]。ZEB1是EMT关键转录因子,能与辅助因子共同结合在E-cadherin启动子的E盒,抑制EMT相关基因转录,而TLE1是肺部特异性致癌因子,通过抑制E-cadherin表达促进EMT的发生[25]。 Vimentin与肺癌的侵袭和转移密切相关,是评判肿瘤患者预后的指标,肺癌细胞尤其是低分化肿瘤细胞可以诱导Vimentin表达,表达异常与肺癌局部浸润和转移潜能密切相关[26, 27]

  • 1.8 肺癌的免疫疗法分子标志物

  • PD-L1(也称CD274和B7-H1)是一种参与免疫抑制的跨膜蛋白,在肿瘤细胞和免疫细胞中表达升高,据报道20%~95%的NSCLC可以表达PD-L1[28]。 肺癌细胞表面的PD-L1可以与活化的T淋巴细胞上的PD-1 受体结合,导致效应T细胞功能减低。目前已经批准了三种(Pembrolizumab、Nivolumab、 Atezolizumab)阻断PD-L1 和PD-1 相互作用的单克隆抗体用于晚期NSCLC患者的治疗[29, 30]。 晚期NSCLC的Ⅰ期临床试验中,肿瘤细胞PD-L1 表达高的患者对pembrolizumab有更高的应答率,具有更长的无进展生存期[31]。PD-L1被称为伴随生物标志物,在临床应用中需要定义阳性的最佳临界点, 确定肿瘤基质细胞(如浸润淋巴细胞) 上PD-L1的存在是否与免疫反应有关,需要进一步调查是否检测到PD-L1对肺癌转移性肿瘤的预测反应优于在肿瘤的原发部位[32, 33]

  • 2 肺癌分子标志物的转化应用

  • 肿瘤分子标志物在临床转化中的应用包括肺癌的筛查和早期诊断、肺癌的疗效观察和预后评估、 肺癌的复发和转移预测、以及基于肺癌分子标志物的药物设计等。现在临床上应用广泛的是进行肺癌的筛查和早期诊断。表1显示了常见肺癌分子标志物在临床检测中的应用。

  • 表1 常见肺癌分子标志物在临床检测中的应用

  • 2.1 肺癌的筛查和早期诊断

  • 肺癌分子标志物可以协助原发性肺癌的诊断和鉴别诊断,在临床上多采用多种肿瘤分子标志物联合检测的方式,提高肺癌的诊断效率[43]。Molina等[44] 检测了472 例NSCLC和175 例SCLC患者血清CEA、CYFRA21-1、NSE、pro-GRP、SCC-Ag、CA125 的水平,多指标联合检测对鉴别NSCLC和SCLC的符合率达到77.4%。另一项包含3 144 例SCLC患者的研究也获得相同的结果,多指标联合检测显著提高诊断的敏感性,可以更好的对肺癌进行早期诊断[45]

  • 2.2 肺癌的疗效观察和预后评估

  • 恶性肿瘤治疗后肿瘤分子标志物的水平变化和肿瘤治疗有一定的相关性。 通过治疗前后肿瘤分子标志物的变化体现对恶性肿瘤的治疗效果。 Hirose等[46] 比较SCLC患者化疗前后血清NSE和Pro-GRP的水平,发现67.3%的化疗复发患者可以检测到NSE和Pro-GRP水平升高,未复发患者未观察到两者的变化。Yonemori等[47] 研究发现放射治疗前Pro-GRP高水平是预测SCLC脑转移治疗失败和脑转移发生率以及患者生存期的重要预测因子。Tang等[48] 检测不同阶段肺癌患者手术切除后患者胸腔积液中NSE的表达,发现胸腔积液NSE高表达患者胸膜无复发生存率和总生存期均降低。 Hou等[49] 检测了SCLC患者循环肿瘤细胞(Circulating Tumor Cells,CTCs) 的水平,发现无论是CTCs基线水平还是化疗一周后CTCs数量的改变均为SCLC独立的预后因子。Naito等[50] 也获得同样结论,CTCs高水平与肺癌患者的不良生存明显相关。

  • 2.3 肺癌的复发和转移预测

  • 肺癌患者治疗后应该每年进行肿瘤分子标志物检测,以评估肿瘤是否发生复发和转移,如果随访中发现肿瘤分子标志物升高,需要引起特别注意。 肺癌分子标志物随着肿瘤治疗状态存在数值变化, 有研究表明,在接受5 个化疗周期的SCLC患者, Pro-GRP水平随化疗的深入逐步降低,而CYFRA21-1 和NSE则呈现无规则波动[51]。Okusuka等[52] 根据肺癌患者的随访研究,发现Pro-GRP对SCLC患者复发有较好的预测作用,NSE可作为SCLC患者复发后生存期的独立预测指标。因此在临床上动态监测并综合分析各种肺癌分子标志物对指导临床疗效监测非常重要。

  • 2.4 基于肺癌分子标志物的药物靶点设计和精准医学研究

  • 肺癌分子靶向治疗主要是针对PD-1/PD-L1的抗体免疫治疗及针对肺癌高表达的EGFR、ALK和ROS的药物治疗。针对特异性的靶标设计了相应的抗体和药物,对肺癌的治疗起到了非常重要的作用, 我们可以利用靶标分子进行药物设计和肺癌的精准治疗。表2显示了用于预测药物作用靶点的分子标志物。

  • 表2 肺癌分子标志物药物靶点设计

  • 血管内皮细胞生长因子(Vascular Endothelial Growth Factor,VEGF) 信号通路在SCLC疾病进展和化疗耐药中起到重要作用。在SCLC患者中, VEGF是独立的负性预测因子,阻断VEGF受体可以减缓肺癌的增殖并增加肺癌对放疗和化疗的敏感性。贝伐单抗是靶向VEGF的单抗,贝伐单抗联合化疗可以对肺癌治疗起到提高疗效的作用。Ⅱ期临床试验结果显示,顺铂联合依托泊苷中加入贝伐单抗,可以提高SCLC患者的PFS[53]。AVE0005 是一种新型重组人源化蛋白,可通过阻止VEGF与细胞表面VEGF受体结合,起到治疗肺癌作用[54]。针对表皮生长因子受体-酪氨酸激酶(Epidermal Growth Factor Receptor Tyrosine Kinase,EGFR-TK)的药物成为治疗肺癌的热点,伊马替尼是广泛应用的EGFR-TK的抑制剂,其抑制SCLC细胞株和异种移植瘤呈现剂量依赖模式[55]。c-Met与配体(HGF) 结合后可以促进SCLC细胞迁移。c-Met在SCLC过表达,表现为c-Met受体的特异性突变[56]。c-Met小分子抑制剂SU011274和PHA665752对肺癌异种移植瘤体现出抗肿瘤活性, 另外XL880、 ARQ197、 MK2461、PF2341066 等c-Met抑制剂治疗SCLC的临床试验正在逐步开展之中。

  • 3 总结和展望

  • 肿瘤分子标志物的研究和转化是转化医学的重要研究内容,针对肿瘤特异性靶点的分子标志物成为肿瘤分类、鉴定、预后的重要研究方向,另外肿瘤分子标志物也是诊断试剂和肿瘤靶向药物研发的突破口。 肿瘤分子标志物的选择要注意个体差异,需要根据不同肿瘤患者的基因型差异, 制定个性化治疗方案,以确保肿瘤治疗的有效性和安全性。

  • 目前肺癌分子标志物存在一定的缺陷, 主要是现在应用的肺癌分子标志物并不是肺癌特异,只是肺癌相关肿瘤分子标志物,所以存在指标和疾病不一致的情况。另外肿瘤分子标志物的研究均为回顾性分析,由于样本容量小、样本均质性差等造成结果可比性较差。良好的肺癌分子标志物的筛选需要通过大规模、多中心的临床试验进行分析,方能找到更适合临床检测的肿瘤分子标志物。 随着科学技术的不断进步,基于DNA甲基化的新一代测序技术[57]、以及循环肿瘤DNA的应用[58] 等会筛选出更多的肺癌分子标志物,肺癌分子标志物的转化为肺癌早期诊断和靶向治疗提供重要研究方向,也成为精准医学的重点研究领域。

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