大气污染和肺癌相关生物标志物的研究进展

近年来,大量的研究探讨大气污染物暴露和肺癌的关系,并且诸多研究均提示长期大气污染物的暴露可能导致肺癌.对大气污染和肺癌关联的生物标志物进行研究,可进一步明确大气污染的健康效应和大气污染致癌过程的作用机制,并有望发现可用于高危人群预警、肺癌患者早期诊治及预后判断的生物标志物.本文对大气污染和肺癌相关联的生物标志物的研究进展作一综述.     

环状RNA：肺癌的潜在生物标志物

环状RNA是一种非编码RNA,能作为RNA的海绵体调节剪切和转录,也能翻译蛋白质以及与RNA结合蛋白相互作用。近年来研究发现,环状RNA在肿瘤组织的表达异常与肺癌的发生、发展以及预后存在密切的关系,有望成为肺癌的诊断、治疗及预后的生物标志物。故本文对环状RNA作为肺癌生物标志物的研究进展作一综述。     

MicroRNA：一种新型的肺癌诊断、预测和治疗的生物标志物

MicroRNA（miRNA）是非蛋白编码的短RNAs,可在转录或转录后水平调节mRNA的表达。大量研究表明,miRNA在细胞增殖、分化、凋亡和代谢方面发挥着重要作用,并参与了癌基因和抗癌基因的信号调控。在多种人类恶性肿瘤中已经检测到异常表达的miRNA,并且发现miRNA与肿瘤的发生、发展、预测、诊断、治疗和预后有关,因此,miRNA作为癌症诊断、预测和治疗的潜在标记物,具有广阔的临床应用前景。miRNA在非小细胞肺癌中扮演着多重角色,包括在肺癌发生过程中发挥促癌基因或抑癌基因的作用,调控肺癌细胞的增殖和分化,参与肺癌的侵袭和转移,影响肺癌对放、化疗的敏感性等。因而,miRNA可以作为一种标志物,在血液或痰液标本中为临床提供诊断依据,在肺癌的化学治疗及放射治疗中成为疗效预测指标,还可能提示肺癌组织的分化程度和患者预后,同时还可以作为肺癌治疗潜在靶点     

小细胞肺癌免疫治疗相关生物标志物研究进展

最近30年来小细胞肺癌(small cell lung cancer,SCLC)的治疗手段无明显突破,整体预后也无显著改善.随着免疫治疗时代的开启,免疫检查点抑制剂在SCLC治疗中取得了重大进展,但整体获益仍有限.如何筛选获益人群以进一步提高免疫治疗效果是当下SCLC研究的热点问题之一.通过概述SCLC现状,聚焦SCL...     

非小细胞肺癌免疫治疗疗效相关生物标志物研究进展

肺癌是全世界最常见的癌症之一,其死亡率一直居高不下。近年来,治疗方法除常规的手术、放疗、化疗外,免疫治疗异军突起,改变了非小细胞肺癌（NSCLC）的治疗模式。然而,在免疫治疗策略下仍只有少部分NSCLC患者能从中持久获益,部分患者接受免疫治疗后甚至出现了病情超进展。因此,精准的免疫治疗需要有效的生物标志物进行指导。本文根据样本来源不同对组织样本、血液样本、肠道微生物菌群等生物标志物进行综述,其中重点对血液样本,包括TCR免疫组库、Tregs细胞、细胞因子、乳酸脱氢酶等标志物进行总结及分析,以期为临床医生诊疗决策提供参考。     

应用SELDI技术筛选肺癌血清标志物的研究

目的:采用SELDI技术筛选肺癌患者的血清标志物.方法:用WCX2芯片SELDI技术分别检测31例肺癌患者、32例健康人血清、29例肺部良性病变.应用Proteinchipsoft ware 3.2软件采集蛋白峰,找出差异蛋白;应用Biomarker Pattern软件建立诊断模型.结果:肺癌患者和健康人血液标本比较,两组间有23个差异蛋白(P＜0.05),用这些差异蛋白构建的诊断模型诊断肺癌敏感度为100%,特异度为96.9%,ROC曲线下面积为100%.肺癌和肺部良性病变患者的血清进行差异蛋白质组学研究发现,两组间有8个差异蛋白(P＜0.05),用这些差异蛋白构建的诊断模型诊断肺癌敏感度为71.0%,特异度为62.1%,ROC曲线下面积为92.68%.结论:SELDI技术可以将肺癌患者、肺部良性病变患者和健康人正确区分,这对肺癌的筛查和早期诊断有重要意义.     

肺癌生物治疗与生物化疗研究进展

肺癌的生物治疗发展迅速,尤其是肺癌的分子靶向治疗,已取得了重大进展,疗效显著。生物化疗作为一种全新的治疗模式,在肺癌的治疗中占有愈来愈重要的地位。本文对近年来肺癌的生物治疗(包括分子靶向治疗、基因修饰树突状细胞治疗)和生物化疗的研究进展进行了综述。     

肺癌早期诊断相关标志物研究进展

肺癌是死亡率居于我国首位的肿瘤,早发现、早诊断是影响肺癌治疗效果的关键,但目前仍然缺乏精准安全的肺癌早期诊断方法,这极大地影响了肺癌患者的生存期。肺癌作为一种高度恶性肿瘤,其诊断生物标志物的相关研究受到了极大的关注。这些诊断生物标志物具有多样性,在肺癌早期诊断中的价值有待进一步探讨。     

肺癌肿瘤标志物的临床价值

随着分子生物学和免疫学的不断发展,血清肿瘤标志物(TM)在肿瘤的普查、诊断、判断预后和转归、评价疗效和随诊等方面占有越来越重要的位置.     

Diagnostic utility of trefoil factor families for the early detection of lung cancer and their correlation with tissue expression

Trefoil factors (TFFs) are upregulated in numerous types of cancer, including those of the breast, the colon, the lung and the pancreas, suggesting their potential utility as biomarkers for screening. In the present study, the clinical relevance of serum or urinary TFFs as biomarkers were comprehensively evaluated and the correlation with TFF expression levels in lung cancer tissue was examined. Serum and urine were collected from 199 patients with lung cancer and 198 healthy individuals. Concentrations of serum and urinary TFF1, TFF2 and TFF3 were measured using ELISA and the potential of TFF levels to discriminate between cancer and non-cancer samples was evaluated. In 100 of the cancer cases, expression of TFF1-3 was analyzed using immunohistochemical staining of paraffin sections. Furthermore, the relationship between TFF levels and clinicopathological factors among these cancer cases was analyzed using immunohistochemistry of tissue specimens, quantified and statistically analyzed. While serum levels of all TFFs measured using ELISA were significantly higher in patients with lung cancer compared with those in healthy individuals, urinary TFFs were lower. Areas under the curve (AUC) of the receiver operating characteristic curves for serum/urinary TFF1, TFF2 and TFF3 were 0.709/0.594, 0.722/0.501 and 0.663/0.665, respectively. Furthermore, the combination of serum TFF1, TFF2, TFF3 and urinary TFF1 and TFF3 demonstrated the highest AUC (0.826). In the clinicopathological analysis, serum TFF1 was higher in the early pathological T-stage (pTis/1/2) compared with the later stage (pT3/4) and TFF2 was higher in the pN0/1 than the pN2 group. With regards to the histological types, urinary TFF1 was higher in squamous cell carcinoma than adenocarcinoma (AC), but TFF2 tended to be higher in AC. Using immunohistochemical analysis, although TFF1 and TFF3 expression showed positive correlation with serum concentrations, TFF2 was inversely correlated. In conclusion, serum and urinary TFF levels are promising predictive biomarkers, and their measurements provide a useful in vivo and non-invasive diagnostic screening tool. In particular, TFF1 and TFF3 could be surrogate markers of clinicopathological profiles of human lung cancer.     

肺癌相关血清学肿瘤标志物研究进展

肿瘤生物标志物近年来一直是肿瘤基础和临床研究的一个十分活跃的领域.尽管迄今尚未找到肺癌特异性抗原,国内外研究人员已发现多种有潜力用于肺癌早期诊断、临床分型和分期、预后判断和疗效观察等的肿瘤生物标志.本文以癌胚抗原、神经元特异性烯醇化酶、细胞角蛋白19片段抗原、碳水化合物抗原242、粘蛋白1抗原、神经细胞粘附分子、组织多肽特异性抗原、干细胞因子、血管内皮生长因子、肝细胞生长因子、肺癌相关抗原和磷脂酰肌醇蛋白聚糖等为例,对肺癌相关血清学肿瘤生物标志物的研究进展作一综述.     

Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy

Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.     

肺癌的表观遗传研究进展

肺癌分子生物标志物早期检测是一种有效发现并且影响治疗癌症的有效分子工具。表观遗传在肺癌的发生、发展过程中起着重要的作用。表观遗传机制的研究从根本上改变了我们传统对于肺癌的发现,诊断及治疗的观点。表观遗传为肺癌的生物标记发展,早期发现和治疗风险评估提供新的见解。     

Prediagnostic serum levels of inflammatory biomarkers are correlated with future development of lung and esophageal cancer

This study tests the hypothesis that prediagnostic serum levels of 20 cancer‐associated inflammatory biomarkers correlate directly with future development of head and neck, esophageal, and lung cancers in a high‐risk prospective cohort. This is a nested case–control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a panel of 20 21cytokines, chemokines, and inflammatory molecules using Luminex technology in serum samples collected 2 or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank sum test, odds ratios, receiver operating characteristic areas of discrimination, and multivariate analysis. Biomarkers were profoundly and globally elevated in future esophageal and lung cancer patients compared to controls. Odds ratios were significant for association between several biomarkers and future development of esophageal cancer, including interleukin‐1Rα (IL‐1Ra; 35.9), interferon α2 (IFN‐a2; 34.0), fibroblast growth factor‐2 (FGF‐2; 17.4), and granulocyte/macrophage colony‐stimulating factor (GM‐CSF; 17.4). The same pattern was observed among future lung cancer cases for G‐CSF (27.7), GM‐CSF (13.3), and tumor necrosis factor‐α (TNF‐a; 8.6). By contrast, the majority of biomarkers studied showed no significant correlation with future head and neck cancer development. This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients 2 or more years before cancer diagnosis.     

蛋白质组学及其研究技术在肺癌分子生物标志物研究中的应用

肺癌是全球发病率和死亡率较高的恶性肿瘤。细胞从正常状态转变为肿瘤的过程中，细胞内蛋白质表达谱必然会发生一系列变化，肿瘤分子标记物就是细胞在非正常状态下产生的分子．以高通量结合生物信息学为特点的蛋白质组学分析技术可以从细胞整体水平上检测到这种变化近年来，为了降低肺癌的死亡率并提高其治疗效果，研究人员利用这一新的手段如利用激光捕获显微切割技术和双相凝胶电泳结合基质辅助激光解析电离飞行时间质谱（MALDI-TOF MS）和表面增强激光解析电离色行时间质谱（SELDI—TOF MS）寻找有效的肺癌标记物。本文对蛋白质组学技术在肺癌生物标志物研究中的应用作了综述。     

Targeting SLC1a5‐mediated glutamine dependence in non‐small cell lung cancer

We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non‐small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma‐l ‐glutamyl‐p‐nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p = 0.01, HR = 1.24, 95% CI: 1.05–1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR = 1.45, 95% CI: 1.15–1.50) and multivariate analyses (p = 0.04, HR = 1.22, 95% CI: 1.01–1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln‐dependent NSCLC.     

The potential of PIVKA-II as a treatment response biomarker in hepatocellular carcinoma: a prospective United Kingdom cohort study

Prothrombin induced by vitamin K absence II (PIVKA-II) has recently been validated internationally as a diagnostic biomarker for hepatocellular carcinoma (HCC), as part of the GALAD model. However, its role as a treatment response biomarker has been less well explored. We, therefore, undertook a prospective study at a tertiary centre in the UK to evaluate the role of PIVKA-II as a treatment response biomarker in patients with early, intermediate and advanced stage HCC. In a cohort of 141 patients, we found that PIVKA-II levels tracked concordantly with treatment response in the majority of patients, across a range of different treatment modalities. We also found that rises in PIVKA-II levels almost always predated radiological progression. Among AFP non-secretors, PIVKA-II was found to be informative in 60% of cases. In a small cohort of patients undergoing liver transplantation, pre-transplant PIVKA-II levels predicted for microvascular invasion and poorer differentiation. Our results demonstrate the potential utility of PIVKA-II as a treatment response biomarker and in predicting microvascular invasion, in a Western population. PIVKA-II demonstrated improved performance over AFP but, as a single biomarker, its performance was still limited. Further larger prospective studies are recommended to evaluate PIVKA-II as a treatment response biomarker, within the GALAD model.