2020, Vol. 47扩展功能
文章信息
- 李峰平, 李志强
- LI Feng-Ping, LI Zhi-Qiang
- 液体活检在胶质瘤诊断中的意义
- Diagnostic value of liquid biopsy in glioma
- 国际神经病学神经外科学杂志, 2020, 47(5): 529-534
- Journal of International Neurology and Neurosurgery, 2020, 47(5): 529-534
-
文章历史
收稿日期: 2020-04-16
修回日期: 2020-08-07
胶质瘤是最常见的中枢神经系统原发性恶性肿瘤，每100000人中约有7.3例患者，其中高级别胶质瘤约占85%，低级别胶质瘤约占15%，多发于成年人[1]。胶质瘤细胞可以起源于不同的前体细胞，少突细胞前体细胞(oligodendrocyte precursor cells，OPCs)是重要的原始细胞之一，将p53和NF1基因敲除后，大部分时间处于稳定状态来源于成年人的OPCs将会被重新激活、增殖直至发生恶变。哺乳动物类雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)信号通路等参与了胶质瘤的发生发展[2]。由于胶质瘤的发生机制非常复杂，绝大部分胶质瘤早期不易发现，确诊胶质瘤仍然面临极大的挑战。传统的诊断技术主要包括病理组织活检和颅脑影像学检查，但两者均有一定的局限性：前者作为侵袭性手段，患者依从性不高；后者鉴别诊断仍有困难而可能延误最佳治疗时机[3-5]。目前，在肿瘤检测的临床研究中，科学家对无创诊断技术即液体活检技术表现出极大兴趣。该技术通过分离检测来自体液的循环肿瘤细胞(circulating tumor cells，CTCs)、循环肿瘤DNA(circulating tumor DNA，ctDNA)、微小RNA(miRNAs)、外泌体等为肿瘤学的临床决策提供丰富信息，它的应用能够较好地弥补传统诊断技术的不足。本文围绕胶质瘤的液体活检技术及新型肿瘤标志物进行综述，探讨其在临床中的巨大应用前景。
1 CTCs通过激活信号通路，表达细胞外黏附分子等机制，来自原发肿瘤的胶质瘤细胞和胶质瘤干细胞(glioma stem cells，GSCs)可进入血管成为CTCs[6]，因CTCs具有干细胞的特性，对放化疗和循环应激诱导的细胞凋亡也具有一定的的耐受性[7]。在GSCs中，增殖细胞核抗原相关因子(proliferating cell nuclear antigen-associated factor，PAF)的过度表达影响了DNA的复制和嘧啶代谢通路，PAF与增殖细胞核抗原(proliferating cell nuclear antigen，PCNA)相互作用并能够调节DNA的跨损伤修复(trans-lesion synthesis，TLS)，因此GSCs拥有强大的自我更新能力，并导致胶质母细胞瘤(glioblastoma multiforme，GBM)患者对放疗不敏感，具有PAF类似作用的还有Akt家族基因以及磷脂酰肌醇3-激酶(phosphoinositide 3-kinase，PI3K)/蛋白激酶B(protein kinase B，Akt)信号通路[8-10]。Krol等首次证实了胶质母细胞瘤患者CTCs簇的存在[11]。为了筛选分析CTCs，Müller等利用胶质细胞原纤维酸性蛋白(glial fibrillary acidic protein，GFAP)作为标志，通过比较基因组杂交技术(comparative genomic hybridization，CGH)、序列分析和荧光原位杂交(fluorescence in situ hybridization，FISH)，进一步证明CTCs来源于GBM，但是，在这一研究中，通过GFAP的免疫染色，仅有20.6%的GBM患者在外周血检测到了CTCs[12]。利用原位杂交技术，同样可以检测CTCs的miRNAs，Ortega等利用MishCTC在上皮来源的循环肿瘤细胞中检测到miRNA-21[13]。因此，利用这项技术有可能让胶质瘤得到早期诊断。由于CTCs获得率和纯度较低、获得的CTCs与原始肿瘤细胞间的异质性等有待研究，所以，该技术真正应用于临床还须进一步探索[14-16]。为了降低背景噪音，提高胶质瘤诊断技术的特异性，有科学家在尝试从脑脊液中分离CTCs，期望能够从中获得胶质瘤细胞[17]。
2 ctDNA循环血液中存在着一种DNA，称之为血浆游离DNA(cell -free DNA，cfDNA)，其中来源于肿瘤细胞的称之为ctDNA。ctDNA的获取方法无创，利于GBM诊断和分型，可以协助制定治疗方案并检测患者对治疗的反应。对获取的ctDNA可以开展包括微滴式数字PCR(droplet digital PCR，ddPCR)定量分析，突变基因检测，基因组、表观基因组和蛋白质组分析等[18-19]。在一项研究中，19位脑脊液中分离检测到ctDNA的患者，仅有3位的cfDNA检测到35个突变位点，包括1p/19q共缺失、突变型IDH1/IDH2和生长因子受体信号通路的改变等，cfDNA的这些突变位点的平均变异等位基因分数远低于脑脊液来源的ctDNA(0.58% vs 23.96%)，且大多数肿瘤组织中的克隆突变也存在于脑脊液中[20]。随着更多特异性突变位点被发现，这些位点的联合检测可以使肿瘤DNA诊断胶质瘤的特异性高达100%[21]。尽管如此，不同体液来源的ctDNA方法学特征和提供的信息仍然具有差异，脑脊液来源的ctDNA提供的信息更加精确，更具有代表性，获得成本更低，相比cfDNA，脑脊液来源的ctDNA突变位点的检测敏感性更高(100% vs 38%)[22]，它的优势得益于检测分析手段的更新，即将体拷贝数改变(somatic copy number alteration，SCNAs)的分析与配对端测序确定的DNA片段模式相结合，借助sWGS数据检测CSF中的肿瘤细胞游离DNA(cell -free tumor DNA，cftDNA)[23-25]，同时将DNA分子片段长度测定联合特异性片段基因测序能够进一步提高ctDNA相关检测技术在胶质瘤诊断中的准确性，将受试者操作特征曲线下面积(area under curve，AUC)从小于0.5提高至大于0.91[26]。鉴于脑脊液中ctDNA的密度低于外周血液，Mair等研究发现循环肿瘤线粒体DNA(circulating tumor mitochondria DNA，tmtDNA)有助于提高胶质母细胞瘤的检测率，可以替代核ctDNA(82% vs 24%)，在脑脊液和尿液中也可以检测到，因此tmtDNA有更加广泛的应用前景[27-28]。
3 miRNAmiRNA是长约22nt的非编码RNA，广泛存在于从病毒到人类的各种生物中，通过与mRNA的3’-UTRs结合抑制mRNA表达或促进mRNA降解，防止蛋白合成[29-30]。许多研究表明miRNA在人类疾病的发生发展扮演重要的角色，如胶质瘤等肿瘤[31-37]。由于恶性肿瘤细胞具有异质性，ctDNA并不会拥有完全相同的序列[38]，相比之下，miRNAs的一致性更高。Zhou等通过荟萃分析得出，在胶质瘤的诊断中，miRNAs的整体检测灵敏度达85%(95%CI：0.81~0.89)，特异性为90%(95%CI：0.85~0.93)，AUC是93%(95%CI：0.91~0.95)，其中来自血液标本的分别是84%(95%CI：0.80~0.88)，85%(95%CI：0.81~0.89)和92%(95%CI：0.89~0.94)，来自脑脊液标本的分别是89%(95%CI：0.73~0.96)，98%(95%CI：0.87~1.00)，98%(95%CI：0.96~0.99)；同时检测一组miRNAs可以提高灵敏度，如(miRNA-93，miRNA-590-3p，miRNA-454)；(miRNA-15b，miRNA-21)等组合[39]。不仅如此，通过测序以及信号通路分析发现miRNA可以用于评估胶质瘤细胞的放化疗敏感性[40]。对患者临床资料的分析结果表明，低表达miRNA-221和miRNA-222的患者预后更好[34]。而且，miRNAs与胶质瘤的侵袭性密切相关，通过慢病毒转导miRNA-1270的LN-18细胞系在雄性裸鼠体内的生长速度和体积得到了抑制；miRNA-605的高表达可以抑制胶质瘤细胞系U251和T98细胞系增殖、迁移和侵袭的进展[32, 35]。相比于肿瘤组织来源的miRNA，基于脑脊液的miRNA因对核糖核酸酶和物理化学条件的耐受性更高，所以更加稳定、精确性也可能更高[41-43]，并可以用于CNS其他恶性病变的鉴别诊断[44]。但是，由于miRNA序列较短，目前的探针不能很好分析pri-，pre-以及成熟形式的区别，而且相关技术只能进行相对定量，因此，需要找到更加标准的内源性对照[41]。除了miRNA，其他细胞外RNA(extracellular RNA，exRNA)在胶质瘤检测中的标记作用也有待进一步挖掘，如Y RNA和tRNA等[43]。其中，tRNAs的产生离不开RNA多聚酶Ⅲ(polymerase Ⅲ，Pol Ⅲ)的指导和转录因子ⅢB和ⅢC(transcription factor ⅢB/C，TFⅢB/C)的控制，对于mRNA的表达至关重要，被证明与包括黑素瘤、GBM在内的多种癌症密切相关，其关键在于癌基因和肿瘤抑制信号通路可以调节Pol Ⅲ和tRNAs的合成，进而影响细胞的生物学行为[45-47]。Yang等发现SOX4通过结合特异的tRNAs，如tRNAiMet等，阻碍TATA box结合蛋白和Pol Ⅲ对tRNAs基因的募集，从而抑制其表达以及GBM细胞的增殖[48]。
4 外泌体外泌体是由多种细胞产生的脂双层分泌体，直径30~100nm，包含miRNAs以及蛋白质等多种物质，参与细胞间信息传递和肿瘤微环境的形成[49-51]。在胶质瘤中，外泌体的产生与间充质干细胞和胶质瘤干细胞密切相关[52-54]，如：来源于GBM的外泌体包含有凝血因子TF/VIIa复合体，进而诱导形成乏氧环境、促进血管生成、增强侵袭性[55]。Sun等证明GBM干细胞通过分泌产生包含Notch1蛋白的外泌体促进GBM的侵袭转移[56]。外泌体凭借其提供的丰富信息可以用于胶质瘤的诊断，预后和治疗[57-58]。Santangelo等发现血浆来源的外泌体包含的mi-21/222/124-3p与胶质瘤的分级和预后有关[59]。表皮生长因子受体(epidermal growth factor receptor，EGFR)与胶质母细胞瘤某一亚型密切相关，以突变型EGFRvⅢ为例，47%左右的GBM患者EGFRvⅢ为阳性，它可以调控外泌体生物发生、细胞间转运和生物学效应[60-61]。大部分胶质瘤患者存在EGFRvⅢ突变体，利用脑脊液来源的外泌体检测EGFRvⅢ突变体，在诊断胶质瘤中特异性高达98%，敏感性只有61%[62]。当分离检测血浆来源的包含长链非编码RNA-HOX转录反义基因间RNA(hox transcript antisense intergenic RNA，HOTAIR)的外泌体时，灵敏度为86.1%，特异性为87.5%，AUC为0.913(95%CI：0.845~0.982，P＜0.0001)[63]。然而由于分离检测方法步骤多耗时长，外泌体的纯度得不到保证，甚至有污染的风险[18]。为了提高临床应用价值，Lobbr等报道了一种有效可重复，室温下能够维持外泌体足够稳定的方法[57]。同样的，经过人工设计的外泌体作为载体，可以顺利的通过血脑屏障，将纳米材料、化学药物和miRNAs靶向运输到病灶，甚至大脑小胶质细胞来源的外泌体也可以作为纳米治疗剂，用于诊断和治疗[53, 64-65]。
通过筛选分析与肿瘤密切相关的细胞、分子与基因等物质，液体活检技术拓展了对肿瘤发生发展机制的认识，提高了诊断治疗的特异性，因其微侵袭性而更容易被患者接受。随着各项研究的开展，越来越多的循环肿瘤标志物被发现，但是由于灵敏度或特异性的限制，能够应用到临床的标记十分有限。更大的挑战在于如何找到合适的标记组合，收集分析不同信息，为胶质瘤的早期诊断分型、治疗方案的制定实施和疗效判定等提供科学依据；如何将基础研究和临床应用相结合，使丰富的生物标志更多地转化为胶质瘤的临床检测方法；如何降低高昂的检测成本，使液体活检技术能够在临床广泛开展。相信随着研究的深入进展，液体活检技术将在胶质瘤的临床应用中大放异彩。
| [1] |
Rasmussen BK, Hansen S, Laursen RJ, et al. Epidemiology of glioma:clinical characteristics, symptoms, and predictors of glioma patients grade Ⅰ-Ⅳ in the the Danish Neuro-Oncology Registry[J]. J Neurooncol, 2017, 135(3): 571-579. DOI:10.1007/s11060-017-2607-5 |
| [2] |
Galvao RP, Kasina A, McNeill RS, et al. Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process[J]. Proc Natl Acad Sci U S A, 2014, 111(40): E4214-E4223. DOI:10.1073/pnas.1414389111 |
| [3] |
Bogsrud TV, Londalen A, Brandal P, et al. 18F-Fluciclovine PET/CT in suspected residual or recurrent high-grade glioma[J]. Clin Nucl Med, 2019, 44(8): 605-611. DOI:10.1097/RLU.0000000000002641 |
| [4] |
Thust SC, Heiland S, Falini A, et al. Glioma imaging in Europe:a survey of 220 centres and recommendations for best clinical practice[J]. Eur Radiol, 2018, 28(8): 3306-3317. DOI:10.1007/s00330-018-5314-5 |
| [5] |
van Dijken BRJ, van Laar PJ, Holtman GA, et al. Diagnostic accuracy of magnetic resonance imaging techniques for treatment response evaluation in patients with high-grade glioma, a systematic review and meta-analysis[J]. Eur Radiol, 2017, 27(10): 4129-4144. DOI:10.1007/s00330-017-4789-9 |
| [6] |
Diksin M, Smith SJ, Rahman R. The molecular and phenotypic basis of the glioma invasive perivascular niche[J]. Int J Mol Sci, 2017, 18(11): 2342. DOI:10.3390/ijms18112342 |
| [7] |
Liu TR, Xu HN, Huang MG, et al. Circulating glioma cells exhibit stem cell-like properties[J]. Cancer Res, 2018, 78(23): 6632-6642. DOI:10.1158/0008-5472.CAN-18-0650 |
| [8] |
Ong DST, Hu B, Ho YW, et al. PAF promotes stemness and radioresistance of glioma stem cells[J]. Proc Natl Acad Sci U S A, 2017, 114(43): E9086-E9095. DOI:10.1073/pnas.1708122114 |
| [9] |
Turner KM, Sun Y, Ji P, et al. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression[J]. Proc Natl Acad Sci U S A, 2015, 112(11): 3421-3426. DOI:10.1073/pnas.1414573112 |
| [10] |
Wei YY, Jiang YZ, Zou F, et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells[J]. Proc Natl Acad Sci USA, 2013, 110(17): 6829-6834. DOI:10.1073/pnas.1217002110 |
| [11] |
Krol I, Castro-Giner F, Maurer M, et al. Detection of circulating tumour cell clusters in human glioblastoma[J]. Br J Cancer, 2018, 119(4): 487-491. DOI:10.1038/s41416-018-0186-7 |
| [12] |
MMüller C, Holtschmidt J, Auer M, et al. Hematogenous dissemination of glioblastoma multiforme[J]. Sci Transl Med, 2014, 6(247): 247ra101. DOI:10.1126/scitranslmed.3009095 |
| [13] |
Ortega FG, Lorente JA, Garcia Puche JL, et al. miRNA in situ hybridization in circulating tumor cells--MishCTC[J]. Sci Rep, 2015, 5: 9207. DOI:10.1038/srep09207 |
| [14] |
Shen ZY, Wu AG, Chen XY. Current detection technologies for circulating tumor cells[J]. Chem Soc Rev, 2017, 46(8): 2038-2056. DOI:10.1039/C6CS00803H |
| [15] |
Watanabe M, Kenmotsu H, Ko R, et al. Isolation and molecular analysis of circulating tumor cells from lung cancer patients using a microfluidic chip type cell sorter[J]. Cancer Sci, 2018, 109(8): 2539-2548. DOI:10.1111/cas.13692 |
| [16] |
Yu M, Bardia A, Aceto N, et al. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility[J]. Science, 2014, 345(6193): 216-220. DOI:10.1126/science.1253533 |
| [17] |
Madhankumar AB, Mrowczynski OD, Patel SR, et al. Interleukin-13 conjugated quantum dots for identification of glioma initiating cells and their extracellular vesicles[J]. Acta Biomater, 2017, 58: 205-213. DOI:10.1016/j.actbio.2017.06.002 |
| [18] |
Campos CDM, Jackson JM, Witek MA, et al. Molecular profiling of liquid biopsy samples for precision medicine[J]. Cancer J, 2018, 24(2): 93-103. DOI:10.1097/PPO.0000000000000311 |
| [19] |
Panditharatna E, Kilburn LB, Aboian MS, et al. Clinically relevant and minimally invasive tumor surveillance of pediatric diffuse midline gliomas using patient-derived liquid biopsy[J]. Clin Cancer Res, 2018, 24(23): 5850-5859. DOI:10.1158/1078-0432.CCR-18-1345 |
| [20] |
Miller AM, Shah RH, Pentsova EI, et al. Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid[J]. Nature, 2019, 565(7741): 654-658. DOI:10.1038/s41586-019-0882-3 |
| [21] |
Zacher A, Kaulich K, Stepanow S, et al. Molecular diagnostics of gliomas using next generation sequencing of a glioma-tailored gene panel[J]. Brain Pathol, 2017, 27(2): 146-159. DOI:10.1111/bpa.12367 |
| [22] |
Pan C, Diplas BH, Chen X, et al. Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA[J]. Acta Neuropathol, 2019, 137(2): 297-306. DOI:10.1007/s00401-018-1936-6 |
| [23] |
De Mattos-Arruda L, Mayor R, Ng CKY, et al. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma[J]. Nat Commun, 2015, 6: 8839. DOI:10.1038/ncomms9839 |
| [24] |
Mouliere F, Mair R, Chandrananda D, et al. Detection of cell-free DNA fragmentation and copy number alterations in cerebrospinal fluid from glioma patients[J]. EMBO Mol Med, 2018, 10(12): e9323. DOI:10.15252/emmm.201809323 |
| [25] |
Ramalingam N, Jeffrey SS. Future of liquid biopsies with growing technological and bioinformatics studies:opportunities and challenges in discovering tumor heterogeneity with single-cell level analysis[J]. Cancer J, 2018, 24(2): 104-108. DOI:10.1097/PPO.0000000000000308 |
| [26] |
Mouliere F, Chandrananda D, Piskorz AM, et al. Enhanced detection of circulating tumor DNA by fragment size analysis[J]. Sci Transl Med, 2018, 10(466): eaat4921. DOI:10.1126/scitranslmed.aat4921 |
| [27] |
Mair R, Mouliere F, Smith CG, et al. Measurement of plasma cell-free mitochondrial tumor DNA improves detection of glioblastoma in patient-derived orthotopic xenograft models[J]. Cancer Res, 2019, 79(1): 220-230. DOI:10.1158/0008-5472.CAN-18-0074 |
| [28] |
Pan WY, Gu W, Nagpal S, et al. Brain tumor mutations detected in cerebral spinal fluid[J]. Clin Chem, 2015, 61(3): 514-522. DOI:10.1373/clinchem.2014.235457 |
| [29] |
Masamha CP, Xia Z, Yang J, et al. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression[J]. Nature, 2014, 510(7505): 412-416. DOI:10.1038/nature13261 |
| [30] |
Wang JX, Gao J, Ding SL, et al. Oxidative modification of miR-184 enables it to target Bcl-xL and bcl-w[J]. Mol Cell, 2015, 59(1): 50-61. DOI:10.1016/j.molcel.2015.05.003 |
| [31] |
He QR, Zhao LN, Liu XB, et al. MOV10 binding circ-DICER1 regulates the angiogenesis of glioma via miR-103a-3p/miR-382-5p mediated ZIC4 expression change[J]. J Exp Clin Cancer Res, 2019, 38(1): 9. DOI:10.1186/s13046-018-0990-1 |
| [32] |
Jia JW, Wang J, Yin MF, et al. microRNA-605 directly targets SOX9 to alleviate the aggressive phenotypes of glioblastoma multiforme cell lines by deactivating the PI3K/Akt pathway[J]. Onco Targets Ther, 2019, 12: 5437-5448. DOI:10.2147/OTT.S213026 |
| [33] |
Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers[J]. Nature, 2005, 435(7043): 834-838. DOI:10.1038/nature03702 |
| [34] |
Swellam M, Ezz El Arab L, Al-Posttany AS, et al. Clinical impact of circulating oncogenic MiRNA-221 and MiRNA-222 in glioblastoma multiform[J]. J Neurooncol, 2019, 144(3): 545-551. DOI:10.1007/s11060-019-03256-2 |
| [35] |
Wei L, Li P, Zhao CJ, et al. Upregulation of microRNA-1270 suppressed human glioblastoma cancer cell proliferation migration and tumorigenesis by acting through WT1[J]. Onco Targets Ther, 2019, 12: 4839-4848. DOI:10.2147/OTT.S192521 |
| [36] |
Yang ZY, Wang Y, Liu Q, et al. microRNA cluster MC-let-7a-1~let-7d promotes autophagy and apoptosis of glioma cells by down-regulating STAT3[J]. CNS Neurosci Ther, 2020, 26(3): 319-331. DOI:10.1111/cns.13273 |
| [37] |
Zheng J, Liu XB, Xue YX, et al. TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway[J]. J Hematol Oncol, 2017, 10(1): 52. DOI:10.1186/s13045-017-0422-2 |
| [38] |
Schroeder B, Shah N, Rostad S, et al. Genetic investigation of multicentric glioblastoma multiforme:case report[J]. J Neurosurg, 2016, 124(5): 1353-1358. DOI:10.3171/2015.4.JNS142231 |
| [39] |
Zhou Q, Liu J, Quan J, et al. MicroRNAs as potential biomarkers for the diagnosis of glioma:a systematic review and meta-analysis[J]. Cancer Sci, 2018, 109(9): 2651-2659. DOI:10.1111/cas.13714 |
| [40] |
Guo XY, Luo ZG, Xia T, et al. Identification of miRNA signature associated with BMP2 and chemosensitivity of TMZ in glioblastoma stem-like cells[J]. Genes Dis, 2020, 7(3): 424-439. DOI:10.1016/j.gendis.2019.09.002 |
| [41] |
Detassis S, Grasso M, Del Vescovo V, et al. microRNAs make the call in cancer personalized medicine[J]. Front Cell Dev Biol, 2017, 5: 86. DOI:10.3389/fcell.2017.00086 |
| [42] |
Qu K, Lin T, Pang Q, et al. Extracellular miRNA-21 as a novel biomarker in glioma:evidence from meta-analysis, clinical validation and experimental investigations[J]. Oncotarget, 2016, 7(23): 33994-34010. DOI:10.18632/oncotarget.9188 |
| [43] |
Wei Z, Batagov AO, Schinelli S, et al. Coding and noncoding landscape of extracellular RNA released by human glioma stem cells[J]. Nat Commun, 2017, 8(1): 1145. DOI:10.1038/s41467-017-01196-x |
| [44] |
Pentsova EI, Shah RH, Tang J, et al. Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid[J]. J Clin Oncol, 2016, 34(20): 2404-2415. DOI:10.1200/JCO.2016.66.6487 |
| [45] |
Birch J, Clarke CJ, Campbell AD, et al. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma[J]. Biol Open, 2016, 5(10): 1371-1379. DOI:10.1242/bio.019075 |
| [46] |
Graczyk D, Cie'sla M, Boguta M. Regulation of tRNA synthesis by the general transcription factors of RNA polymerase Ⅲ-TFⅢB and TFⅢC, and by the MAF1 protein[J]. Biochim Biophys Acta Gene Regul Mech, 2018, 1861(4): 320-329. DOI:10.1016/j.bbagrm.2018.01.011 |
| [47] |
Macari F, El-Houfi Y, Boldina G, et al. TRM6/61 connects PKCα with translational control through tRNAi(Met) stabilization:impact on tumorigenesis[J]. Oncogene, 2016, 35(14): 1785-1796. DOI:10.1038/onc.2015.244 |
| [48] |
Yang JJ, Smith DK, Ni HQ, et al. SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells[J]. Proc Natl Acad Sci U S A, 2020, 117(11): 5782-5790. DOI:10.1073/pnas.1920200117 |
| [49] |
Guo XF, Qiu W, Liu QL, et al. Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten pathways[J]. Oncogene, 2018, 37(31): 4239-4259. DOI:10.1038/s41388-018-0261-9 |
| [50] |
Huang K, Fang C, Yi KK, et al. The role of PTRF/Cavin1 as a biomarker in both glioma and serum exosomes[J]. Theranostics, 2018, 8(6): 1540-1557. DOI:10.7150/thno.22952 |
| [51] |
Shao NY, Xue L, Wang R, et al. miR-454-3p is an exosomal biomarker and functions as a tumor suppressor in glioma[J]. Mol Cancer Ther, 2019, 18(2): 459-469. DOI:10.1158/1535-7163.MCT-18-0725 |
| [52] |
Figueroa J, Phillips LM, Shahar T, et al. Exosomes from glioma-associated mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587[J]. Cancer Res, 2017, 77(21): 5808-5819. DOI:10.1158/0008-5472.CAN-16-2524 |
| [53] |
Lang FM, Hossain A, Gumin J, et al. Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas[J]. Neuro Oncol, 2018, 20(3): 380-390. DOI:10.1093/neuonc/nox152 |
| [54] |
Wang ZF, Liao F, Wu H, et al. Glioma stem cells-derived exosomal miR-26a promotes angiogenesis of microvessel endothelial cells in glioma[J]. J Exp Clin Cancer Res, 2019, 38(1): 201. DOI:10.1186/s13046-019-1181-4 |
| [55] |
Svensson KJ, Kucharzewska P, Christianson HC, et al. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells[J]. Proc Natl Acad Sci U S A, 2011, 108(32): 13147-13152. DOI:10.1073/pnas.1104261108 |
| [56] |
Sun Z, Wang L, Zhou YL, et al. Glioblastoma stem cell-derived exosomes enhance stemness and tumorigenicity of glioma cells by transferring notch1 protein[J]. Cell Mol Neurobiol, 2020, 40(5): 767-784. DOI:10.1007/s10571-019-00771-8 |
| [57] |
Lobb RJ, Becker M, Wen SW, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma[J]. J Extracell Vesicles, 2015, 4: 27031. DOI:10.3402/jev.v4.27031 |
| [58] |
Ricklefs FL, Alayo Q, Krenzlin H, et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles[J]. Sci Adv, 2018, 4(3): eaar2766. DOI:10.1126/sciadv.aar2766 |
| [59] |
Santangelo A, Imbrucè P, Gardenghi B, et al. A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker[J]. J Neurooncol, 2018, 136(1): 51-62. DOI:10.1007/s11060-017-2639-x |
| [60] |
Choi D, Montermini L, Kim DK, et al. The impact of oncogenic EGFRvⅢ on the proteome of extracellular vesicles released from glioblastoma cells[J]. Mol Cell Proteomics, 2018, 17(10): 1948-1964. DOI:10.1074/mcp.RA118.000644 |
| [61] |
Skog J, Würdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers[J]. Nat Cell Biol, 2008, 10(12): 1470-1476. DOI:10.1038/ncb1800 |
| [62] |
Figueroa JM, Skog J, Akers J, et al. Detection of wild-type EGFR amplification and EGFRvⅢ mutation in CSF-derived extracellular vesicles of glioblastoma patients[J]. Neuro Oncol, 2017, 19(11): 1494-1502. DOI:10.1093/neuonc/nox085 |
| [63] |
Tan SK, Pastori C, Penas C, et al. Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme[J]. Mol Cancer, 2018, 17(1): 74. |
| [64] |
Jia G, Han Y, An YL, et al. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo[J]. Biomaterials, 2018, 178: 302-316. DOI:10.1016/j.biomaterials.2018.06.029 |
| [65] |
Murgoci AN, Cizkova D, Majerova P, et al. Brain-cortex microglia-derived exosomes:nanoparticles for glioma therapy[J]. Chemphyschem, 2018, 19(10): 1205-1214. DOI:10.1002/cphc.201701198 |