外泌体在肿瘤疾病诊断中的研究进展

doi:10.3969/j.issn.1673-8640.2018.12.021

摘要/Abstract

摘要：

外泌体是具有磷脂双分子膜结构的纳米级囊泡,内含微小RNA（miRNA）、mRNA、DNA 片段、蛋白质等多种生物活性物质。外泌体存在于多种类型的细胞中,广泛分布于血清、尿液、唾液等体液中。目前发现肿瘤来源的外泌体与肿瘤的发生、发展密切相关。外泌体可以作为一种生物标志物在肿瘤诊断和治疗过程中发挥作用。因此,肿瘤外泌体内容物的检测和分析可以用于肿瘤的早期辅助诊断、疗效评价和预后评估。文章就外泌体在肿瘤诊断中的研究进展进行综述。

关键词: 外泌体, 肿瘤, 肿瘤标志物, 诊断

Abstract:

Exosomes are nanoscale vesicle with a double lipid membrane structure,which contain a broad array of biologically active materials,including microRNA（miRNA）,mRNA,DNA fragments and functional proteins. Exosomes can be secreted by almost all types of cells and widely distributed in serum,saliva,urine and other body fluids. Recently,tumor-derived exosomes have close relationship with tumor progression,and they have the potential of being biomarker in the diagnosis and treatment of tumor. Therefore,the determination and analysis of tumor-derived exosomes can provide a reference for the early diagnosis,treatment assessment and prognosis evaluation of tumors. This review summarizes the research progress of exosomes in tumor diagnosis.

Key words: Exosome, Tumor, Tumor marker, Diagnosis

中图分类号:

R446.1

王琪, 王保龙. 外泌体在肿瘤疾病诊断中的研究进展[J]. 检验医学, 2018, 33(12): 1148-1152.

WANG Qi, WANG Baolong. Research progress of exosomes in tumor diagnosis[J]. Laboratory Medicine, 2018, 33(12): 1148-1152.

图/表 1

参考文献 44

1	KAHLERT C,KALLURI R.Exosomes in tumor microenvironment influence cancer progression and metastasis[J]. J Mol Med(Berl),2013,91(4):431-437.
2	JOHNSTONE R M,ADAM M,HAMMOND J R,et al.Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles(exosomes)[J]. J Biol Chem,1987,262(19):9412-9420.
3	SIMONS M,RAPOSE G.Exosmes-vesicular carriers for intercellular communication[J]. Curr Opin Cell Biol,2009,21(4):575-581.
4	CHEVILLET J R,KANG Q,RUF I K,et al.Quantitative and stoichiometric analysis of the microRNA content of exosomes[J]. Proc Natl Acad Sci U S A,2014,111(41):14888-14893.
5	D'SOUZA-SCHOREY C,CLANCY J W. Tumor-derived microvesicles:shedding light on novel microenvironment modulators and prospective cancer biomarkers[J]. Genes Dev,2012,26(12):1287-1299.
6	YU S,CAO H,SHEN B,et al.Tumor-derived exosomes in cancer progression and treatment failure[J]. Oncotarget,2015,6(35):37151-37168.
7	FUJITA Y,YOSHIOKA Y,OCHIYA T.Extracellular vesicle transfer of cancer pathogenic components[J]. Cancer Sci,2016,107(4):385-390.
8	RAPOSO G,STOORVOGEL W.Extracellular vesicles:exosomes,microvesicles,and friends[J]. J Cell Biol,2013,200(4):373-383.
9	CHO W C.Molecular diagnostics for monitoring and predicting therapeutic effect in cancer[J]. Expert Rev Mol Diagn,2011,11(1):9-12.
10	KEERTHIKUMAR S,CHISANGA D,ARIYARATNE D,et al.ExoCarta:a web-based compendium of exosomal cargo[J]. J Mol Biol,2016,428(4):688-692.
11	HE M,ZENG Y.Microfluidic exosome analysis toward liquid biopsy for cancer[J]. J Lab Autom,2016,21(4):599-608.
12	TANG H,WU H,YANG Y,et al.Progress in study on the role of exosome-derived microRNA in diagnosis and treatment of diseases[J]. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2015,40(11):1270-1275.
13	CAZZOLI R,BUTTITTA F,DI NICOLA M
	et al. microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer[J]. J Thorac Oncol,2013,8(9):1156-1162.
14	SILVA J,GARCÍA V,ZABALLOS Á,et al.Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival[J]. Eur Respir J,2011,37(3):617-623.
15	KOMATSU S,ICHIKAWA D,TAKESHITA H,et al.Circulating microRNAs in plasma of patients with oesophageal squamous cell carcinoma[J]. Br J Cancer,2011,105(1) :104-111.
16	MADHAVAN B,YUE S,GALLI U,et al.Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity[J]. Int J Cancer,2015,136(11):2616-2627.
17	OGATA-KAWATA H,IZUMIYA M,KURIOKA D,et al.Circulating exosomal microRNAs as biomarkers of colon cancer[J]. PLoS One,2014,9(4):e92921.
18	WANG F,NAZARALI A J,JI S.Circular RNAs as potential biomarkers for cancer diagnosis and therapy[J]. Am J Cancer Res,2016,6(6):1167-1176.
19	张云,庹敏,刘胜武. 血清外泌体来源的 miRNA-122对肝癌诊断的研究[J]. 检验医学与临床,2017,14(9):1260-1261.
20	HARRIES L W.Long non-coding RNAs and human disease[J]. Biochem Soc Trans,2012,40(4):902-906.
21	LI Q,SHAO Y,ZHANG X,et al.Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer[J]. Tumour Biol,2015,36(3):2007-2012.
22	BRYANT R J,PAWLOWSKI T,CATTO J W,et al.Changes in circulating microRNA levels associated with prostate cancer[J]. Br J Cancer,2012,106(4):768-774.
23	MOTAMEDINIA P,SCOTT A N,BATE K L,et al.Urine exosomes for non-invasive assessment of gene expression and mutations of prostate cancer[J]. PLoS One,2016,11(5):e0154507.
24	LONG J D,SULLIVAN T B,HUMPHREY J,et al.A non-invasive miRNA based assay to detect bladder cancer in cell-free urine[J]. Am J Transl Res,2015,7(11):2500-2509.
25	TAYLOR D D,GERCEL-TAYLOR C.MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer[J]. Gynecol Oncol,2008,110(1):13-21.
26	HANNAFON B N,TRIGOSO Y D,CALLOWAY C L,et al.Plasma exosome microRNAs are indicative of breast cancer[J]. Breast Cancer Res,2016,18(1):90.
27	MANTEROLA L,GURUCEAGA E,GÁLLEGO PÉREZ J,et al.A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool[J]. Neuro Oncol,2014,16(4):520-527.
28	ROCCARO A M,SACCO A,MAISO P,et al.BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression[J]. J Clin Invest,2013,123(4): 1542-1555.
29	CLATON A,MASON M D.Exosomes in tumor immunity[J]. Curr Oncol,2009,16(3):46-49.
30	LI C,LIU D R,LI G G,et al.CD97 promotes gastric cancer cell proliferation and invasion through exosome-mediated MAPK signaling pathway[J]. World J Gastroenterol,2015,21(20):6215-6228.
31	BARAN J,BAJ-KRZYWORZEKA M,WEGLARCZYK K,et al.Circulating tumour-derived microvesicles in plasma of gastric cancer patients[J]. Cancer Immunol Immunother,2009,59(6):841-850.
32
33	MELO S A,LUECKE L B,KAHLERT C,et al.Glypican-1 identifies cancer exosomes and detects early pancreatic cancer[J]. Nature,2015,523(7559):177-182.
34	COSTA-SILVA B,AIELLO N M,OCEAN A J,et al.Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver[J]. Nat Cell Biol,2015,17(6):816-826.
35	ROBBINS P D,MORELLI A E.Regulation of immune responses by extracellular vesicles[J]. Nat Rev Immunol,2014,14(3):195-208.
36	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.
37	NILSSON J,SKOG J,NORDSTRAND A,et al.Prostate cancer-derived urine exosomes:a novel approach to biomarkers for prostate cancer[J]. Br J Cancer,2009,100(10):1603-1607.
38	BECKHAM C J,OLSEN J,YIN P N,et al.Bladder cancer exosomes contain EDIL-3/Del1 and facilitate cancer progression[J]. J Urol,2014,192(2):583-592.
39	刘晓庆,黄波. 外泌体应用于肿瘤液体活检的研究进展[J]. 实验与检验医学,2016,34(5):535-538.
40	YANG J,WEI F,SCHAFER C,et al.Detection of tumor cell-specific mRNA and protein in exosome-like microvesicles from blood and saliva[J]. PLoS One,2014,9(11): e110641.
41	WELTON J L,KHANNA S,GILES P J,et al.Proteomics analysis of bladder cancer exosomes[J]. Mol Cell Proteomics,2010,9(6):1324-1338.
42	SHIMODA M,PRINCIPE S,JACKSON H W,et al.Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state[J]. Nat Cell Biol,2014,16( 9) :889-901.
43	SANTONOCITO M,VENTO M,GUGLIELMINO M R,et al.Molecular characterization of exosomes and their microRNA cargo in human follicular fluid:bioinformatic analysis reveals that exosomal microRNAs control pathways involved in follicular maturation[J]. Fertil Steril,2014,102( 6) :1751-1761.
44	PITT J M,ANERÉ F,AMIGORENA S,et al.Dendritic cell-derived exosomes for cancer therapy[J]. J Clin Invest,2016,126(4):1224-1232.

肿瘤类型	蛋白标志物	参考文献
胃癌	HER-2/neu、CCR6、CD97	[30-31]
卵巢癌	紧密连接蛋白4、MAGE3/6、 TGF-β1	[32]
胰腺癌	GPC-1、MIF、EGFR	[33-34]
黑色素瘤	CD63、窖蛋白-1	[35]
胶质母细胞瘤	EGFR-vⅢ、TGF-β	[36]

肿瘤类型	蛋白标志物	参考文献
胃癌	HER-2/neu、CCR6、CD97	[30-31]
卵巢癌	紧密连接蛋白4、MAGE3/6、 TGF-β1	[32]
胰腺癌	GPC-1、MIF、EGFR	[33-34]
黑色素瘤	CD63、窖蛋白-1	[35]
胶质母细胞瘤	EGFR-vⅢ、TGF-β	[36]

[1]	周韵斓, 沈立松. 液体活检标志物在非小细胞肺癌中的临床应用和挑战[J]. 检验医学, 2023, 38(9): 807-811.
[2]	王杨淑怡, 叶威, 林志豪, 黄约诺, 方涛, 董晓亭. 肺腺癌焦亡相关特征模型的构建和验证[J]. 检验医学, 2023, 38(9): 833-841.
[3]	彭伟, 李运改, 许静, 刘华, 杨翠霞, 沈云岳. 血清炎症因子联合PSA、f-PSA可辅助诊断前列腺癌[J]. 检验医学, 2023, 38(9): 849-854.
[4]	王慧英, 汤昱, 董利利, 王静. 肺炎支原体RNA检测用于肺炎患儿疾病诊断和疗效监测[J]. 检验医学, 2023, 38(9): 865-869.
[5]	孙信林, 叶星明, 李倩, 赵丽君. 支气管镜检查联合痰TB-RNA、血清TB-SA检测诊断菌阴肺结核[J]. 检验医学, 2023, 38(9): 870-873.
[6]	卫明珠, 潘继文, 罗锐, 陈俊辉. 凝血4项和肿瘤标志物对乙型肝炎相关肝癌的辅助诊断价值[J]. 检验医学, 2023, 38(9): 901-904.
[7]	丁肖媛, 戴劲盛, 焦荣红, 马素丽, 朱海峰, 吴梦雅, 车艳然, 张蕾. 肥胖/超重对哮喘发作期患儿Th1/Th2和Th17/Treg细胞因子的影响[J]. 检验医学, 2023, 38(8): 748-752.
[8]	陈文举, 周勇, 徐佳佳, 王攀. 血清外泌体miR-23b-3p和miR-4429诊断HCC的价值[J]. 检验医学, 2023, 38(7): 624-628.
[9]	王腾飞, 陈珊, 安和兵, 周蕾. 急性白血病患者外周血lncRNA CRNDE、miR-384表达及其临床意义[J]. 检验医学, 2023, 38(7): 686-691.
[10]	韩雪, 闻柳, 宛杨. 唐氏筛查临界或高风险孕妇羊水染色体核型和基因组拷贝数变异结果分析[J]. 检验医学, 2023, 38(6): 548-552.
[11]	张楚, 王建红, 李瑞, 肖艳华, 王恒, 张品肖, 徐凝馨, 夏半半. 5 696例孕妇拓展性无创产前基因检测结果[J]. 检验医学, 2023, 38(6): 553-558.
[12]	张敏, 王彬宇, 迟伟群, 刘禹. 外泌体非编码RNA作为疾病诊断生物标志物的研究进展[J]. 检验医学, 2023, 38(6): 594-598.
[13]	赵婧, 王佩, 卢丹丹, 齐丹丹, 李轩. 出血性脑卒中患者血清miR-4443、TRAF4相对表达量变化的临床意义[J]. 检验医学, 2023, 38(5): 413-418.
[14]	高锋. 新型肿瘤标志物的临床应用——前景与挑战[J]. 检验医学, 2023, 38(4): 303-306.
[15]	张国良, 刘鷖雯, 何怡青, 许静, 杨翠霞, 高锋, 刘华. 血清HYAL1、HA在结直肠癌辅助诊断和疗效监测中的价值[J]. 检验医学, 2023, 38(4): 313-319.