外泌体的功能及其在临床应用中的研究进展
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摘要
外泌体(exosome)是通过细胞内多泡体与细胞膜融合产生的纳米级细胞外膜泡,广泛分布在血清、尿液、唾液和其他生物液体中。外泌体作为细胞间通信和遗传物质的重要转移载体,可通过受体介导的相互作用或通过各种生物活性分子(如细胞膜受体、蛋白质、mRNA和miRNA)的转移直接刺激靶细胞,从而发挥其生物学功能。文章主要综述了外泌体内含蛋白质和miRNA的功能及外泌体在临床中的应用。外泌体内蛋白质和miRNA的功能包括生理状态下诱导机体免疫、递呈抗原、参与细胞间信号传导;病理状态下改变肿瘤微环境、促进癌细胞增殖、侵袭、加快血管生成、促进癌症发展;以及某些病毒可将其组分包装、整合到外泌体中来实现细胞间传播,或劫持外泌体,实现免疫逃避。作者主要介绍了其作为肺癌、乳腺癌、胰腺癌及结直肠癌等多种癌症早期诊断的生物性标志物,以及作为稳定性高、转运效率高、靶向性强的药物载体在临床中的应用。
Exosome is a nanoscale extracellular vesicle produced by fusion of intracellular multivesicular bodies with cell membranes.They are widely distributed in serum,urine,saliva and other biological fluids.As an important transfer vector for intercellular communication and genetic material,exosomes can directly stimulate target cells through receptor-mediated interactions or through the transfer of various biologically active molecules such as cell membrane receptors,proteins,mRNAs and miRNAs,thereby exerts its biological functions.The article mainly reviews the functions of proteins and miRNAs in exosomes and the clinical application of exosomes.The functions of proteins and miRNAs in exosomes include inducing immunity,presenting antigens,and participating in intercellular signaling under physiological conditions;Changing the tumor microenvironment under pathological conditions,promoting cancer cell proliferation,invasion,accelerating angiogenesis,and promoting cancer development;Certain viruses can package and integratetheir components into exosomes to achieve intercellular transmission,or hijack exosomes for immune evasion.Exosome in the clinical should mainly introduce its biological markers for early diagnosis of various cancers such as lung cancer,breast cancer,pancreatic cancer and colorectal cancer,as well as high stability,high transport efficiency and strong targeting drug carrier is used for treatment.
Exosome is a nanoscale extracellular vesicle produced by fusion of intracellular multivesicular bodies with cell membranes.They are widely distributed in serum,urine,saliva and other biological fluids.As an important transfer vector for intercellular communication and genetic material,exosomes can directly stimulate target cells through receptor-mediated interactions or through the transfer of various biologically active molecules such as cell membrane receptors,proteins,mRNAs and miRNAs,thereby exerts its biological functions.The article mainly reviews the functions of proteins and miRNAs in exosomes and the clinical application of exosomes.The functions of proteins and miRNAs in exosomes include inducing immunity,presenting antigens,and participating in intercellular signaling under physiological conditions;Changing the tumor microenvironment under pathological conditions,promoting cancer cell proliferation,invasion,accelerating angiogenesis,and promoting cancer development;Certain viruses can package and integratetheir components into exosomes to achieve intercellular transmission,or hijack exosomes for immune evasion.Exosome in the clinical should mainly introduce its biological markers for early diagnosis of various cancers such as lung cancer,breast cancer,pancreatic cancer and colorectal cancer,as well as high stability,high transport efficiency and strong targeting drug carrier is used for treatment.
引文
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[34] YAN S,DANG G,ZHANG X,et al.Downregulation of circulating exosomal miR-638predicts poor prognosis in colon cancer patients[J].Oncotarget,2017,8(42):72220-72226.
[35] ZHOU X,WEN W,ZHU J,et al.A six-microRNA signature in plasma was identified as a potential biomarker in diagnosis of esophageal squamous cell carcinoma[J].Oncotarget,2017,8(21):34468-34480.
[36] LI S D,HOU X,QI H Z,et al.Exosomes:Provide naturally occurring endogenous nanocarriers for effective drug delivery strategies[J].Progress in Chemistry,2016,28(2-3):353-362.
[37]赵安,郭利伟,陈爱萍,等.肿瘤外泌体:诊断与治疗[J].中国肿瘤,2017,26(3):190-195.ZHAO A,GUO L W,CHEN A P,et al.Exosome in tumor:Diagnosis and therapy[J].China Cancer,2017,26(3):190-195.(in Chinese)
[38] KHAN M,NICKOLOFF E,ABRAMOVA T,et al.Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction[J].Circulation Research,2015,117(1):52-64.
[39] SUN D,ZHUANG X,XIANG X,et al.A novel nanoparticle drug delivery system:The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes[J].Molecular Therapy,2010,18(9):1606-1614.
[40] PASCUCCI L,COCCE V,BONOMI A,et al.Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth:A new approach for drug delivery[J].Journal of Controlled Release,2014,192(28):262-270.
[41] TIAN Y,LI S,SONG J,et al.A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy[J].Biomaterials,2014,35(7):2383-2390.
[2] RAPOSO G,NIJMAN H W,STOORVOGEL W,et al.B lymphocytes secrete antigen-presenting vesicles[J].Journal of Experimental Medicine,1996,183(3):1161-1172.
[3] MATHIVANAN S,FAHNER C J,REID G E,et al.ExoCarta 2012:Database of exosomal proteins,RNA and lipids[J].Nucleic Acids Research,2012,40(Database issue):D1241-1244.
[4] LI W,LI C,ZHOU T,et al.Role of exosomal proteins in cancer diagnosis[J].Molecular Cancer,2017,16(1):145.
[5] MATHIVANAN S,SIMPSON R J.ExoCarta:A compendium of exosomal proteins and RNA[J].Proteomics,2010,9(21):4997-5000.
[6]吴金恩,丁军涛.外泌体生物学功能及应用研究进展[J].动物医学进展,2016,37(12):90-94.WU J N,DING J T.Research advances in biological function and application of exosomes[J].Bulletin of Animal Health,2016,37(12):90-94.(in Chinese)
[7] CLARK D J,FONDRIE W E,YANG A,et al.Triple SILAC quantitative proteomic analysis reveals differential abundance of cell signaling proteins between normal and lung cancer-derived exosomes[J].Journal of Proteomics,2016,133:161-169.
[8] FEDELE C,SINGH A,ZERLANKO B J,et al.Theαvβ6integrin is transferred intercellularly via exosomes[J].Journal of Biological Chemistry,2015,290(8):4545-4551.
[9] HOSHINO A,COSTA-SILVA B,SHEN T L,et al.Tumour exosome integrins determine organotropic metastasis[J].Nature,2015,527(7578):329-335.
[10] YU S,CAO H,SHEN B,et al.Tumor-derived exosomes in cancer progression and treatment failure[J].Oncotarget,2015,6(35):37151-37168.
[11] YANG W W,YANG L Q,ZHAO F,et al.Epiregulin promotes lung metastasis of salivary adenoid cystic carcinoma[J].Theranostics,2017,7(15):3700-3714.
[12] VALADI H,EKSTROM K,BOSSIOS A,et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells[J].Nature Cell Biology,2007,9(6):654-659.
[13] LIU Y,LUO F,WANG B,et al.STAT3-regulated exosomal miR-21promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells[J].Cancer Letters,2016,370(1):125-135.
[14] FANG T,LV H,LV G,et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer[J].Nature Communications,2018,9(1):191.
[15] QU Z,WU J.Exosomal miR-665as a novel minimally invasive biomarker for hepatocellular carcinoma diagnosis and prognosis[J].Oncotarget,2017,8(46):80666-80678.
[16] LI X J,REN Z J,TANG J H,et al.Exosomal microRNA miR-1246promotes cell proliferation,invasion and drug resistance by targeting CCNG2in breast cancer[J].Cellular Physiology and Biochemistry,2017,44(5):1741-1748.
[17] XU B,ZHANG Y,DU X F,et al.Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity[J].Cell Research,2017,27(7):882-897.
[18] YE Y,LI S L,MA Y Y,et al.Exosomal miR-141-3p regulates osteoblast activity to promote the osteoblastic metastasis of prostate cancer[J].Oncotarget,2017,8(55):94834-94849.
[19]周昌娈,谭磊,丁铲.RNA病毒利用外泌体促进病毒感染的研究进展[J].微生物学通报,2017,44(12):2988-2996.ZHOU C L,TAN L,DING C.Advances of RNA virus increasing viral infection through the exosomes[J].Microbiology China,2017,44(12):2988-2996.(in Chinese)
[20] SATO Y,OCHIAI S,MURATA T,et al.Elimination of LMP1-expressing cells from a monolayer of gastric cancer AGS cells[J].Oncotarget,2017,8(24):39345-39355.
[21] JAWORSKI E,NARAYANAN A,VAN DUYNE R,et al.Human tlymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein[J].Journal of Biological Chemistry,2014,289(32):22284-22305.
[22] SILVAS J A,POPOV V L,PAULUCCI H A,et al.Extracellular vesicles mediate receptor-independent transmission of novel tick-borne bunyavirus[J].Journal of Virology,2015,90(2):873-886.
[23]张莉.外泌小体介导猪瘟病毒在ST细胞之间扩散的机制研究[D].长春:吉林农业大学,2016.ZHANG L.Exosome-mediated transmission of classical swine fever virus between ST cells[D].Changchun:Jilin Agricultural University,2016.(in Chinese)
[24] PLEET M L,MATHIESEN A,DEMARINO C,et al.Ebola VP40in exosomes can cause immune cell dysfunction[J].Frontiers in Microbiology,2018,9(139):1765-1772.
[25] KOUWAKI T,FUKUSHIMA Y,DAITO T,et al.Extracellular vesicles including exosomes regulate innate immune responses to hepatitis B virus infection[J].Frontiers in Immunology,2016,7:335-345.
[26] SANDFELD-PAULSEN B,JAKOBSEN K R.Exosomal proteins as diagnostic biomarkers in lung cancer[J].Journal of Thoracic Oncology,2016,11(10):1701-1710.
[27] ZHANG L,SHAN X,WANG J,et al.A three-microRNA signature for lung squamous cell carcinoma diagnosis in Chinese male patients[J].Oncotarget,2017,8(49):86897-86907.
[28] CHEN I H,XUE L,HSU C C,et al.Phosphoproteins in extracellular vesicles as candidate markers for breast cancer[J].Proceedings of the National Academy of Sciences of the United States of America,2017,114(12):3175-3180.
[29] MOON P G,LEE J E,CHO Y E,et al.Fibronectin on circulating extracellular vesicles as a liquid biopsy to detect breast cancer[J].Oncotarget,2016,7(26):40189-40199.
[30] MOON P G,LEE J E,CHOY E,et al.Identification of developmental endothelial locus-1on circulating extracellular vesicles as a novel biomarker for early breast cancer detection[J].Clinical Cancer Research,2016,22(7):1757-1766.
[31] KIBRIA G,RAMOS E K,LEE K E,et al.A rapid,automated surface protein profiling of single circulating exosomes in human blood[J].Scientific Reports,2016,6:36502.
[32] HANNAFON B N,TRIGOSO Y D,CALLOWA C L,et al.Plasma exosome microRNAs are indicative of breast cancer[J].Breast Cancer Research,2016,18(1):90.
[33] MELO S A,LUECKE L B,KAHLERT C,et al.Glypican-1identifies cancer exosomes and detects early pancreatic cancer[J].Nature,2015,523(7559):177-182.
[34] YAN S,DANG G,ZHANG X,et al.Downregulation of circulating exosomal miR-638predicts poor prognosis in colon cancer patients[J].Oncotarget,2017,8(42):72220-72226.
[35] ZHOU X,WEN W,ZHU J,et al.A six-microRNA signature in plasma was identified as a potential biomarker in diagnosis of esophageal squamous cell carcinoma[J].Oncotarget,2017,8(21):34468-34480.
[36] LI S D,HOU X,QI H Z,et al.Exosomes:Provide naturally occurring endogenous nanocarriers for effective drug delivery strategies[J].Progress in Chemistry,2016,28(2-3):353-362.
[37]赵安,郭利伟,陈爱萍,等.肿瘤外泌体:诊断与治疗[J].中国肿瘤,2017,26(3):190-195.ZHAO A,GUO L W,CHEN A P,et al.Exosome in tumor:Diagnosis and therapy[J].China Cancer,2017,26(3):190-195.(in Chinese)
[38] KHAN M,NICKOLOFF E,ABRAMOVA T,et al.Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction[J].Circulation Research,2015,117(1):52-64.
[39] SUN D,ZHUANG X,XIANG X,et al.A novel nanoparticle drug delivery system:The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes[J].Molecular Therapy,2010,18(9):1606-1614.
[40] PASCUCCI L,COCCE V,BONOMI A,et al.Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth:A new approach for drug delivery[J].Journal of Controlled Release,2014,192(28):262-270.
[41] TIAN Y,LI S,SONG J,et al.A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy[J].Biomaterials,2014,35(7):2383-2390.