外泌体与肿瘤转移

1、外泌体与肿瘤转移外泌体（exosome）是Pan在研究网织红细胞多泡体胞外细胞质融合时首先发现的 HYPERLINK l _ENREF_1 o Pan, 1985 #70 ADDIN EN.CITE Pan1985701707017Pan, B. T.Teng, K.Wu, C.Adam, M.Johnstone, R. M.Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytesJ Cell BiolThe Jou

2、rnal of cell biologyJ Cell BiolThe Journal of cell biologyJ Cell BiolThe Journal of cell biology942-810131985/09/01AnimalsCell DifferentiationCytoplasmic Granules/metabolismExocytosisIntracellular Membranes/metabolismMicroscopy, ElectronReceptors, Cell Surface/*metabolismReceptors, TransferrinReticu

3、locytes/*metabolism/ultrastructureSheepTime FactorsTransferrin/*metabolism1985Sep0021-9525 (Print)0021-95252993317Pmc2113705Nlmeng1，是细胞内多囊泡体与细胞膜融合后，释放到胞外基质中的一类直径约为30-100nm的膜性囊泡，其分布和来源广泛，可由多种细胞所分泌 ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK l _ENREF_2 o Cocucci, 2015 #289 2, HYPERLINK l _ENREF_3 o Bar

4、ile, 2016 #100 3。且其内容物丰富，携带有蛋白、脂质、DNA和非编码NA等，参与了如免疫应答、抗原提呈、胞间通讯、蛋白质和RNA转运等多种生理过程，是一种重要的胞间物质和信息交流的工具 ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK l _ENREF_4 o Tang, 2015 #291 4, HYPERLINK l _ENREF_5 o Milane, 2015 #293 5。尽管外泌体可由多种细胞类型分泌，但其数量和内容物的种类与母细胞的生理状况息息相关 HYPERLINK l _ENREF_6 o Zhang, 2016 #98 AD

5、DIN EN.CITE Zhang2016986989817Zhang, Z. G.Chopp, M.Exosomes in stroke pathogenesis and therapyJ Clin InvestThe Journal of clinical investigationJ Clin InvestThe Journal of clinical investigationJ Clin InvestThe Journal of clinical investigation1190-712642016/04/02AnimalsBrain/*metabolismExosomes/*me

6、tabolismHumansNerve Tissue Proteins/metabolismNeural Stem Cells/*metabolismRNA/metabolismStroke/*metabolism/*therapy2016Apr 10021-973827035810Pmc481113010.1172/jci81133NlmEng6。研究表明，病理条件下的细胞（如肿瘤细胞）释放外泌体的水平显著增加，且外泌体的内容物组分较正常生理条件下的有所不同，这不仅强调了母细胞对外泌体内容物的靶向精密调节，也暗示了其在肿瘤形成和发展过程中的重要作用 ADDIN EN.CITE ADDIN E

7、N.CITE.DATA HYPERLINK l _ENREF_7 o Melo, 2014 #295 7, HYPERLINK l _ENREF_8 o Riches, 2014 #298 8。例如，暴露于低氧环境中的乳腺癌细胞通过低氧诱导因子HIF-1一定程度地上调了外泌体的分泌量；而低氧条件下的鳞状细胞癌细胞所分泌的外泌体中含有更高水平的与血管生成相关的蛋白 ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK l _ENREF_9 o King, 2012 #299 9, HYPERLINK l _ENREF_10 o Park, 2010 #300 10

8、。越来越多的基础和临床研究表明，肿瘤细胞的外泌体与肿瘤的发生、发展和转移有关 HYPERLINK l _ENREF_11 o Syn, 2016 #99 ADDIN EN.CITE ADDIN EN.CITE.DATA 11-13，其能够调控免疫功能，促进肿瘤血管新生和侵袭转移，甚至直接作用于其他肿瘤或非肿瘤细胞，从而影响细胞或组织的命运 HYPERLINK l _ENREF_7 o Melo, 2014 #295 ADDIN EN.CITE ADDIN EN.CITE.DATA 7。如当肿瘤外泌体与初始活化的T细胞共培养时，发现其能下调CD3、JAK3的表达并介导Fas/FasL驱使的CD8

9、+T细胞凋亡，反映出肿瘤外泌体的免疫抑制特性 HYPERLINK l _ENREF_14 o Whiteside, 2013 #301 ADDIN EN.CITE Whiteside20133011430130117Whiteside, T. L.Departments of Pathology, Immunology and Otolaryngology, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. whit

10、esidetlImmune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes)Biochem Soc TransBiochem Soc Trans245-514112013/01/30ApoptosisCell DifferentiationExosomes/*immunologyHumansKiller Cells, Natural/cytology/*immunologyNeoplasms/*immunology/pathologySignal Tran

11、sductionT-Lymphocytes, Regulatory/cytology/*immunology2013Feb 11470-8752 (Electronic)0300-5127 (Linking)23356291/pubmed/23356291372134710.1042/BST20120265BST20120265 piieng14。而且，肿瘤细胞外泌体介导了VEGF和CXCR4信号通路的调控，从而增强血管生成和肿瘤生长 HYPERLINK l _ENREF_15 o Zhu, 2012 #308 ADDIN EN.CITE Zhu20123081530830817Zhu, W.

12、Huang, L.Li, Y.Zhang, X.Gu, J.Yan, Y.Xu, X.Wang, M.Qian, H.Xu, W.School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivoCancer LettCancer Lett28-3731512011/11/08AnimalsBone Mar

13、row Cells/*cytology/metabolismCell Differentiation/physiologyCell Growth Processes/physiologyExosomes/*physiologyHumansImmunohistochemistryMaleMesenchymal Stromal Cells/*cytologyMiceMice, Inbred BALB CNeoplasms/*pathologyXenograft Model Antitumor Assays2012Feb 11872-7980 (Electronic)0304-3835 (Linki

14、ng)22055459/pubmed/2205545910.1016/j.canlet.2011.10.002S0304-3835(11)00615-X piieng15。研究发现，外泌体通过其特定内容物能够介导肿瘤细胞迁移，如所包含的MMP-2具有降解胞外基质胶原纤维的作用 HYPERLINK l _ENREF_16 o McCready, 2010 #318 ADDIN EN.CITE McCready20103181631831817McCready, J.Sims, J. D.Chan, D.Jay, D. G.Department of Physiology, Tufts Unive

15、rsity, 136 Harrison Ave, Boston, MA 02111, USA.Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activationBMC CancerBMC Cancer294102010/06/18Cell Line, Tumor*Cell MovementCell ShapeEnzyme ActivationExosomes/enzymology/*secretionFibrinolysin/*m

16、etabolismHSP90 Heat-Shock Proteins/genetics/metabolism/*secretionHumansImmunoprecipitationMass SpectrometryNeoplasm InvasivenessNeoplasms/enzymology/genetics/pathology/*secretionPlasminogen/*metabolismProtein BindingRNA InterferenceTissue Plasminogen Activator/*metabolism20101471-2407 (Electronic)14

17、71-2407 (Linking)20553606/pubmed/20553606308731810.1186/1471-2407-10-2941471-2407-10-294 piieng16；外泌体跨膜四超家族通过改变宿主微环境介导癌症转移 HYPERLINK l _ENREF_17 o Lu, 2017 #71 ADDIN EN.CITE Lu20177117717117Lu, J.Li, J.Liu, S.Wang, T.Ianni, A.Bober, E.Braun, T.Xiang, R.Yue, S.Department of General Surgery, Hefei Sec

18、ond People's Hospital, Hefei, China.School of Medicine, Nankai University, Tianjin, China.The State International Science & Technology Cooperation Base of Tumor Immunology and Biological Vaccines, Nankai University, Tianjin, China.Department of Cardiac Development and Remodeling, Max-Planck-Ins

19、titute for Heart and Lung Research, Bad Nauheim, Germany.Exosomal tetraspanins mediate cancer metastasis by altering host microenvironmentOncotargetOncotargetOncotargetOncotargetOncotargetOncotarget62803-628158372017/10/062017Sep 221949-255328977990Pmc561755010.18632/oncotarget.19119Nlmeng17。黑色素瘤细胞的

20、外泌体载有MET受体酪氨酸激酶，当其转移至骨髓细胞中可促进肿瘤的转移 HYPERLINK l _ENREF_18 o Peinado, 2012 #329 ADDIN EN.CITE ADDIN EN.CITE.DATA 18；而体外实验发现，外泌体影响了肿瘤细胞的定向迁移 HYPERLINK l _ENREF_19 o Sung, 2015 #330 ADDIN EN.CITE ADDIN EN.CITE.DATA 19；其所包含的异常高水平microRNAs能够促进肿瘤细胞的侵袭和转移 HYPERLINK l _ENREF_20 o Le, 2014 #331 ADDIN EN.CITE

21、ADDIN EN.CITE.DATA 20-22。由于外泌体含有microRNAs，且肿瘤在形成和发展过程中伴随着外泌体向胞外基质的释放，因此通过对体液中外泌体及外泌体RNA（eRNA）的检测将为肿瘤的临床诊断和预后评估提供新的视野 ADDIN EN.CITE ADDIN EN.CITE.DATA HYPERLINK l _ENREF_23 o Boukouris, 2015 #335 23, HYPERLINK l _ENREF_24 o Guo, 2015 #336 24。不同细胞分泌的外泌体具有不同的成分和功能，外泌体可作为肿瘤诊断的生物标志物。Wang N等 HYPERLINK l _

22、ENREF_25 o Wang, 2017 #72 ADDIN EN.CITE ADDIN EN.CITE.DATA 25研究发现胃癌患者血清中外泌体miR-19b-3p和miR-106a-5p 较正常对照组呈现异常高表达，二者联合检测对胃癌诊断具有高度特异性（90）和敏感性（95）。 Li DB等 HYPERLINK l _ENREF_26 o Li, 2017 #73 ADDIN EN.CITE Li20177326737317Li, D. B.Liu, J. L.Wang, W.Li, R. Y.Yu, D. J.Lan, X. Y.Li, J. P.Department of Neur

23、ology, The First Affiliated Hospital, Guangxi Medical University, Nanning 530021. China.Department of Neurology, The Third People's Hospital of Nanning, Guangxi. China.Plasma exosomal miR-422a and miR-125b-2-3p serve as biomarkers for ischemic strokeCurr Neurovasc ResCurrent neurovascular resea

24、rchCurr Neurovasc ResCurrent neurovascular researchCurr Neurovasc ResCurrent neurovascular research2017/10/072017Oct 051567-20262898233110.2174/1567202614666171005153434Nlmeng26研究发现血浆外泌体中miR-422a和miR-125b-2-3p可作为缺血性卒中患者的血液生物标志物进行监测和诊断。同时外泌体可以用于肿瘤的预后观察。Tanaka Y等 HYPERLINK l _ENREF_27 o Tanaka, 2013 #

25、74 ADDIN EN.CITE ADDIN EN.CITE.DATA 27发现血清外泌体中 miR-21 水平在食管鳞状细胞癌患者中显著增加，并与晚期肿瘤分类、阳性淋巴结状态、转移与炎症等相关。 外泌体还有促进肿瘤细胞耐药的功能。Liu T等 HYPERLINK l _ENREF_28 o Liu, 2017 #75 ADDIN EN.CITE ADDIN EN.CITE.DATA 28在研究口腔鳞状细胞癌（OSCC）时，发现外泌体中miR-21可以通过结合OSCC细胞上的特异性靶点PTEN和PDCD4， 介导OSCC细胞对顺铂耐药。总之，外泌体作为肿瘤微环境中的一个重要组分，参与了胞间信号

26、转导以及肿瘤形成和恶化过程。随着人们对肿瘤外泌体研究的深入，将有助于肿瘤的早期预测、临床分期以及诊断、治疗。外泌体作为肿瘤药物载体时，可表现出极低的免疫原性和生物毒性，但是目前人们对于外泌体的认识还比较局限，其在免疫调节和肿瘤靶向治疗等方面，尚待深入研究. 参考文献 ADDIN EN.REFLIST 1.Pan BT, Teng K, Wu C, Adam M, Johnstone RM. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in shee

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