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1、The role of exosomes in cancer metastasis外泌体在肿瘤转移中的作用,1,Exosome,1986年,绵羊红细胞上清液中发现了一种有膜结构的小囊泡,命名为外泌体。1996年,B细胞分泌外泌体，可通过MHC激活T细胞；其他APC细胞也可。2013年诺贝尔生物/医学奖,2,Morphology,40-100 nm圆形双脂质层来源广泛，几乎所有细胞都可分泌分布广泛，血液、尿液、胸水、唾液作用广泛，包含信息丰富,3,biogenesis,4,5,Exosomal content,6,7,Biological functions and effects,antige
2、n presentationimmune regulationtissue developmentcell-to-cell spread of infectiousdiscards membrane proteinscancer development,8,外泌体的临床应用,BiomarkerDrug delivery,9,肿瘤转移,1.EMT2.Detachment 3.circulation4.Adhesion5.Migration 6.invasion 7.MET8.Engraftment 9.Proliferation10.cancer stroma/immune scape,10,1
3、.exosomes as mediators in EMT,Snail(zinc finger proteins Snail and Slug),Zeb(zinc finger andhomeodomain proteins Zeb 1 and 2)and Twist(basic helix-loop-helix proteins E12,E47,Twist1,Twist 2 and Id)pathways,11,EMT and migration,TDEs from tumor cells who have undergone EMT can in turn stimulate neighb
4、ouring cells to acquire EMT like features,creating a synergistic effectEBV infection-nasopharyngeal carcinoma cells-exosme-HIF1a-Snail and Twist pathway-more invasive phenotype in recipient cells muscle-invasive bladder cancer cells-exosome-urothelial cells-EMT increase(exosome from embryonic kidney
5、 cells failed)Exosomal miR-23a,MiR-191 and let7a,12,2.Exosome and invasion,HighlightsmiR-105 is uniquely expressed and secreted by metastatic breast cancer cellsmiR-105 directly targets the tight junction protein ZO-1Cancer-secreted miR-105 destroys endothelial barriers in the hostCirculating miR-10
6、5 predicts metastasis in early-stage breast cancer patients,13,Blocking of astrocyte-exosomes inhibits brain metastasis,14,Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype,15,3.Exosomes and CAFs,We found that some c
7、ancer-derived exosomes could trigger elevated-smooth muscle actin expression and other changes consistent with the process of fibroblast differentiation into myofibroblasts.We show that TGF-is expressed at the exosome surface in association with the transmembrane proteoglycan betaglycan.Although exi
8、sting in a latent state,this complex was fully functional in eliciting SMAD-dependent signaling.Soluble TGF-b1 alone is not able to drive stroma differentiation to a cancer-associated phenotype.Exosome-depleted cancer cells fail to gain astroma-mediated growth advantage in vivo and the TGF-b1 effect
9、on stroma differentiation is abrogated by blocking of exosomes,16,CAFs produce exosomes,which stimulate the Wnt-pathway in breast cancer cells and enhance their migratory capabilities,17,4.Engraftment of metastatic cells,CAFs stimulate neoangiogenesis via secretion of exosomalSDF-1(stromal cell deri
10、ved factor-1)TDEs stimulate endothelial progenitor cells to form tube-like structures.Induction of neoangiogenesis is not only due to the exosomes transport of paracrine signaling factors but also due to direct transport of relevant mRNA to the surrounding stroma.,18,5.Exosomes in organotropic metas
11、tatic growth,1.A pre-metastatic niche formation is required for tumor cells to engraft a distant organ Our data show that exosome production,transfer and education of bone marrow cells supports tumor growth and metastasis,has prognostic value and offers promise for new therapeutic directions in the
12、metastatic process.In addition,we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2,VLA-4,HSP70,an HSP90 isoform and the MET oncoprotein.2.,19,20,M.Y.Fong,W.Zhou,L.Liu,A.Y.Alontaga,M.Chandra,J.Ashby,et al.,Breast-cancer-secreted miR-122 re
13、programs glucose metabolism in premetastatic niche to promote metastasis,Nat.Cell Biol.17(2)(2015)183194.,Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the premetastatic niche,by secreting vesicles that carry high levels of the miR-122 microRNA.High miR-122 levels
14、 in the circulation have been associated with metastasis in breast cancer patients,and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in the premetastatic niche.Mechanistically,cancer-cell-derived miR-122 suppresses glucose uptake by niche cellsi
15、nvitroandinvivo by downregulating the glycolytic enzyme pyruvate kinase.Invivo inhibition of miR-122 restores glucose uptake in distant organs,including brain and lungs,and decreases the incidence of metastasis.,21,22,7.Immune-modulating effects of exosomes,23,A central event involves an aberrant ex
16、pression of COX-2 which influences cell-cycle progression and contribute to the acquisition of a cell migratory phenotype through the induction of epithelial mesenchymal transition genes and down-regulation of E-cadherin expression.The identification of novel molecular determinants involved in the c
17、ross-talk between platelets and cancer cells has led to identify novel targets for anti-cancer drug development.,24,25,TDEs and cellular immune response,1.In an in vitro culture model of AML,TDEs decreased the count of CD8+-T-cells by activation of Fas/FasL-mediated apoptosis 2.They further promoted
18、 CD4+-T-cell proliferation and conversion into regulatory T-cells with increased expression of IL-10(interleukin-10),TGF-b1,CTLA-4(cytotoxic lymphocyte antigen-4)and GrB(granzyme B).These mediators reduce cytotoxic activity of NK cells,26,3.In an in vitro model of nasopharyngeal cancer,immunosuppres
19、sive miRNAs(hsa-miR-24-3p,hsa-miR-891a,hsa-miR-106a-5p,hsa-miR-20a-5p,and hsa-miR-1908)were found in TDEs4.TDEs activate human myeloid derived suppressor cells through HSP72/TLR-2(toll-likereceptor 2)via the STAT3 pathway and IL-6 expression,27,TDEs and humoral immune response,neutralize antitumor-a
20、ntibodies In breast cancer cells it was demonstrated that TDEs express Her2 and EpCAM antigens,which bind and neutralize anti-bodies interfering with ADCC of tumor cells expressing these antigens.As a consequence,these TDEs may reduce the therapeutic effect of Trastuzumab Accordingly,B-cell lymphoma
21、 cells secrete exosomes,which carry CD20,neutralizing the therapeutic effect of Rituximab(anti-CD20-antibody)in vivo.,28,TDEs and cancer-promoting proinflammatory effects,TDEs create a protumorigenic inflammatory response and support the establishment and maintenance of a pre-metastatic niche.1.TDEs
22、 stimulate macrophages by activating NF-kB(nuclear factor-kB).These effects are mediated through toll-like receptors(TLRs)on the surface of macrophages,which interact with TDEs,especially TLR-2.Activation of macrophages by TLRs(TLR-7 and 8)could be achieved by binding of exosomal miRNAs(mi-R21,mi-R29a 2.TDEs of pancreatic ductal adenocarcinoma cells interact with Kupffer-cells in the liver to promote pre-metastatic niche formation,29,总结,Exosome在肿瘤转移的各个环节中都有一定作用1.EMT2.Detachment 3.circulation4.Adhesion5.Migration 6.invasion 7.MET8.Engraftment 9.Proliferation10.cancer stroma/immune scape,30,
