exosome-外泌体在肿瘤转移中的作用教学课件.pptx

1、The role of exosomes in cancer metastasis外泌体在肿瘤转移中的作用1Exosome 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2Morphology 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3biogenesis45Exosomal content67Biological functions and effects antigen prese

2、ntation immune regulation tissue development cell-to-cell spread of infectious discards membrane proteins cancer development8外泌体的临床应用 Biomarker Drug delivery9肿瘤转移 1.EMT 2.Detachment 3.circulation 4.Adhesion 5.Migration 6.invasion 7.MET 8.Engraftment 9.Proliferation 10.cancer stroma/immune scape101.e

3、xosomes as mediators in EMTSnail(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 11EMT and migration TDEs from tumor cells who have undergone EMT can in turn stimulate neighbouri

4、ng cells to acquire EMT like features,creating a synergistic effect EBV 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 ce

5、lls failed)Exosomal miR-23a,MiR-191 and let7a 122.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-105 pr

6、edicts metastasis in early-stage breast cancer patients13 Blocking of astrocyte-exosomes inhibits brain metastasis 14Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype153.Exosomes and CAFs We found that some cancer-de

7、rived 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 existing in

8、 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 effecton strom

9、a differentiation is abrogated by blocking of exosomes 16CAFs produce exosomes,which stimulate the Wnt-pathway in breast cancer cells and enhance their migratory capabilities 174.Engraftment of metastatic cells1.CAFs stimulate neoangiogenesis via secretion of exosomalSDF-1(stromal cell derived facto

10、r-1)2.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.185.Exosomes in organotropic metastatic gro

11、wth1.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 metastatic

12、 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.2.1920M.Y.Fong,W.Zhou,L.Liu,A.Y.Alontaga,M.Chandra,J.Ashby,et al.,Breast-cancer-secreted miR-122 reprograms gluc

13、ose 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 in the circul

14、ation 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 cells invitro and in

15、vivoby downregulating the glycolytic enzyme pyruvate kinase.Invivoinhibition of miR-122 restores glucose uptake in distant organs,including brain and lungs,and decreases the incidence of metastasis.21227.Immune-modulating effects of exosomes 23A central event involves an aberrant expression of COX-2

16、 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 cross-talk between

17、 platelets and cancer cells has led to identify novel targets for anti-cancer drug development.2425TDEs 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 CD4+-T-cell prolife

18、ration 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 263.In an in vitro model of nasopharyngeal cancer,immunosuppressive miRNAs(hsa-miR-2

19、4-3p,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 27TDEs and humoral immune response1.neutralize antitumor-antibodies In breast c

20、ancer 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 cells secrete exosom

21、es,which carry CD20,neutralizing the therapeutic effect of Rituximab(anti-CD20-antibody)in vivo.28TDEs and cancer-promoting proinflammatory effects TDEs create a protumorigenic inflammatory response and support the establishment and maintenance of a pre-metastatic niche.1.TDEs stimulate macrophages

22、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.EMT 2.Detachment 3.circulation 4.Adhesion 5.Migration 6.invasion 7.MET 8.Engraftment 9.Proliferation 10.cancer stroma/immune scape30