单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,The role of exosomes in cancer metastasis,外泌体在肿瘤转移中的作用,1,The role of exosomes in c,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,Exosome1986年,绵羊红细胞上清液中发现了一种有膜结,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,Morphology40-100 nm3,biogenesis,4,biogenesis4,5,5,Exosomal content,6,Exosomal content6,7,7,Biological functions and effects,antigen presentation,immune regulation,tissue develop,ment,cell-to-cell spread of infectious,discards membrane proteins,cancer development,8,Biological functions and effec,外泌体的临床应用,Biomarker,Drug delivery,9,外泌体的临床应用 Biomarker9,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 scape,10,肿瘤转移1.EMT10,1.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,11,1.exosomes as mediators in EM,EMT and migration,TDEs from tumor cells who have undergone EMT can in turn stimulate neighbouring 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 cells failed),Exosomal miR-23a,MiR-191 and let7a,12,EMT and migrationTDEs from tum,2.Exosome and invasion,Highlights,miR-105 is uniquely expressed and secreted by metastatic breast cancer cells,miR-105 directly targets the tight junction protein ZO-1,Cancer-secreted miR-105 destroys endothelial barriers in the host,Circulating miR-105 predicts metastasis in early-stage breast cancer patients,13,2.Exosome and invasion Highl,Blocking of astrocyte-exosomes inhibits brain metastasis,14,Blocking of astrocyte-exosomes,Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype,15,Exosomes Derived from Hypoxic,3.Exosomes and CAFs,We found that some cancer-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 existing 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 effecton stroma differentiation is abrogated by blocking of exosomes,16,3.Exosomes and CAFs We found t,CAFs produce exosomes,which stimulate the Wnt-pathway in breast cancer cells and enhance their migratory capabilities,17,CAFs produce exosomes,which s,4.Engraftment of metastatic cells,CAFs stimulate neoangiogenesis via secretion of exosomalSDF-1(stromal cell derived 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.,18,4.Engraftment of metastatic ce,5.Exosomes in organotropic metastatic 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 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.,19,5.Exosomes in organotropic me,20,20,M.Y.Fong,W.Zhou,L.Liu,A.Y.Alontaga,M.Chandra,J.Ashby,et al.,Breast-cancer-secreted,miR-122,reprograms 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 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 cells,invitro,and,invivo,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,M.Y.Fong,W.Zhou,L.Liu,A.,22,22,7.Im