（医学课件）exosome 外泌体在肿瘤转移中的作用

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 effec

2、ts,antigen presentation immune regulation tissue development cell-to-cell spread of infectious discards membrane proteins cancer development,8,外泌体的临床应用,Biomarker Drug delivery,9,肿瘤转移,1. EMT 2. Detachment 3. circulation 4. Adhesion 5. Migration 6. invasion 7. MET 8. Engraftment 9. Proliferation 10. c

3、ancer stroma/immune scape,10,1. 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,EMT and migration,TDEs from tumor cells who have un

4、dergone 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 - urothe

5、lial cells - EMT increase (exosome from embryonic kidney cells failed) Exosomal miR-23a, MiR-191 and let7a,12,2. 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-1

6、05 destroys endothelial barriers in the host Circulating miR-105 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 Prom

7、etastatic Phenotype,15,3.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 assoc

8、iation 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

9、to gain astroma-mediated growth advantage in vivo and the TGF- b1 effecton 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 s

10、timulate 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

11、 relevant mRNA to the surrounding stroma.,18,5. 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 metastasi

12、s, 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.,19,20,M.Y. F

13、ong, 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 prem

14、etastatic 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 th

15、e premetastatic niche. Mechanistically, cancer-cell-derived miR-122 suppresses glucose uptake by niche cells in vitro and in vivo by downregulating the glycolytic enzyme pyruvate kinase. In vivo inhibition of miR-122 restores glucose uptake in distant organs, including brain and lungs, and decreases

16、 the incidence of metastasis.,21,22,7.Immune-modulating effects of exosomes,23,A central event involves an aberrant expression 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 g

17、enes and down-regulation of E-cadherin expression. The identification of novel molecular determinants involved in the cross-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 mo

18、del of AML, TDEs decreased the count of CD8+-T-cells by activation of Fas/FasL-mediated apoptosis 2. They further promoted 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 (gr

19、anzyme B).These mediators reduce cytotoxic activity of NK cells ,26,3. In an in vitro model of nasopharyngeal cancer, immunosuppressive miRNAs (hsa-miR-24-3p, hsa-miR-891a, hsa-miR-106a-5p, hsa-miR-20a-5p, and hsa-miR-1908) were found in TDEs 4. TDEs activate human myeloid derived suppressor cells t

20、hrough HSP72/TLR-2 (toll-likereceptor 2) via the STAT3 pathway and IL-6 expression,27,TDEs and humoral immune response,neutralize antitumor-antibodies In breast cancer cells it was demonstrated that TDEs express Her2 and EpCAM antigens, which bind and neutralize anti-bodies interfering with ADCC of

21、tumor cells expressing these antigens. As a consequence, these TDEs may reduce the therapeutic effect of Trastuzumab Accordingly, B-cell lymphoma 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