肿瘤外泌体促进肿瘤生长机制研究进展
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摘要
外泌体是一种由活细胞分泌的,粒径在30～150 nm之间的纳米级囊泡,在其被发现初期被认作是"废弃物",但后续的研究发现,外泌体可携带mRNAs、miRNAs、DNAs、蛋白质和脂质等物质,目前,在外泌体中发现超过3 000多种的RNA,2 700多种MicroRNA以及近千种脂类。外泌体作为细胞间信息交流的载体,可以通过分泌内容物作用于靶细胞,进而调节靶细胞的生理过程。肿瘤细胞亦可以通过外泌体与外界进行信息交流,进而促进自身的生长,其主要机制包括:介导肿瘤细胞血管新生、免疫逃逸、肿瘤转移、以及参与肿瘤耐药等,外泌体也有望成为肿瘤临床治疗和诊断的新靶标。文章对肿瘤外泌体促进肿瘤自身生长的机制予以综述。
Exosomes are a type of nano-sized vesicles secreted by living cells with a particle size between 30 and 150 nm. They were identified as"waste"at the beginning of their discovery,but subsequent studies have found that exosome can carry substances,such as mRNAs,miRNAs,DNAs,proteins and lipids. Currently,more than 3 000 kinds of RNA,more than 2 700 kinds of microRNAs and nearly a thousand kinds of lipids are found in exosomes. As a carrier of intercellular communication,exosomes can act on target cells by secreting contents,thereby regulating the physiological processes of target cells. Tumor cells can also communicate with the outside world through exosomes,thereby promoting their growth. The main mechanisms include: angiogenesis of tumor cells,immune escape,tumor metastasis,and involvement in tumor resistance. Exosomes perhaps will become a new target for clinical treatment and diagnosis of cancer. This article has reviewed the mechanisms by which tumor exosomes promote tumor growth.
Exosomes are a type of nano-sized vesicles secreted by living cells with a particle size between 30 and 150 nm. They were identified as"waste"at the beginning of their discovery,but subsequent studies have found that exosome can carry substances,such as mRNAs,miRNAs,DNAs,proteins and lipids. Currently,more than 3 000 kinds of RNA,more than 2 700 kinds of microRNAs and nearly a thousand kinds of lipids are found in exosomes. As a carrier of intercellular communication,exosomes can act on target cells by secreting contents,thereby regulating the physiological processes of target cells. Tumor cells can also communicate with the outside world through exosomes,thereby promoting their growth. The main mechanisms include: angiogenesis of tumor cells,immune escape,tumor metastasis,and involvement in tumor resistance. Exosomes perhaps will become a new target for clinical treatment and diagnosis of cancer. This article has reviewed the mechanisms by which tumor exosomes promote tumor growth.
引文
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[29]Liu H,Chen W,Zhi X,et al.Tumor-derived exosomes promote tumor self-seeding in hepatocellular carcinoma by transferring miRNA-25-5p to enhance cell motility[J].Oncogene,2018,37(36):4964-4978.
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[2]Harding C,Heuser J,Stahl P.Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes[J].J Cell Biol,1983,97(2):329-339.
[3]Todorova D,Lacroix R.Extracellular vesicles in angiogenesis[J].Circul Res,2017,120(10):1658-1673.
[4]Lin XJ,Fang JH,Yang XJ,et al.Hepatocellular carcinoma cellsecreted exosomalmicroRNA-210 promotes angiogenesis,in vitro,and,in vivo[J].Molec Ther-Nucleic Acids,2018,11:243-252.
[5]Tang MKS,Yue PYK,Ip PP,et al.Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface[J].Nature Commun,2018,11,9(1):2270-2285.
[6]Liu Y,Cao X.Characteristics and significance of the pre-metastatic niche[J].Cancer Cell,2016,30(5):668-681.
[7]Sun X,Ma X,Wang J,et al.Glioma stem cells-derived exosomes promote the angiogenic ability of endothelial cells through miR-21/VEGF signal[J].Oncotarget,2017,8(22):36137-36148.
[8]Li Y,Liang JM,Hu J,et al.Down-regulation of exosomal miR-106b-5p derived from cholesteatoma perimatrix fibroblasts promotes angiogenesis in endothelial cells by overexpression of Angiopoietin 2[J].Cell Biol Internat,2018,42(10):1300-1310.
[9]Zhou X,Yan T,Huang C,et al.Melanoma cell-secreted exosomal miR-155-5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway[J].JExperimen Clinic Cancer Res,2018,37(1):242-257.
[10]Maj T,Wang W,Crespo J,et al.Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor[J].Nature Immunol,2017,18(12):1332-1347.
[11]Yang Y,Li CW,Chan LC,et al.Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth[J].Cell Res,2018,28(8):862-865.
[12]Gang C,Huang AC,Wei Z,etal.Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response[J].Nature,2018560(7718):382-386.
[13]Wynn T A,Chawla A,Pollard J W.Macrophage biology in development,homeostasis and disease[J].Nature,2013,496(7446):445-455.
[14]Wang X,Luo G,Zhang K,et al.Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγto promote pancreatic cancer metastasis[J].Cancer Res,2018,78(16):4586-4598.
[15]Meng X,Jianjun Z,Wanjun C,et al.M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma[J].Experimen Clinic Cancer Res,2018,37(1):143-158.
[16]Ostrand-rosenberg S,Sinha P.Myeloid-Derived Suppressor Cells:Linking Inflammation and Cancer[J].J Immunol,2009,182(8):4499-4506.
[17]Guo X,Qiu W,Wang J,et al.Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways[J].Internat J Cancer,2018,144(12):3111-3126.
[18]Fridlender ZG,Sun J,Kim S,et al.Polarization of tumor-associated neutrophil phenotype by TGF-beta:“N1”versus“N2”TAN[J].Cancer Cell,2009,16(3):183-194.
[19]Zhang X,Shi H,Yuan X,et al.Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration[J].Mol Cancer,2018,6;17(1):146-162.
[20]Ye L,Zhang Q,Cheng Y,et al.Tumor-derived exosomal HMGB1fosters hepatocellular carcinoma immune evasion by promoting TIM-1+regulatory B cell expansion[J].J Immunother Cancer,2018,6(1):145-160.
[21]Hoshino A,Costasilva B,Shen T L,et al.Tumour exosome integrins determine organotropic metastasis[J].Nature,2015,527(7578):329-335.
[22]Zeng Z,Li Y,Pan Y,et al.Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis[J].Nature Commun,2018,9(1):5395-5409.
[23]Liu Y,Gu Y,Han Y,et al.Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils[J].Cancer Cell,2016,30(2):243-256.
[24]Wen S,Niu Y,Shuyuan Y,et al.BM-MSCs promote prostate cancer progression via the conversion of normal fibroblasts to cancer-associated fibroblasts[J].Internat J Oncol,2015,47(2):719-727.
[25]Wang J,Guan X,Zhang Y,et al.Exosomal miR-27a derived from gastric cancer cells regulates the transformation of fibroblasts into cancer-associated fibroblasts[J].Cellular Physiol Biochem,2018,49(3):869-883.
[26]Li J,Li Z,Jiang P,et al.Circular RNA IARS(circ-IARS)secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis[J].J Experimen Clinical Cancer Res,2018,37(1):177-193.
[27]Semenza LG.Cancer-stromal cell interactions mediated by hypoxiainducible factors promote angiogenesis,lymphangiogenesis,and metastasis[J].Oncogene,2013,32(35):4057-4063.
[28]Zhou CF,Ma J,Huang L,et al.Cervical squamous cell carcinomasecreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1[J].Oncogene,2019,38(8):1256-1268.
[29]Liu H,Chen W,Zhi X,et al.Tumor-derived exosomes promote tumor self-seeding in hepatocellular carcinoma by transferring miRNA-25-5p to enhance cell motility[J].Oncogene,2018,37(36):4964-4978.
[30]Wang G,Liu W,Zou Y,et al.Three isoforms of exosomal circ PT-GR1 promote hepatocellular carcinoma metastasis via the miR449a-MET pathway[J].E Bio Med,2019,40(6):432-445.
[31]Li Z,Tao Y,Wang X,et al.Tumor-secreted exosomal miR-222promotes tumor progression via regulating P27 expression and relocalization in pancreatic cancer[J].Cellular Physiol Biochem,2018,51(2):610-629.
[32]Kang M,Ren M,Li Y,et al.Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA[J].J Experim Clinic Cancer Res,2018,37(1):171-187.
[33]Simon T,Pinioti S,Schellenberger P,et al.Shedding of bevacizumab in tumour cells-derived extracellular vesicles as a new therapeutic escape mechanism in glioblastoma[J].Molec Cancer,2018,17(1):132-139.