外泌体在骨肉瘤侵袭转移及耐药性中的研究进展
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摘要
骨肉瘤(osteosarcoma)是一种具有高度侵袭性的恶性肿瘤,已成为青少年人群中导致癌相关死亡的首要疾病。但由于其早期高发的肺转移率以及广泛的对化疗药物耐药性问题,骨肉瘤在临床上的治疗仍存在巨大挑战。目前,骨肉瘤的早期诊断及基因治疗已经在国内外的基础研究和临床应用中取得了一定的进展,其中外泌体(exosomes)在骨肉瘤中的诊断治疗具有极大的应用前景。外泌体是一种可由多种活细胞分泌的纳米级(40～100 nm)微囊泡,它具有传递mRNA、miRNA、DNA和蛋白质等各种信息和功能性物质的功能。它可由多种活性细胞产生和分泌,存在于多种体液和细胞间液中。由于其特殊的存在和传递形式以及所搭载的信息和物质,因此,骨肉瘤来源的外泌体可通过多种途径和方式促进骨肉瘤的发生、侵袭转移、耐药性及免疫逃逸。利用这些特点,外泌体可被人为搭载靶向药物或治疗性基因等物质,或通过多种方式对其分泌和释放进行调控来治疗多种肿瘤。近年来,关于外泌体在骨肉瘤方面作用和应用的研究成为热点,但仍停留在基础研究且尚未在临床的诊断及治疗中进行应用。本文旨在对外泌体在骨肉瘤侵袭转移及耐药性上的作用机理、临床诊断、治疗方面的研究进展进行总结,望有助于为利用外泌体诊断、治疗和改善骨肉瘤预后提供参考。
Osteosarcoma is a malignant tumor with a poor prognosis, and it has become the leading cause of cancer-related deaths in adolescents. However, due to its early high rate of lung metastasis and extensive resistance to chemotherapeutic drugs, clinical treatment of osteosarcoma remains a huge challenge. At present, advances in the early diagnosis and gene therapy of osteosarcoma have achieved some progress in fundamental researches and clinical applications worldwide. Among them, exosomes have great research prospects in the diagnosis and treatment of osteosarcoma.Exosomes are nanoscale microvesicles(40-100 nm) that can be secreted by a variety of living cells and have the ability to transmit multiple messages and functional substances such as mRNA, miRNA, DNA, and proteins.It can be produced and secreted by a variety of living cells and is present in a variety of body fluids and intercellular fluids. Because of its special existence and transfer form, as well as the information and substances it carries, osteosarcoma-derived exosomes can promote the tumorigenesis, invasion, metastasis, drug resistance, and immune escape of osteosarcoma in many ways. Using above characteristics, exosomes can be artificially loaded with targeted drugs or therapeutic genes, or they can be regulated in various ways to adjust the secretion and release in multiple tumor cells. In recent years,research on the role and application of exosomes in osteosarcoma has become a hotspot, but it still remains in basic research and has not yet been applied in clinical diagnosis and treatment. This article aims to summarize the functional mechanisms of exosomes on the invasion, metastasis and drug resistance in osteosarcoma, as well as the research progress in clinical diagnosis and treatment, hoping this will contribute to develop novel strategies to diagnose, treat and improve the prognosis in osteosarcoma.
Osteosarcoma is a malignant tumor with a poor prognosis, and it has become the leading cause of cancer-related deaths in adolescents. However, due to its early high rate of lung metastasis and extensive resistance to chemotherapeutic drugs, clinical treatment of osteosarcoma remains a huge challenge. At present, advances in the early diagnosis and gene therapy of osteosarcoma have achieved some progress in fundamental researches and clinical applications worldwide. Among them, exosomes have great research prospects in the diagnosis and treatment of osteosarcoma.Exosomes are nanoscale microvesicles(40-100 nm) that can be secreted by a variety of living cells and have the ability to transmit multiple messages and functional substances such as mRNA, miRNA, DNA, and proteins.It can be produced and secreted by a variety of living cells and is present in a variety of body fluids and intercellular fluids. Because of its special existence and transfer form, as well as the information and substances it carries, osteosarcoma-derived exosomes can promote the tumorigenesis, invasion, metastasis, drug resistance, and immune escape of osteosarcoma in many ways. Using above characteristics, exosomes can be artificially loaded with targeted drugs or therapeutic genes, or they can be regulated in various ways to adjust the secretion and release in multiple tumor cells. In recent years,research on the role and application of exosomes in osteosarcoma has become a hotspot, but it still remains in basic research and has not yet been applied in clinical diagnosis and treatment. This article aims to summarize the functional mechanisms of exosomes on the invasion, metastasis and drug resistance in osteosarcoma, as well as the research progress in clinical diagnosis and treatment, hoping this will contribute to develop novel strategies to diagnose, treat and improve the prognosis in osteosarcoma.
引文
[1]ENDO-MUNOZ L,CAI N,CUMMING A,et al.Progression of osteosarcoma from a non-metastatic to a metastatic phenotype is causally associated with activation of an autocrine and paracrine uPA axis[J].PLo SOne,2015,10(8):e0133592.
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[3]BOTTER S M,NERI D,FUCHS B.Recent advances in osteosarcoma[J].Curr Opin Pharmacol,2014,16(1):15-23.
[4]LI S,SUN W,WANG H,et al.Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal[J].Tumour Biol,2015,36(3):1329-1338.
[5]MU X,AGARWAL R,MARCH D,et al.Notch signaling mediates skeletal muscle atrophy in cancer cachexia caused by osteosarcoma[J].Sarcoma,2016.doi:10.1155/2016/3758162.
[6]TORREGGIANI E,RONCUZZI L,PERUT F,et al.Multimodal transfer of MDR by exosomes in human osteosarcoma[J].Int J Oncol,2016,49(1):189-196.
[7]YU D D,WU Y,SHEN H Y,et al.Exosomes in development,metastasis and drug resistance of breast cancer[J].Cancer Sci,2015,106(8):959-964.
[8]TROYER R M,RUBY C E,GOODALL C P,et al.Exosomes from Osteosarcoma and normal osteoblast differ in proteomic cargo and immunomodulatory effects on T cells[J].Exp Cell Res,2017,358(2):369-376.
[9]XU J F,WANG Y P,ZHANG S J,et al.Exosomes containing differential expression of microRNA and mRNA in osteosarcoma that can predict response to chemotherapy[J].Oncotarget,2017,8(44):75968-75978.
[10]SOUNG Y H,NGUYEN T,CAO H,et al.Emerging roles of exosomes in cancer invasion and metastasis[J].BMB Rep,2016,49(1):18-25.
[11]GONG L,BAO Q,HU C,et al.Exosomal miR-675 from metastatic osteosarcoma promotes cell migration and invasion by targeting CALN1[J].Biochem Biophys Res Commun,2018,500(2):170-176.
[12]JEREZ S,ARAYA H,THALER R,et al.Proteomic analysis of exosomes and exosome-free conditioned media from human osteosarcoma cell lines reveals secretion of proteins related to tumor progression[J].J Cell Biochem,2017,118(2):351-360.
[13]GUO W,GAO Y,LI N,et al.Exosomes:New players in cancer(Review)[J].Oncol Rep,2017,38(2):665-675.
[14]KHALYFA A,YOUSSEFNIA N,FOSTER G E,et al.Plasma exosomes and improvements in endothelial function by angiotensin 2Type 1 receptor or cyclooxygenase 2 blockade following intermittent hypoxia[J].Front Neurol,2017,8:709.
[15]LI P,FENG J,LIU Y,et al.Novel therapy for glioblastoma multiforme by restoring LRRC4 in tumor cells:LRRC4 inhibits tumor-infitrating regulatory T cells by cytokine and programmed cell death 1-containing exosomes[J].Front Immunol,2017,8:1748.
[16]LI X,WANG X.The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer[J].Mol Cancer,2017,16(1):92.
[17]LOBB R J,LIMA L G,MLLER A.Exosomes:Key mediators of metastasis and pre-metastatic niche formation[J].Semin Cell Dev Biol,2017,67:3-10.
[18]AN T,QIN S,XU Y,et al.Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis[J].J Extracell Vesicles,2015,4:27522.
[19]GREENING D W,JI H,CHEN M,et al.Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo[J].Sci Rep,2016,6:32643.
[20]VILLASANTE A,MARTURANO-KRUIK A,AMBATI S R,et al.Recapitulating the size and cargo of tumor exosomes in a tissue-engineered model[J].Theranostics,2016,6(8):1119-1130.
[21]COLLETTI M,PETRETTO A,GALARDI A,et al.Proteomic analysis of neuroblastoma-derived exosomes:new insights into a metastatic signature[J].Proteomics,2017,17(23-24):1600430.
[22]ZHOU L,LV T,ZHANG Q,et al.The biology,function and clinical implications of exosomes in lung cancer[J].Cancer Lett,2017,407:84-92.
[23]ROMA-RODRIGUES C,FERNANDES A R,BAPTISTA P V.Exosome in tumour microenvironment:overview of the crosstalk between normal and cancer cells[J].Biomed Res Int,2014,2014(7):179486.
[24]HE C,ZHENG S,LUO Y,et al.Exosome theranostics:biology and translational medicine[J].Theranostics,2018,8(1):237-255.
[25]LV C Y,DING W J,WANG Y L,et al.A PEG-based method for the isolation of urinary exosomes and its application in renal fibrosis diagnostics using cargo miR-29c and miR-21 analysis[J].Int Urol Nephrol,2018,50(5):973-982.
[26]ALMENDROS I,KHALYFA A,TRZEPIZUR W,et al.Tumor cell malignant properties are enhanced by circulating exosomes in sleep apnea[J].Chest,2016,150(5):1030-1041.
[27]SHIMBO K,MIYAKI S,ISHITOBI H,et al.Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration[J].Biochem Biophys Res Commun,2014,445(2):381-387.
[28]ALECˇKOVI C'M,KANG Y.Welcoming treat:astrocyte-derived exosomes induce PTEN suppression to foster brain metastasis[J].Cancer Cell,2015,28(5):554-556.
[29]ZHAO C,GAO F,WENG S,et al.Pancreatic cancer and associated exosomes[J].Cancer Biomark,2017,20(4):357-367.
[30]CHAHAR H S,CORSELLO T,KUDLICKI A S,et al.Respiratory syncytial virus infection changes cargo composition of exosome released from airway epithelial cells[J].Sci Rep,2018,8(1):387.
[31]QI J,ZHOU Y,JIAO Z,et al.Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway[J].Cell Physiol Biochem,2017,42(6):2242-2254.
[32]UMEZU T,IMANISHI S,AZUMA K,et al.Replenishing exosomes from older bone marrow stromal cells with miR-340 inhibits myelomarelated angiogenesis[J].Blood Adv,2017,1(13):812-823.
[33]LUNDHOLM M,SCHRDER M,NAGAEVA O,et al.Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+T cells:mechanism of immune evasion[J].PLo S One,2014,9(9):e108925.
[34]SHI S,ZHANG Q,XIA Y,et al.Mesenchymal stem cell-derived exosomes facilitate nasopharyngeal carcinoma progression[J].Am JCancer Res,2016,6(2):459-472.
[35]DE VRIJ J,MAAS S L,KWAPPENBERG K M,et al.Glioblastomaderived extracellular vesicles modify the phenotype of monocytic cells[J].Int J Cancer,2015,137(7):1630-1642.
[36]GONG L,BAO Q,HU C,et al.Exosomal miR-675 from metastatic osteosarcoma promotes cell migration and invasion by targeting CALN1[J].Biochem Biophys Res Commun,2018,500(2):170-176.
[37]BAKER E K,TAYLOR S,GUPTE A,et al.Wnt inhibitory factor 1(WIF1)is a marker of osteoblastic differentiation stage and is not silenced by DNA methylation in osteosarcoma[J].Bone,2015,73:223-232.
[38]BIELACK S S,HECKER-NOLTING S,BLATTMANN C,et al.Advances in the management of osteosarcoma[J].F1000Res,2016,5:2767.
[39]WANG J,SUN X,ZHAO J,et al.Exosomes:a novel strategy for treatment and prevention of diseases[J].Front Pharmacol,2017,8:300.
[40]GREENING D W,GOPAL S K,XU R,et al.Exosomes and their roles in immune regulation and cancer[J].Semin Cell Dev Biol,2015,40:72-81.
[41]ISLA LARRAIN M T,RABASSA M E,LACUNZA E,et al.IDO is highly expressed in breast cancer and breast cancer-derived circulating microvesicles and associated to aggressive types of tumors by in silico analysis[J].Tumour Biol,2014,35(7):6511-6519.
[42]ZHANG C,YANG X,QI Q,et al.lncRNA-HEIH in serum and exosomes as a potential biomarker in the HCV-related hepatocellular carcinoma[J].Cancer Biomark,2018,21(3):651-659.
[43]GREEN T M,ALPAUGH M L,BARSKY S H,et al.Breast cancerderived extracellular vesicles:characterization and contribution to the metastatic phenotype[J].Biomed Res Int,2015,2015(19):634865.
[44]ROBERSON C D,ATAY S,GERCEL-TAYLOR C,et al.Tumor-derived exosomes as mediators of disease and potential diagnostic biomarkers[J].Cancer biomark,2010,8:281-291.
[45]SUCHORSKA W M,LACH M S.The role of exosomes in tumor progression and metastasis(Review)[J].Oncol Rep,2016,35(3):1237-1244.
[46]KOSAKA N,IGUCHI H,YOSHIOKA Y,et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells[J].J Biol Chemist,2010,285:17442-17452.
[2]李强,赵永生,陈修福,等.RNA干扰骨肉瘤中抗增殖蛋白基因的表达对骨肉瘤细胞增殖和凋亡的影响[J].中国临床研究,2017,30(10):1301-1305.
[3]BOTTER S M,NERI D,FUCHS B.Recent advances in osteosarcoma[J].Curr Opin Pharmacol,2014,16(1):15-23.
[4]LI S,SUN W,WANG H,et al.Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal[J].Tumour Biol,2015,36(3):1329-1338.
[5]MU X,AGARWAL R,MARCH D,et al.Notch signaling mediates skeletal muscle atrophy in cancer cachexia caused by osteosarcoma[J].Sarcoma,2016.doi:10.1155/2016/3758162.
[6]TORREGGIANI E,RONCUZZI L,PERUT F,et al.Multimodal transfer of MDR by exosomes in human osteosarcoma[J].Int J Oncol,2016,49(1):189-196.
[7]YU D D,WU Y,SHEN H Y,et al.Exosomes in development,metastasis and drug resistance of breast cancer[J].Cancer Sci,2015,106(8):959-964.
[8]TROYER R M,RUBY C E,GOODALL C P,et al.Exosomes from Osteosarcoma and normal osteoblast differ in proteomic cargo and immunomodulatory effects on T cells[J].Exp Cell Res,2017,358(2):369-376.
[9]XU J F,WANG Y P,ZHANG S J,et al.Exosomes containing differential expression of microRNA and mRNA in osteosarcoma that can predict response to chemotherapy[J].Oncotarget,2017,8(44):75968-75978.
[10]SOUNG Y H,NGUYEN T,CAO H,et al.Emerging roles of exosomes in cancer invasion and metastasis[J].BMB Rep,2016,49(1):18-25.
[11]GONG L,BAO Q,HU C,et al.Exosomal miR-675 from metastatic osteosarcoma promotes cell migration and invasion by targeting CALN1[J].Biochem Biophys Res Commun,2018,500(2):170-176.
[12]JEREZ S,ARAYA H,THALER R,et al.Proteomic analysis of exosomes and exosome-free conditioned media from human osteosarcoma cell lines reveals secretion of proteins related to tumor progression[J].J Cell Biochem,2017,118(2):351-360.
[13]GUO W,GAO Y,LI N,et al.Exosomes:New players in cancer(Review)[J].Oncol Rep,2017,38(2):665-675.
[14]KHALYFA A,YOUSSEFNIA N,FOSTER G E,et al.Plasma exosomes and improvements in endothelial function by angiotensin 2Type 1 receptor or cyclooxygenase 2 blockade following intermittent hypoxia[J].Front Neurol,2017,8:709.
[15]LI P,FENG J,LIU Y,et al.Novel therapy for glioblastoma multiforme by restoring LRRC4 in tumor cells:LRRC4 inhibits tumor-infitrating regulatory T cells by cytokine and programmed cell death 1-containing exosomes[J].Front Immunol,2017,8:1748.
[16]LI X,WANG X.The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer[J].Mol Cancer,2017,16(1):92.
[17]LOBB R J,LIMA L G,MLLER A.Exosomes:Key mediators of metastasis and pre-metastatic niche formation[J].Semin Cell Dev Biol,2017,67:3-10.
[18]AN T,QIN S,XU Y,et al.Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis[J].J Extracell Vesicles,2015,4:27522.
[19]GREENING D W,JI H,CHEN M,et al.Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo[J].Sci Rep,2016,6:32643.
[20]VILLASANTE A,MARTURANO-KRUIK A,AMBATI S R,et al.Recapitulating the size and cargo of tumor exosomes in a tissue-engineered model[J].Theranostics,2016,6(8):1119-1130.
[21]COLLETTI M,PETRETTO A,GALARDI A,et al.Proteomic analysis of neuroblastoma-derived exosomes:new insights into a metastatic signature[J].Proteomics,2017,17(23-24):1600430.
[22]ZHOU L,LV T,ZHANG Q,et al.The biology,function and clinical implications of exosomes in lung cancer[J].Cancer Lett,2017,407:84-92.
[23]ROMA-RODRIGUES C,FERNANDES A R,BAPTISTA P V.Exosome in tumour microenvironment:overview of the crosstalk between normal and cancer cells[J].Biomed Res Int,2014,2014(7):179486.
[24]HE C,ZHENG S,LUO Y,et al.Exosome theranostics:biology and translational medicine[J].Theranostics,2018,8(1):237-255.
[25]LV C Y,DING W J,WANG Y L,et al.A PEG-based method for the isolation of urinary exosomes and its application in renal fibrosis diagnostics using cargo miR-29c and miR-21 analysis[J].Int Urol Nephrol,2018,50(5):973-982.
[26]ALMENDROS I,KHALYFA A,TRZEPIZUR W,et al.Tumor cell malignant properties are enhanced by circulating exosomes in sleep apnea[J].Chest,2016,150(5):1030-1041.
[27]SHIMBO K,MIYAKI S,ISHITOBI H,et al.Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration[J].Biochem Biophys Res Commun,2014,445(2):381-387.
[28]ALECˇKOVI C'M,KANG Y.Welcoming treat:astrocyte-derived exosomes induce PTEN suppression to foster brain metastasis[J].Cancer Cell,2015,28(5):554-556.
[29]ZHAO C,GAO F,WENG S,et al.Pancreatic cancer and associated exosomes[J].Cancer Biomark,2017,20(4):357-367.
[30]CHAHAR H S,CORSELLO T,KUDLICKI A S,et al.Respiratory syncytial virus infection changes cargo composition of exosome released from airway epithelial cells[J].Sci Rep,2018,8(1):387.
[31]QI J,ZHOU Y,JIAO Z,et al.Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway[J].Cell Physiol Biochem,2017,42(6):2242-2254.
[32]UMEZU T,IMANISHI S,AZUMA K,et al.Replenishing exosomes from older bone marrow stromal cells with miR-340 inhibits myelomarelated angiogenesis[J].Blood Adv,2017,1(13):812-823.
[33]LUNDHOLM M,SCHRDER M,NAGAEVA O,et al.Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+T cells:mechanism of immune evasion[J].PLo S One,2014,9(9):e108925.
[34]SHI S,ZHANG Q,XIA Y,et al.Mesenchymal stem cell-derived exosomes facilitate nasopharyngeal carcinoma progression[J].Am JCancer Res,2016,6(2):459-472.
[35]DE VRIJ J,MAAS S L,KWAPPENBERG K M,et al.Glioblastomaderived extracellular vesicles modify the phenotype of monocytic cells[J].Int J Cancer,2015,137(7):1630-1642.
[36]GONG L,BAO Q,HU C,et al.Exosomal miR-675 from metastatic osteosarcoma promotes cell migration and invasion by targeting CALN1[J].Biochem Biophys Res Commun,2018,500(2):170-176.
[37]BAKER E K,TAYLOR S,GUPTE A,et al.Wnt inhibitory factor 1(WIF1)is a marker of osteoblastic differentiation stage and is not silenced by DNA methylation in osteosarcoma[J].Bone,2015,73:223-232.
[38]BIELACK S S,HECKER-NOLTING S,BLATTMANN C,et al.Advances in the management of osteosarcoma[J].F1000Res,2016,5:2767.
[39]WANG J,SUN X,ZHAO J,et al.Exosomes:a novel strategy for treatment and prevention of diseases[J].Front Pharmacol,2017,8:300.
[40]GREENING D W,GOPAL S K,XU R,et al.Exosomes and their roles in immune regulation and cancer[J].Semin Cell Dev Biol,2015,40:72-81.
[41]ISLA LARRAIN M T,RABASSA M E,LACUNZA E,et al.IDO is highly expressed in breast cancer and breast cancer-derived circulating microvesicles and associated to aggressive types of tumors by in silico analysis[J].Tumour Biol,2014,35(7):6511-6519.
[42]ZHANG C,YANG X,QI Q,et al.lncRNA-HEIH in serum and exosomes as a potential biomarker in the HCV-related hepatocellular carcinoma[J].Cancer Biomark,2018,21(3):651-659.
[43]GREEN T M,ALPAUGH M L,BARSKY S H,et al.Breast cancerderived extracellular vesicles:characterization and contribution to the metastatic phenotype[J].Biomed Res Int,2015,2015(19):634865.
[44]ROBERSON C D,ATAY S,GERCEL-TAYLOR C,et al.Tumor-derived exosomes as mediators of disease and potential diagnostic biomarkers[J].Cancer biomark,2010,8:281-291.
[45]SUCHORSKA W M,LACH M S.The role of exosomes in tumor progression and metastasis(Review)[J].Oncol Rep,2016,35(3):1237-1244.
[46]KOSAKA N,IGUCHI H,YOSHIOKA Y,et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells[J].J Biol Chemist,2010,285:17442-17452.