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• W3090177881 abstract "Recent advances in exosome biology have uncovered a significant role of exosomes in cancer and make them a determining factor in intercellular communication. Exosomes are types of extracellular vesicles that are involved in the communication between cells by exchanging various signaling molecules between the surrounding cells. Among various signaling molecules, long non-coding RNAs (lncRNAs), a type of non-coding RNA having a size of more than 200 nt in length and lacking protein-coding potential, have emerged as crucial regulators of intercellular communication. Tumor-derived exosomes containing various lncRNAs, known as exosomal lncRNAs, reprogram the microenvironment by regulating numerous cellular functions, including the regulation of gene transcription that favors cancer growth and progression, thus significantly determining the biological effects of exosomes. In addition, deregulated expression of lncRNAs is found in various human cancers and serves as a diagnostic biomarker to predict cancer type. The present review discusses the role of exosomal lncRNAs in the crosstalk between tumor cells and the surrounding cells of the microenvironment. Furthermore, we also discuss the involvement of exosomal lncRNAs within the tumor microenvironment in favoring tumor growth, metabolic reprogramming of tumor cells, and tumor-supportive autophagy. Therefore, lncRNAs can be used as a therapeutic target in the treatment of various human cancers. Recent advances in exosome biology have uncovered a significant role of exosomes in cancer and make them a determining factor in intercellular communication. Exosomes are types of extracellular vesicles that are involved in the communication between cells by exchanging various signaling molecules between the surrounding cells. Among various signaling molecules, long non-coding RNAs (lncRNAs), a type of non-coding RNA having a size of more than 200 nt in length and lacking protein-coding potential, have emerged as crucial regulators of intercellular communication. Tumor-derived exosomes containing various lncRNAs, known as exosomal lncRNAs, reprogram the microenvironment by regulating numerous cellular functions, including the regulation of gene transcription that favors cancer growth and progression, thus significantly determining the biological effects of exosomes. In addition, deregulated expression of lncRNAs is found in various human cancers and serves as a diagnostic biomarker to predict cancer type. The present review discusses the role of exosomal lncRNAs in the crosstalk between tumor cells and the surrounding cells of the microenvironment. Furthermore, we also discuss the involvement of exosomal lncRNAs within the tumor microenvironment in favoring tumor growth, metabolic reprogramming of tumor cells, and tumor-supportive autophagy. Therefore, lncRNAs can be used as a therapeutic target in the treatment of various human cancers. Exosomes are single-membrane vesicles of about 30–150 nm in diameter that are formed from endocytic vesicles.1Zaborowski M.P. Balaj L. Breakefield X.O. Lai C.P. Extracellular vesicles: composition, biological relevance, and methods of study.Bioscience. 2015; 65: 783-797Crossref PubMed Scopus (244) Google Scholar,2Soares Martins T. Catita J. Martins Rosa I. A B da Cruz E Silva O. Henriques A.G. Exosome isolation from distinct biofluids using precipitation and column-based approaches.PLoS ONE. 2018; 13: e0198820Crossref PubMed Scopus (76) Google Scholar During endocytosis, the target extracellular material is surrounded by an area of the plasma membrane, which invaginates and forms a vesicle containing the ingested material.3Kumari S. Mg S. Mayor S. Endocytosis unplugged: multiple ways to enter the cell.Cell Res. 2010; 20: 256-275Crossref PubMed Scopus (255) Google Scholar Once internalized, this membrane-bound vesicle fuses with the early endosome, which serves as a sorting station for this cargo containing mainly proteins and lipids.4Jovic M. Sharma M. Rahajeng J. Caplan S. The early endosome: a busy sorting station for proteins at the crossroads.Histol. Histopathol. 2010; 25: 99-112PubMed Google Scholar Early endosomes are highly dynamic vesicles that form either multivesicular bodies (MVBs), also called late endosomes, or recycling endosomes that are part of the multiple tubulovesicular recycling system.5Piper R.C. Katzmann D.J. Biogenesis and function of multivesicular bodies.Annu. Rev. Cell Dev. Biol. 2007; 23: 519-547Crossref PubMed Scopus (431) Google Scholar,6Goldenring J.R. Recycling endosomes.Curr. Opin. Cell Biol. 2015; 35: 117-122Crossref PubMed Scopus (69) Google Scholar This recycling system transports cargo from early endosomes to the plasma membrane, Golgi network, or endoplasmic reticulum. Recycling of cargo from early endosomes to the plasma membrane via recycling endosomes is called a slow recycling pathway.7Sheff D.R. Daro E.A. Hull M. Mellman I. The receptor recycling pathway contains two distinct populations of early endosomes with different sorting functions.J. 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Multiple routes of protein transport from endosomes to the trans Golgi network.FEBS Lett. 2009; 583: 3811-3816Crossref PubMed Scopus (53) Google Scholar Most proteins that are recycled back to the plasma membrane are cell surface receptors, adhesion molecules, ion channels, or proteins involved in cell polarization,11Grant B.D. Donaldson J.G. Pathways and mechanisms of endocytic recycling.Nat. Rev. Mol. Cell Biol. 2009; 10: 597-608Crossref PubMed Scopus (846) Google Scholar whereas there is a wide range of functionally diverse proteins that utilize a retrograde pathway.12Johannes L. Popoff V. Tracing the retrograde route in protein trafficking.Cell. 2008; 135: 1175-1187Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar Late endosomes fuse with the lysosomes to form endolysosomes, resulting in the degradation of their cargo through lysosomal hydrolases. When early endosomes mature into late endosomes, they accumulate small vesicles inside their lumen that are formed by inward budding of early endosomes and contain proteins, lipids, and nucleic acids that are specifically sorted.13Huotari J. Helenius A. Endosome maturation.EMBO J. 2011; 30: 3481-3500Crossref PubMed Scopus (1148) Google Scholar The presence of intraluminal vesicles (ILVs) inside late endosomes gives them a multivesicular appearance. Therefore, they are often referred to MVBs.14Piper R.C. Luzio J.P. Late endosomes: sorting and partitioning in multivesicular bodies.Traffic. 2001; 2: 612-621Crossref PubMed Scopus (154) Google Scholar Not all ILVs are destined for degradation; some are secreted out in the extracellular space due to the fusion of MVBs with the plasma membrane in a highly regulated process. These small, secreted ILVs are referred to as exosomes. They are different from other types of similar-sized extracellular vesicles (EVs) secreted by cells, including microvesicles, ectosomes, and apoptotic bodies based on their origin, structure, and presence of specific markers on their membranes.15Holme P.A. Solum N.O. Brosstad F. Røger M. Abdelnoor M. Demonstration of platelet-derived microvesicles in blood from patients with activated coagulation and fibrinolysis using a filtration technique and western blotting.Thromb. Haemost. 1994; 72: 666-671Crossref PubMed Scopus (89) Google Scholar, 16Hess C. Sadallah S. Hefti A. Landmann R. Schifferli J.A. Ectosomes released by human neutrophils are specialized functional units.J. Immunol. 1999; 163: 4564-4573PubMed Google Scholar, 17Kerr J.F. Wyllie A.H. Currie A.R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.Br. J. 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Primdal-Bengtson B. Dingli F. Loew D. Tkach M. Théry C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.Proc. Natl. Acad. Sci. USA. 2016; 113: E968-E977Crossref PubMed Scopus (1184) Google Scholar The term exosome was first coined in 1987 by Johnstone et al.22Johnstone R.M. Adam M. Hammond J.R. Orr L. Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes).J. Biol. Chem. 1987; 262: 9412-9420Abstract Full Text PDF PubMed Google Scholar in sheep reticulocytes, where they reported the secretion and loss of transferrin receptor into small-sized vesicles (50 nm) to the extracellular space during reticulocyte maturation into erythrocytes. The group harvested these vesicles from sheep reticulocytes by centrifugation at 100,000 × g for 90 min. The lysed vesicles contained transferrin receptor and had many activities that were characteristic of the reticulocyte plasma membrane and were reduced or absent in mature erythrocytes. These activities include acetylcholinesterase, cytochalasin B binding (glucose transporter), nucleoside binding (i.e., nucleoside transporter), and Na+-independent amino acid transport, suggesting that proteins performing these activities are secreted out through exosomes during reticulocyte maturation.22Johnstone R.M. Adam M. Hammond J.R. Orr L. Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes).J. Biol. Chem. 1987; 262: 9412-9420Abstract Full Text PDF PubMed Google Scholar Since then, exosomes have been discovered in most cell types, such as immune cells (T lymphocytes,23Wahlgren J. Karlson Tde.L. Glader P. Telemo E. Valadi H. 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Biol. 2017; 998: 187-206Crossref PubMed Scopus (5) Google Scholar and mesenchymal stem cells,30Yin K. Wang S. Zhao R.C. Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm.Biomark. Res. 2019; 7: 8Crossref PubMed Scopus (36) Google Scholar adipocytes,31Deng Z.B. Poliakov A. Hardy R.W. Clements R. Liu C. Liu Y. Wang J. Xiang X. Zhang S. Zhuang X. et al.Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance.Diabetes. 2009; 58: 2498-2505Crossref PubMed Scopus (212) Google Scholar and glial cells,32Frühbeis C. Fröhlich D. Kuo W.P. Krämer-Albers E.M. Extracellular vesicles as mediators of neuron-glia communication.Front. Cell. Neurosci. 2013; 7: 182Crossref PubMed Scopus (204) Google Scholar and also in biological fluids such as blood, urine, semen, and breast milk.33Keller S. Ridinger J. Rupp A.K. Janssen J.W. Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics.J. Transl. Med. 2011; 9: 86Crossref PubMed Scopus (396) Google Scholar Exosomes perform a wide range of functions, including cell-to-cell communications through the delivery of DNA, RNA, lipids, or proteins from target to recipient cells,34Bang C. Thum T. Exosomes: new players in cell-cell communication.Int. J. Biochem. Cell Biol. 2012; 44: 2060-2064Crossref PubMed Scopus (251) Google Scholar immune regulation,35Li X.B. Zhang Z.R. Schluesener H.J. Xu S.Q. Role of exosomes in immune regulation.J. Cell. Mol. Med. 2006; 10: 364-375Crossref PubMed Scopus (0) Google Scholar and selective loss of biological macromolecules during cell maturation,22Johnstone R.M. Adam M. Hammond J.R. Orr L. Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes).J. Biol. 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Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers.Acta Neuropathol. 2018; 136: 41-56Crossref PubMed Scopus (106) Google Scholar diseases. Cancer-derived exosomes are vital in cancer cell survival and play an important role in the modulation of the tumor microenvironment to favor cancer progression and metastasis.39Zhang L. Yu D. Exosomes in cancer development, metastasis, and immunity.Biochim. Biophys. Acta Rev. Cancer. 2019; 1871: 455-468Crossref PubMed Scopus (37) Google Scholar,40Wortzel I. Dror S. Kenific C.M. Lyden D. Exosome-mediated metastasis: communication from a distance.Dev. Cell. 2019; 49: 347-360Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Many cancer cell types secrete exosomes that help to communicate with surrounding cancer or normal cells such as immune cells, stromal cells, vascular endothelial cells, and cancer-associated fibroblasts (CAFs). This helps in the establishment of a favorable tumor microenvironment, which promotes immune escape,41Kim D.H. Kim H. Choi Y.J. Kim S.Y. Lee J.E. Sung K.J. Sung Y.H. Pack C.G. Jung M.K. Han B. et al.Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer.Exp. Mol. Med. 2019; 51: 1-13Google Scholar tumor invasion,42Cai Z. Yang F. Yu L. Yu Z. Jiang L. Wang Q. Yang Y. Wang L. Cao X. Wang J. Activated T cell exosomes promote tumor invasion via Fas signaling pathway.J. Immunol. 2012; 188: 5954-5961Crossref PubMed Scopus (142) Google Scholar, migration,43Harada T. Yamamoto H. Kishida S. Kishida M. Awada C. Takao T. Kikuchi A. Wnt5b-associated exosomes promote cancer cell migration and proliferation.Cancer Sci. 2017; 108: 42-52Crossref PubMed Scopus (0) Google Scholar and formation of premetastatic niches in secondary organs.44Feng W. Dean D.C. Hornicek F.J. Shi H. Duan Z. Exosomes promote pre-metastatic niche formation in ovarian cancer.Mol. Cancer. 2019; 18: 124Crossref PubMed Scopus (42) Google Scholar Exosomes secreted by cancer cells suppress T cell receptors (TCRs) and inhibit the proliferation of CD8+ cytotoxic T lymphocytes (CTLs) that specifically target cancer cells and kill them. Coincubation of activated CD8+ T cells with exosomes isolated from tumor cell lines, including head and neck squamous cell carcinoma PCL-13 and melanoma cell line Mel-SW, inhibits their proliferation.45Wieckowski E.U. Visus C. Szajnik M. Szczepanski M.J. Storkus W.J. Whiteside T.L. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes.J. Immunol. 2009; 183: 3720-3730Crossref PubMed Scopus (302) Google Scholar CD8+ Jurkat cells (T lymphocyte cell line) coincubated with tumor exosomes undergo apoptosis and have fragmented DNA,45Wieckowski E.U. Visus C. Szajnik M. Szczepanski M.J. Storkus W.J. Whiteside T.L. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes.J. Immunol. 2009; 183: 3720-3730Crossref PubMed Scopus (302) Google Scholar suggesting immune suppression by cancer-derived exosomes. The stem-like brain tumor-initiating cells (BTICs) secrete high amounts of extracellular matrix protein tenascin-C (TNC) in exosomes, which inhibits T cell proliferation and activity by binding to α5β1 and αvβ6 integrins on T lymphocytes that blocks TCR signaling.46Mirzaei R. Sarkar S. Dzikowski L. Rawji K.S. Khan L. Faissner A. Bose P. Yong V.W. Brain tumor-initiating cells export tenascin-C associated with exosomes to suppress T cell activity.OncoImmunology. 2018; 7: e1478647Crossref PubMed Scopus (0) Google Scholar TNC promotes glioblastoma invasion and is associated with an immunosuppressive phenotype and worse overall survival in glioblastoma patients.46Mirzaei R. Sarkar S. Dzikowski L. Rawji K.S. Khan L. Faissner A. 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Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth.Cell Res. 2018; 28: 862-864Crossref PubMed Scopus (84) Google Scholar Exosomal PD-L1 isolated from cell culture supernatants of breast cancer cell lines MDA-MB-231 (human) and 4T1 (mouse mammary tumor cells), colon cancer cell line RKO, and lung cancer cell line HCC827 blocks T cell functions by inhibiting the CD3/CD28-triggered T cell activation signaling pathway.48Yang Y. Li C.W. Chan L.C. Wei Y. Hsu J.M. Xia W. Cha J.H. Hou J. Hsu J.L. Sun L. Hung M.C. Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth.Cell Res. 2018; 28: 862-864Crossref PubMed Scopus (84) Google Scholar Interestingly, the exosomes can transfer functional PD-L1 to other cells with low or no PD-L1 expression, suggesting the role of tumor-derived exosomes in enhancing the anti-tumor response.48Yang Y. Li C.W. Chan L.C. Wei Y. Hsu J.M. Xia W. Cha J.H. Hou J. Hsu J.L. Sun L. Hung M.C. Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth.Cell Res. 2018; 28: 862-864Crossref PubMed Scopus (84) Google Scholar Moreover, PD-L1 knockdown in mouse 4T1 cells injected into mice shows tumor regression, whereas PD-L1 knockdown tumors injected with exosomal PD-L1 shows high tumor growth and reduced cytotoxic T cell activity.48Yang Y. Li C.W. Chan L.C. Wei Y. Hsu J.M. Xia W. Cha J.H. Hou J. Hsu J.L. Sun L. Hung M.C. Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth.Cell Res. 2018; 28: 862-864Crossref PubMed Scopus (84) Google Scholar Except for proteins, exosomes are enriched in lipids, DNA, RNA, and metabolites that are specific to the cell of origin and play an important role in exosome functions.18Théry C. Zitvogel L. Amigorena S. 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In this review, we will focus on the role of lncRNAs secreted through exosomes in the modulation of the tumor microenvironment and its role in cancer development, growth, and response to therapy. Non-coding RNAs are functional RNA molecules that do not code for proteins. Only a few RNAs (less than 2%) are translated into proteins or are mRNAs, even though 90% of the human genome is transcribed.57Lander E.S. Linton L.M. Birren B. Nusbaum C. Zody M.C. Baldwin J. Devon K. Dewar K. Doyle M. FitzHugh W. et al.International Human Genome Sequencing ConsortiumInitial sequencing and analysis of the human genome.Nature. 2001; 409: 860-921Crossref PubMed Scopus (16016) Google Scholar, 58Venter J.C. Adams M.D. Myers E.W. Li P.W. Mural R.J. Sutton G.G. Smith H.O. Yandell M. Evans C.A. Holt R.A. et al.The sequence of the human genome.Science. 2001; 291: 1304-1351Crossref PubMed Scopus (9749) Google Scholar, 59Carninci P. Kasukawa T. Katayama S. Gough J. Frith M.C. Maeda N. Oyama R. Ravasi T. 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• W3090177881 created "2020-10-08" @default.
• W3090177881 creator A5001658268 @default.
• W3090177881 creator A5087616711 @default.
• W3090177881 date "2021-03-01" @default.
• W3090177881 modified "2023-10-15" @default.
• W3090177881 title "Exosomal Long Non-coding RNAs: Emerging Players in the Tumor Microenvironment" @default.
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