Hitting the target: cell signaling pathways modulation by extracellular vesicles

Abstract

Extracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released outside the cell. EVs have drawn attention not only for their role in cell waste disposal, but also as additional tools for cell-to-cell communication. Their complex contents include not only lipids, but also proteins, nucleic acids (RNA, DNA), and metabolites. A large part of these molecules are involved in mediating or influencing signal transduction in target cells. In multicellular organisms, EVs have been suggested to modulate signals in cells localized either in the neighboring tissue or in distant regions of the body by interacting with the cell surface or by entering the cells via endocytosis or membrane fusion. Most of the EV-modulated cell signaling pathways have drawn considerable attention because they affect morphogenetic signaling pathways, as well as pathways activated by cytokines and growth factors. Therefore, they are implicated in relevant biological processes, such as embryonic development, cancer initiation and spreading, tissue differentiation and repair, and immune response. Furthermore, it has recently emerged that multicellular organisms interact with and receive signals through EVs released by their microbiota as well as by edible plants. This review reports studies investigating EV-mediated signaling in target mammalian cells, with a focus on key pathways for organism development, organ homeostasis, cell differentiation and immune response.

Keywords

Extracellular vesicles / exosomes / microvesicles / Wnt / Notch / Hedgehog / TGF-β / EGFR / Hippo

References

[1] Couch Y,Di Vizio D.A brief history of nearly EV-erything - the rise and rise of extracellular vesicles.J Extracell Vesicles2021;10:e12144 PMCID:PMC8681215

[2] Vidal M.Exosomes: revisiting their role as “garbage bags”.Traffic2019;20:815-28

[3] Raposo G.Extracellular vesicles: a new communication paradigm?.Nat Rev Mol Cell Biol2019;20:509-10

[4] Yáñez-Mó M,Andreu Z.Biological properties of extracellular vesicles and their physiological functions.J Extracell Vesicles2015;4:27066 PMCID:PMC4433489

[5] Kalluri R.The biology, function, and biomedical applications of exosomes.Science2020;367:eaau6977 PMCID:PMC7717626

[6] Clancy JW,D'Souza-Schorey C.The ins and outs of microvesicles.FASEB Bioadv2021;3:399-406 PMCID:PMC8171306

[7] Battistelli M.Apoptotic bodies: particular extracellular vesicles involved in intercellular communication.Biology (Basel)2020;9:21 PMCID:PMC7168913

[8] Kowal J,Colombo M.Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.Proc Natl Acad Sci U S A2016;113:E968-77 PMCID:PMC4776515

[9] Théry C,Aikawa E.Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines.J Extracell Vesicles2018;7:1535750 PMCID:PMC6322352

[10] Welsh JA,O'Driscoll L.MISEV ConsortiumMinimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches.J Extracell Vesicles2024;13:e12404

[11] Jiang Y,Ye J.Migrasomes, a new mode of intercellular communication.Cell Commun Signal2023;21:105 PMCID:PMC10165304

[12] Ciardiello C,Leone A.Large extracellular vesicles: size matters in tumor progression.Cytokine Growth Factor Rev2020;51:69-74

[13] Jeppesen DK,Franklin JL.Extracellular vesicles and nanoparticles: emerging complexities.Trends Cell Biol2023;33:667-81 PMCID:PMC10363204

[14] Zhang H,Kim HS.Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation.Nat Cell Biol2018;20:332-43 PMCID:PMC5931706

[15] Zhang Q,Higginbotham JN.Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets.Nat Cell Biol2021;23:1240-54

[16] Colombo M,van Niel G.Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles.J Cell Sci2013;126:5553-65

[17] Urbanelli L,Buratta S.Signaling pathways in exosomes biogenesis, secretion and fate.Genes (Basel)2013;4:152-70 PMCID:PMC3899971

[18] Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles.Nat Rev Mol Cell Biol2018;19:213-28

[19] Tricarico C,D'Souza-Schorey C.Biology and biogenesis of shed microvesicles.Small GTPases2017;8:220-32 PMCID:PMC5680703

[20] Sagini K,Emiliani C,Urbanelli L.Extracellular vesicles as conveyors of membrane-derived bioactive lipids in immune system.Int J Mol Sci2018;19:1227 PMCID:PMC5979532

[21] Hurley JH.ESCRTs are everywhere.EMBO J2015;34:2398-407 PMCID:PMC4601661

[22] Chiaradia E,Emiliani C.Extracellular vesicles under oxidative stress conditions: biological properties and physiological roles.Cells2021;10:1763 PMCID:PMC8306565

[23] Valadi H,Bossios A,Lee JJ.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.Nat Cell Biol2007;9:654-9

[24] Li Z,Huang S.Extracellular vesicle long non-coding RNAs and circular RNAs: biology, functions and applications in cancer.Cancer Lett2020;489:111-20

[25] Liu DSK,Asim M,Frampton AE.The clinical significance of transfer RNAs present in extracellular vesicles.Int J Mol Sci2022;23:3692 PMCID:PMC8998272

[26] Hur JY.Characteristics and clinical application of extracellular vesicle-derived DNA.Cancers (Basel)2021;13:3827 PMCID:PMC8345206

[27] Tóth EÁ,Visnovitz T.Formation of a protein corona on the surface of extracellular vesicles in blood plasma.J Extracell Vesicles2021;10:e12140 PMCID:PMC8439280

[28] Yates AG,Erdbrügger U.In sickness and in health: the functional role of extracellular vesicles in physiology and pathology in vivo: part I: Health and Normal Physiology: Part I: Health and Normal Physiology.J Extracell Vesicles2022;11:e12151 PMCID:PMC8765331

[29] Zabeo D,Lässer C,Lötvall J.Exosomes purified from a single cell type have diverse morphology.J Extracell Vesicles2017;6:1329476 PMCID:PMC5505001

[30] Prada I.Binding and fusion of extracellular vesicles to the plasma membrane of their cell targets.Int J Mol Sci2016;17:1296 PMCID:PMC5000693

[31] Liu YJ.A review of the regulatory mechanisms of extracellular vesicles-mediated intercellular communication.Cell Commun Signal2023;21:77 PMCID:PMC10100201

[32] French KC,Cerione RA.Extracellular vesicle docking at the cellular port: extracellular vesicle binding and uptake.Semin Cell Dev Biol2017;67:48-55 PMCID:PMC5484727

[33] O'Brien K,Mahjoum S,Breakefield XO.Uptake, functionality, and re-release of extracellular vesicle-encapsulated cargo.Cell Rep2022;39:110651 PMCID:PMC9074118

[34] Yoon YJ,Yoon CM.Egr-1 activation by cancer-derived extracellular vesicles promotes endothelial cell migration via ERK1/2 and JNK signaling pathways.PLoS One2014;9:e115170 PMCID:PMC4264882

[35] Zhou D,Zhang M.Mesenchymal stem cell-derived extracellular vesicles promote apoptosis in RSC96 schwann cells through the activation of the ERK pathway.Int J Clin Exp Pathol2018; 11:5157-70 PMCID:PMC6963017

[36] Zhang Y,Shi L.Extracellular vesicles microRNA-592 of melanoma stem cells promotes metastasis through activation of MAPK/ERK signaling pathway by targeting PTPN7 in non-stemness melanoma cells.Cell Death Discov2022;8:428 PMCID:PMC9614017

[37] Bai X,Li Z.Platelet-derived extracellular vesicles encapsulate microRNA-34c-5p to ameliorate inflammatory response of coronary artery endothelial cells via PODXL-mediated P38 MAPK signaling pathway.Nutr Metab Cardiovasc Dis2022;32:2424-38

[38] Nakano M.Potential effects of mesenchymal stem cell derived extracellular vesicles and exosomal miRNAs in neurological disorders.Neural Regen Res2021;16:2359-66 PMCID:PMC8374551

[39] Xin Q,He C,Wang H.The effect of different sources of mesenchymal stem cells on microglia states.Front Aging Neurosci2023;15:1237532 PMCID:PMC10483832

[40] Adamo A,Caligola S.Extracellular vesicles mediate mesenchymal stromal cell-dependent regulation of B cell PI3K-AKT signaling pathway and actin cytoskeleton.Front Immunol2019;10:446 PMCID:PMC6423067

[41] Liu M,Xue Z.Small extracellular vesicles derived from embryonic stem cells restore ovarian function of premature ovarian failure through PI3K/AKT signaling pathway.Stem Cell Res Ther2020;11:3 PMCID:PMC6942273

[42] Liu W,Liu D.Extracellular vesicles from adipose-derived stem cells promote diabetic wound healing via the PI3K-AKT-mTOR-HIF-1α signaling pathway.Tissue Eng Regen Med2021;18:1035-44 PMCID:PMC8599548

[43] Ma Y,Zhang H,Qian F.Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote the proliferation of schwann cells by regulating the PI3K/AKT signaling pathway via transferring miR-21.Stem Cells Int2021;2021:1496101 PMCID:PMC8452411

[44] Huang D,Jin Q.Role of CD147 in the development and diagnosis of hepatocellular carcinoma.Front Immunol2023;14:1149931 PMCID:PMC10115957

[45] Wang SJ,Chen FW.Bone marrow mesenchymal stem cell-derived extracellular vesicles containing miR-181d protect rats against renal fibrosis by inhibiting KLF6 and the NF-κB signaling pathway.Cell Death Dis2022;13:535 PMCID:PMC9174332

[46] Fafián-Labora JA.NF-κB/IKK activation by small extracellular vesicles within the SASP.Aging Cell2021;20:e13426 PMCID:PMC8282244

[47] Wolpert L.Positional information and pattern formation. Essays on developmental biology, part B. Elsevier; 2016. p. 597-608.

[48] Matusek T,Thérond PP.Functions of Wnt and Hedgehog-containing extracellular vesicles in development and disease.J Cell Sci2020;133:jcs209742

[49] Nusse R.Three decades of Wnts: a personal perspective on how a scientific field developed.EMBO J2012;31:2670-84 PMCID:PMC3380217

[50] Qin K,Fan J.Canonical and noncanonical Wnt signaling: multilayered mediators, signaling mechanisms and major signaling crosstalk.Genes Dis2024;11:103-34 PMCID:PMC10425814

[51] Liu J,Xiao J.Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities.Signal Transduct Target Ther2022;7:3 PMCID:PMC8724284

[52] Daulat AM.Wnt/planar cell polarity signaling: new opportunities for cancer treatment.Trends Cancer2017;3:113-25

[53] Menck K,Baden C.The WNT/ROR pathway in cancer: from signaling to therapeutic intervention.Cells2021;10:142 PMCID:PMC7828172

[54] Chairoungdua A,Pochard P,Caplan MJ.Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling.J Cell Biol2010;190:1079-91 PMCID:PMC3101591

[55] Gross JC,Bartscherer K.Active Wnt proteins are secreted on exosomes.Nat Cell Biol2012;14:1036-45

[56] Koles K,Korkut C.Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons.J Biol Chem2012;287:16820-34 PMCID:PMC3351299

[57] Menck K,Gross JC,Wenzel D.Induction and transport of Wnt 5a during macrophage-induced malignant invasion is mediated by two types of extracellular vesicles.Oncotarget2013;4:2057-66 PMCID:PMC3875769

[58] Dovrat S,Zilberberg A.14-3-3 and β-catenin are secreted on extracellular vesicles to activate the oncogenic Wnt pathway.Mol Oncol2014;8:894-911 PMCID:PMC5528515

[59] Kalra H,Fonseka P.Extracellular vesicles containing oncogenic mutant β-catenin activate Wnt signalling pathway in the recipient cells.J Extracell Vesicles2019;8:1690217 PMCID:PMC6883417

[60] Scavo MP,Rizzi F.FZD10 carried by exosomes sustains cancer cell proliferation.Cells2019;8:777 PMCID:PMC6721576

[61] Irmer B,Reitnauer LE.Extracellular vesicle-associated tyrosine kinase-like orphan receptors ROR1 and ROR2 promote breast cancer progression.Cell Commun Signal2023;21:171 PMCID:PMC10331971

[62] Schubert A.Extracellular vesicles and oncogenic signaling.Mol Oncol2021;15:3-26 PMCID:PMC7782092

[63] Lin R,Zhao RC.Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model.Mol Cell Biochem2013;383:13-20

[64] Harada T,Kishida S.Wnt5b-associated exosomes promote cancer cell migration and proliferation.Cancer Sci2017;108:42-52 PMCID:PMC5276837

[65] Koch R,Aung T.Populational equilibrium through exosome-mediated Wnt signaling in tumor progression of diffuse large B-cell lymphoma.Blood2014;123:2189-98

[66] Chen Y,Zhan Y,Jiang X.Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b.Oncogene2017;36:4692-705 PMCID:PMC5562851

[67] Qiu JJ,Tang XY,Hua KQ.Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the β-catenin signaling pathway.J Exp Clin Cancer Res2020;39:260 PMCID:PMC7687741

[68] Hu YB,Mu L.Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance.Oncogene2019;38:1951-65 PMCID:PMC6756234

[69] Lerner N,Beit-Yannai E.Extracellular vesicle-mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signalling pathway and ECM remodelling.J Cell Mol Med2020;24:4646-58 PMCID:PMC7176886

[70] Kholia S,Deregibus MC,Camussi G.Human liver stem cell derived extracellular vesicles alleviate kidney fibrosis by interfering with the β-Catenin pathway through miR29b.Int J Mol Sci2021;22:10780 PMCID:PMC8509541

[71] Wang T,Meng X.Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 in extracellular vesicles promotes hepatic stellate cell activation, liver fibrosis and β-catenin signaling pathway.Front Physiol2022;13:792182 PMCID:PMC8882958

[72] Echelard Y,St-Jacques B.Sonic Hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity.Cell1993;75:1417-30

[73] Jia Y,Xie J.The Hedgehog pathway: role in cell differentiation, polarity and proliferation.Arch Toxicol2015;89:179-91 PMCID:PMC4630008

[74] Doheny D,Wong GL.Hedgehog signaling and truncated GLI1 in cancer.Cells2020;9:2114 PMCID:PMC7565963

[75] Kong JH,Rohatgi R.Biochemical mechanisms of vertebrate Hedgehog signaling.Development2019;146:dev166892 PMCID:PMC6550017

[76] Liégeois S,Garnier JM,Labouesse M.The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in caenorhabditis elegans.J Cell Biol2006;173:949-61 PMCID:PMC2063919

[77] Matusek T,Polès S.The ESCRT machinery regulates the secretion and long-range activity of Hedgehog.Nature2014;516:99-103

[78] Gradilla AC,Seijo I.Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion.Nat Commun2014;5:5649

[79] Vyas N,Tate D.Vertebrate Hedgehog is secreted on two types of extracellular vesicles with different signaling properties.Sci Rep2014;4:7357 PMCID:PMC4258658

[80] Parchure A,Ferguson C,Mayor S.Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion.Mol Biol Cell2015;26:4700-17 PMCID:PMC4678025

[81] Coulter ME,Lodewijk GA.The ESCRT-III protein CHMP1A mediates secretion of sonic Hedgehog on a distinctive subtype of extracellular vesicles.Cell Rep2018;24:973-86.e8 PMCID:PMC6178983

[82] Hurbain I,Romao M.Microvilli-derived extracellular vesicles carry Hedgehog morphogenic signals for drosophila wing imaginal disc development.Curr Biol2022;32:361-73.e6

[83] Zhao G,Guo Q.Exosomal sonic Hedgehog derived from cancer-associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma.Cancer Med2020;9:2500-13 PMCID:PMC7131837

[84] Arasu UT,Pasonen-Seppänen S.HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the Hedgehog signaling pathway in target cells.Cell Mol Life Sci2020;77:4093-115 PMCID:PMC7532973

[85] Li L,Zhang Q.Cancer cell-derived exosomes promote HCC tumorigenesis through Hedgehog pathway.Front Oncol2021;11:756205 PMCID:PMC8529041

[86] Bhat A,Thakur K.Exosomes from cervical cancer cells facilitate pro-angiogenic endothelial reconditioning through transfer of Hedgehog-GLI signaling components.Cancer Cell Int2021;21:319 PMCID:PMC8223267

[87] Zhou H,Wu RX.Periodontitis-compromised dental pulp stem cells secrete extracellular vesicles carrying miRNA-378a promote local angiogenesis by targeting Sufu to activate the Hedgehog/Gli1 signalling.Cell Prolif2021;54:e13026 PMCID:PMC8088471

[88] Ji Z,Gu S.Exosomes derived from human adipose-derived stem cells inhibit lipogenesis involving Hedgehog signaling pathway.Front Bioeng Biotechnol2021;9:734810 PMCID:PMC8439418

[89] Sachan N,Mutsuddi M.Notch signalling: multifaceted role in development and disease.FEBS J2024;291:3030-59

[90] Henrique D.Mechanisms of Notch signaling: a simple logic deployed in time and space.Development2019;146:dev172148

[91] Steinbuck MP.A review of Notch processing with new insights into ligand-independent Notch signaling in T-cells.Front Immunol2018;9:1230 PMCID:PMC5992298

[92] Zhou B,Long Y.Notch signaling pathway: architecture, disease, and therapeutics.Signal Transduct Target Ther2022;7:95 PMCID:PMC8948217

[93] Ayaz F.Non-canonical notch signaling in cancer and immunity.Front Oncol2014;4:345 PMCID:PMC4255497

[94] Xia R,Yang J.The role of Hedgehog and Notch signaling pathway in cancer.Mol Biomed2022;3:44 PMCID:PMC9751255

[95] Sheldon H,Turley H.New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes.Blood2010;116:2385-94

[96] Sharghi-Namini S,Ong LL,Asada HH.Dll4-containing exosomes induce capillary sprout retraction in a 3D microenvironment.Sci Rep2014;4:4031 PMCID:PMC3916896

[97] Tan E,Ge R.Extracellular vesicle-carried Jagged-1 inhibits HUVEC sprouting in a 3D microenvironment.Angiogenesis2018;21:571-80

[98] Wang X,Pan Y.Fetal dermal mesenchymal stem cell-derived exosomes accelerate cutaneous wound healing by activating Notch signaling.Stem Cells Int2019;2019:2402916 PMCID:PMC6590601

[99] Wang Q.Plasma membrane-derived extracellular microvesicles mediate non-canonical intercellular NOTCH signaling.Nat Commun2017;8:709 PMCID:PMC5617834

[100] Boelens MC,Nabet BY.Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.Cell2014;159:499-513 PMCID:PMC4283810

[101] Wang B,Wang X.Extracellular vesicles carrying miR-887-3p promote breast cancer cell drug resistance by targeting BTBD7 and activating the Notch1/Hes1 signaling pathway.Dis Markers2022;2022:5762686 PMCID:PMC9152417

[102] Yang J,Wang L,Yu L.Human umbilical vein endothelial cells derived-exosomes promote osteosarcoma cell stemness by activating Notch signaling pathway.Bioengineered2021;12:11007-17 PMCID:PMC8810022

[103] Giannandrea D,Colombo M.Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way.Haematologica2022;107:2183-94 PMCID:PMC9425323

[104] Pasquale EB.Eph receptors and ephrins in cancer: bidirectional signalling and beyond.Nat Rev Cancer2010;10:165-80 PMCID:PMC2921274

[105] Darling TK.Emerging roles for eph receptors and ephrin ligands in immunity.Front Immunol2019;10:1473 PMCID:PMC6620610

[106] Zhao Y,Zhang H,Li S.Eph/ephrin family anchored on exosome facilitate communications between cells.Cell Biol Int2018;42:1458-62

[107] Choi DS,Jang SC.Proteomic analysis of microvesicles derived from human colorectal cancer ascites.Proteomics2011;11:2745-51

[108] Sun W,Li Y.Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity.Cell Discov2016;2:16015 PMCID:PMC4886818

[109] Gong J,Gaitanos L.Exosomes mediate cell contact-independent ephrin-Eph signaling during axon guidance.J Cell Biol2016;214:35-44 PMCID:PMC4932373

[110] Takasugi M,Takahashi A,Watanabe S.Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2.Nat Commun2017;8:15729 PMCID:PMC5467215

[111] Sato S,Eskaros A.EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling.JCI Insight2019;4:132447 PMCID:PMC6962030

[112] Han B,Tian R.Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling.Theranostics2022;12:4127-46 PMCID:PMC9169374

[113] Kany S,Relja B.Cytokines in inflammatory disease.Int J Mol Sci2019;20:6008 PMCID:PMC6929211

[114] Rodrigues-Junior DM,Lim SK,Moustakas A.Extracellular vesicles and transforming growth factor β signaling in cancer.Front Cell Dev Biol2022;10:849938 PMCID:PMC9043557

[115] Cohen MJ,Lipke PN.Through the back door: unconventional protein secretion.Cell Surf2020;6:100045 PMCID:PMC7666356

[116] Frawley T.Extracellular vesicle dissemination of epidermal growth factor receptor and ligands and its role in cancer progression.Cancers (Basel)2020;12:3200 PMCID:PMC7693808

[117] Morikawa M,Miyazono K.TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology.Cold Spring Harb Perspect Biol2016;8:a021873 PMCID:PMC4852809

[118] Robertson IB.Regulation of the bioavailability of TGF-β and TGF-β-related proteins.Cold Spring Harb Perspect Biol2016;8:a021907 PMCID:PMC4888822

[119] Chaikuad A.Structural basis of intracellular TGF-β signaling: receptors and Smads.Cold Spring Harb Perspect Biol2016;8:a022111 PMCID:PMC5088531

[120] Zhang YE.Non-Smad signaling pathways of the TGF-β family.Cold Spring Harb Perspect Biol2017;9:a022129 PMCID:PMC5287080

[121] Xiang X,Liu C.Induction of myeloid-derived suppressor cells by tumor exosomes.Int J Cancer2009;124:2621-33 PMCID:PMC2757307

[122] Xie Y,Yuan J.Tumor apoptotic bodies inhibit CTL responses and antitumor immunity via membrane-bound transforming growth factor-beta1 inducing CD8⁺ T-cell anergy and CD4⁺ Tr1 cell responses.Cancer Res2009;69:7756-66

[123] Wada J,Suzuki H.Surface-bound TGF-beta1 on effusion-derived exosomes participates in maintenance of number and suppressive function of regulatory T-cells in malignant effusions.Anticancer Res2010; 30:3747-57.

[124] Yamada N,Kumazaki M,Taniguchi K.Colorectal cancer cell-derived extracellular vesicles induce phenotypic alteration of T cells into tumor-growth supporting cells with transforming growth factor-β1-mediated suppression.Oncotarget2016;7:27033-43 PMCID:PMC5053630

[125] Szczepanski MJ,Welsh A,Boyiadzis M.Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1.Haematologica2011;96:1302-9 PMCID:PMC3166100

[126] Berchem G,Bosseler M.Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer.Oncoimmunology2016;5:e1062968 PMCID:PMC4839360

[127] Ludwig N,Azambuja JH.TGFβ⁺ small extracellular vesicles from head and neck squamous cell carcinoma cells reprogram macrophages towards a pro-angiogenic phenotype.J Extracell Vesicles2022;11:e12294 PMCID:PMC9764108

[128] Fu XH,Li XY.M2-macrophage-derived exosomes promote meningioma progression through TGF-β signaling pathway.J Immunol Res2022;2022:8326591 PMCID:PMC9146444

[129] Huang F,Hu W.Enhancement of anti-leukemia immunity by leukemia-derived exosomes via downregulation of TGF-β1 expression.Cell Physiol Biochem2017;44:240-54

[130] de Miguel-Perez D,Gunasekaran M.Baseline extracellular vesicle TGF-β is a predictive biomarker for response to immune checkpoint inhibitors and survival in non-small cell lung cancer.Cancer2023;129:521-30

[131] Krishnamachary B,Kumar A.Extracellular vesicle TGF-β1 is linked to cardiopulmonary dysfunction in human immunodeficiency virus.Am J Respir Cell Mol Biol2021;65:413-29 PMCID:PMC8525206

[132] Webber J,Mason MD,Clayton A.Cancer exosomes trigger fibroblast to myofibroblast differentiation.Cancer Res2010;70:9621-30

[133] Webber JP,Sanders AJ.Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes.Oncogene2015;34:290-302

[134] Shelke GV,Jang SC.Endosomal signalling via exosome surface TGFβ-1.J Extracell Vesicles2019;8:1650458 PMCID:PMC6764367

[135] Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFβ signaling.Mol Cancer Res2018;16:1196-204

[136] Gu J,Shen L.Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway.PLoS One2012;7:e52465 PMCID:PMC3527492

[137] Baglio SR,Pérez-Lanzón M.Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression.Clin Cancer Res2017;23:3721-33

[138] Hao Y,Ten Dijke P.TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis.Int J Mol Sci2019;20:2767 PMCID:PMC6600375

[139] Qu Z,Pan H,Duan Y.Exosomes derived from HCC cells with different invasion characteristics mediated EMT through TGF-β/Smad signaling pathway.Onco Targets Ther2019;12:6897-905 PMCID:PMC6711569

[140] Nakayama F,Kimoto A.Pancreatic cancer cell-derived exosomes induce epithelial-mesenchymal transition in human pancreatic cancer cells themselves partially via transforming growth factor β1.Med Mol Morphol2022;55:227-35 PMCID:PMC9043512

[141] Yin Y,Lässer C,Lötvall J.Extracellular vesicles from mast cells induce mesenchymal transition in airway epithelial cells.Respir Res2020;21:101 PMCID:PMC7193353

[142] Feng Y,Zhong Y.Effects of human umbilical cord mesenchymal stem cells derived from exosomes on migration ability of endometrial glandular epithelial cells.Mol Med Rep2020;22:715-22 PMCID:PMC7339775

[143] Tan C,Xu Z.Small extracellular vesicles deliver TGF-β1 and promote adriamycin resistance in breast cancer cells.Mol Oncol2021;15:1528-42 PMCID:PMC8096780

[144] Borges FT,Özdemir BC.TGF-β1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis.J Am Soc Nephrol2013;24:385-92 PMCID:PMC3582210

[145] Zhu QJ,Xu XX,Wu YG.Exosomes from high glucose-treated macrophages activate glomerular mesangial cells via TGF-β1/Smad3 pathway in vivo and in vitro.FASEB J2019;33:9279-90

[146] Li J,Xu C.TGF-β1-containing exosomes derived from bone marrow mesenchymal stem cells promote proliferation, migration and fibrotic activity in rotator cuff tenocytes.Regen Ther2020;15:70-6 PMCID:PMC7770343

[147] Zhang L,Ai X.Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-β/Smad2/3 pathway.Cell Death Dis2021;12:1068 PMCID:PMC8578653

[148] Han T,Wu Z.MSC secreted extracellular vesicles carrying TGF-beta upregulate Smad 6 expression and promote the regrowth of neurons in spinal cord injured rats.Stem Cell Rev Rep2022;18:1078-96 PMCID:PMC8942898

[149] Languino LR,Prisco M.Exosome-mediated transfer from the tumour microenvironment increases TGFβ signaling in squamous cell carcinoma.Am J Transl Res2016; 8:2432-7. PMCID:PMC4891457

[150] Gautheron F,Garrido C.Bone marrow-derived extracellular vesicles carry the TGF-β signal transducer Smad2 to preserve hematopoietic stem cells in mice.Cell Death Discov2023;9:117 PMCID:PMC10076352

[151] Wee P.Epidermal growth factor receptor cell proliferation signaling pathways.Cancers (Basel)2017;9:52 PMCID:PMC5447962

[152] Singh B,Coffey RJ.EGF receptor ligands: recent advances.F1000Res2016;5:2270 PMCID:PMC5017282

[153] Uribe ML,Yarden Y.EGFR in cancer: signaling mechanisms, drugs, and acquired resistance.Cancers (Basel)2021;13:2748 PMCID:PMC8197917

[154] Al-Nedawi K,Micallef J.Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells.Nat Cell Biol2008;10:619-24

[155] Skog J,van Rijn S.Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers.Nat Cell Biol2008;10:1470-6 PMCID:PMC3423894

[156] Sanderson MP,Alonso A,Dempsey PJ.Generation of novel, secreted epidermal growth factor receptor (EGFR/ErbB1) isoforms via metalloprotease-dependent ectodomain shedding and exosome secretion.J Cell Biochem2008;103:1783-97 PMCID:PMC4922250

[157] Read J,Al Saleh HA.Nuclear transportation of exogenous epidermal growth factor receptor and androgen receptor via extracellular vesicles.Eur J Cancer2017;70:62-74

[158] Al-Nedawi K,Kerbel RS,Rak J.Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR.Proc Natl Acad Sci U S A2009;106:3794-9 PMCID:PMC2656159

[159] Song X,Liu G.Cancer cell-derived exosomes induce mitogen-activated protein kinase-dependent monocyte survival by transport of functional receptor tyrosine kinases.J Biol Chem2016;291:8453-64 PMCID:PMC4861419

[160] Gao L,Dai T.Tumor-derived exosomes antagonize innate antiviral immunity.Nat Immunol2018;19:233-45

[161] Yu S,Qin X.EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells.Oncogene2020;39:2643-57

[162] Fujiwara T,Sogawa C.Carcinogenic epithelial-mesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab.Oral Oncol2018;86:251-7

[163] Zhang H,Liu R.Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis.Nat Commun2017;8:15016 PMCID:PMC5394240

[164] Meckes DG Jr,Marquitz AR,Edwards RH.Human tumor virus utilizes exosomes for intercellular communication.Proc Natl Acad Sci U S A2010;107:20370-5 PMCID:PMC2996715

[165] Higginbotham JN,Gephart JD.Amphiregulin exosomes increase cancer cell invasion.Curr Biol2011;21:779-86 PMCID:PMC3417320

[166] Corrado C,Raimondo S,De Leo G.Chronic myelogenous leukaemia exosomes modulate bone marrow microenvironment through activation of epidermal growth factor receptor.J Cell Mol Med2016;20:1829-39 PMCID:PMC4876029

[167] Taverna S,Giallombardo M.Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway.Sci Rep2017;7:3170 PMCID:PMC5466625

[168] Raimondo S,Vicario E.Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis.J Hematol Oncol2019;12:2 PMCID:PMC6325886

[169] Yang WW,Zhao F.Epiregulin promotes lung metastasis of salivary adenoid cystic carcinoma.Theranostics2017;7:3700-14 PMCID:PMC5667342

[170] Zhang Q,Jeppesen DK.Transfer of functional cargo in exomeres.Cell Rep2019;27:940-54.e6 PMCID:PMC6559347

[171] Shibuya M.Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies.Genes Cancer2011;2:1097-105 PMCID:PMC3411125

[172] Mou S,Li Y.Extracellular vesicles from human adipose-derived stem cells for the improvement of angiogenesis and fat-grafting application.Plast Reconstr Surg2019;144:869-80

[173] Masoumi-Dehghi S,Sadeghizadeh M.microRNA-141-3p-containing small extracellular vesicles derived from epithelial ovarian cancer cells promote endothelial cell angiogenesis through activating the JAK/STAT3 and NF-κB signaling pathways.J Cell Commun Signal2020;14:233-44 PMCID:PMC7272520

[174] Lee JK,Jung BK.Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells.PLoS One2013;8:e84256 PMCID:PMC3877259

[175] Taraboletti G,Giusti I.Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH.Neoplasia2006;8:96-103 PMCID:PMC1578512

[176] Feng Q,Lum D.A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis.Nat Commun2017;8:14450 PMCID:PMC5316898

[177] Treps L,Edmond S,Gavard J.Glioblastoma stem-like cells secrete the pro-angiogenic VEGF-A factor in extracellular vesicles.J Extracell Vesicles2017;6:1359479 PMCID:PMC5549846

[178] Wang CA,Hou PC.DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination.J Extracell Vesicles2020;9:1746529 PMCID:PMC7170376

[179] Wang CS,Monteggia LM.BDNF signaling in context: from synaptic regulation to psychiatric disorders.Cell2022;185:62-76 PMCID:PMC8741740

[180] Wang Y,Xu B,Wu Z.TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury.Life Sci2024;336:122282

[181] Barcellos N,de Meireles LCF.Effects of exercise modalities on BDNF and IL-1β content in circulating total extracellular vesicles and particles obtained from aged rats.Exp Gerontol2020;142:111124

[182] Suire CN,Shaffer NC.Walking speed decline in older adults is associated with elevated pro-BDNF in plasma extracellular vesicles.Exp Gerontol2017;98:209-16 PMCID:PMC5642035

[183] Chung CC,Chan L,Chien LN.Plasma exosomal brain-derived neurotrophic factor correlated with the postural instability and gait disturbance-related motor symptoms in patients with parkinson’s disease.Diagnostics (Basel)2020;10:684 PMCID:PMC7555255

[184] Solana-Balaguer J,Martín-Flores N.Neuron-derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB-mediated signalling and preserve neuronal complexity.J Extracell Vesicles2023;12:e12355 PMCID:PMC10518375

[185] Li D.Pattern recognition receptors in health and diseases.Signal Transduct Target Ther2021;6:291 PMCID:PMC8333067

[186] Kawasaki T.Toll-like receptor signaling pathways.Front Immunol2014;5:461 PMCID:PMC4174766

[187] Picca A,Calvani R.Extracellular vesicles and damage-associated molecular patterns: a pandora’s box in health and disease.Front Immunol2020;11:601740 PMCID:PMC7701251

[188] Fu M,Lan T,Luo T.The Hippo signalling pathway and its implications in human health and diseases.Signal Transduct Target Ther2022;7:376 PMCID:PMC9643504

[189] Azad T,Surendran A.Hippo signaling pathway as a central mediator of receptors tyrosine kinases (RTKs) in tumorigenesis.Cancers (Basel)2020;12:2042 PMCID:PMC7463967

[190] Misra JR.The Hippo signaling network and its biological functions.Annu Rev Genet2018;52:65-87 PMCID:PMC6322405

[191] Hu J,Xiong Z.Exosomal Mst1 transfer from cardiac microvascular endothelial cells to cardiomyocytes deteriorates diabetic cardiomyopathy.Biochim Biophys Acta Mol Basis Dis2018;1864:3639-49

[192] Ren Y,He W,Zhao X.Exosomes secreted from bone marrow mesenchymal stem cells suppress cardiomyocyte hypertrophy through Hippo-YAP pathway in heart failure.Genet Mol Biol2023;46:e20220221 PMCID:PMC10021068

[193] Ji C,Zhu Y.Exosomes derived from hucMSC attenuate renal fibrosis through CK1δ/β-TRCP-mediated YAP degradation.Cell Death Dis2020;11:327 PMCID:PMC7205986

[194] Li Z,Zheng J.Human umbilical cord mesenchymal stem cell-derived exosomes improve ovarian function and proliferation of premature ovarian insufficiency by regulating the Hippo signaling pathway.Front Endocrinol (Lausanne)2021;12:711902 PMCID:PMC8397419

[195] Wang Y,Li W.BMSC-derived small extracellular vesicles induce cartilage reconstruction of temporomandibular joint osteoarthritis via autotaxin-YAP Signaling axis.Front Cell Dev Biol2021;9:656153 PMCID:PMC8047210

[196] Sun H,Gong A.Extracellular vesicles derived from astrocytes facilitated neurite elongation by activating the Hippo pathway.Exp Cell Res2022;411:112937

[197] Li FL.The two sides of Hippo pathway in cancer.Semin Cancer Biol2022;85:33-42

[198] Zanconato F,Piccolo S.YAP/TAZ at the roots of cancer.Cancer Cell2016;29:783-803 PMCID:PMC6186419

[199] Furth N.The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway.Cell Death Differ2017;24:1488-501 PMCID:PMC5563998

[200] Song H,Topol L.Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.Proc Natl Acad Sci U S A2010;107:1431-6 PMCID:PMC2824397

[201] Wang Z,Ji X.The Hippo-TAZ axis mediates vascular endothelial growth factor C in glioblastoma-derived exosomes to promote angiogenesis.Cancer Lett2021;513:1-13

[202] Wang S,Xu M.Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway.Stem Cell Res Ther2019;10:117 PMCID:PMC6458638

[203] Wang W,Tian J.Cervical cancer cells-derived extracellular vesicles containing microRNA-146a-5p affect actin dynamics to promote cervical cancer metastasis by activating the Hippo-YAP signaling pathway via WWC2.J Oncol2022;2022:4499876 PMCID:PMC9256433

[204] Yang P,Wang T.CAF-derived exosomal WEE2-AS1 facilitates colorectal cancer progression via promoting degradation of MOB1A to inhibit the Hippo pathway.Cell Death Dis2022;13:796 PMCID:PMC9485119

[205] Wang H,Xu C.Hypoxia-elicited exosomes promote the chemoresistance of pancreatic cancer cells by transferring LncROR via Hippo signaling. J Cancer. 2023;14:1075-87. PMCID:PMC10158512

[206] Saxena M.NOD-like receptors: master regulators of inflammation and cancer.Front Immunol2014;5:327 PMCID:PMC4095565

[207] Rehwinkel J.RIG-I-like receptors: their regulation and roles in RNA sensing.Nat Rev Immunol2020;20:537-51 PMCID:PMC7094958

[208] Motwani M,Fitzgerald KA.DNA sensing by the cGAS-STING pathway in health and disease.Nat Rev Genet2019;20:657-74

[209] Drouin M,Chiffoleau E.C-Type lectin-like receptors: head or tail in cell death immunity.Front Immunol2020;11:251 PMCID:PMC7040094

[210] Duan T,Xing C,Wang RF.Toll-like receptor signaling and its role in cell-mediated immunity.Front Immunol2022;13:812774 PMCID:PMC8927970

[211] Mielcarska MB,Toka FN.Cell surface expression of endosomal toll-like receptors-a necessity or a superfluous duplication?.Front Immunol2020;11:620972 PMCID:PMC7882679

[212] Balka KR.Understanding early TLR signaling through the myddosome.J Leukoc Biol2019;105:339-51

[213] Liu Y,Zhuang X.Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells.Am J Pathol2010;176:2490-9 PMCID:PMC2861113

[214] Chalmin F,Mignot G.Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells.J Clin Invest2010;120:457-71 PMCID:PMC2810085

[215] Bretz NP,Rupp AK.Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via Toll-like receptor signaling.J Biol Chem2013;288:36691-702 PMCID:PMC3868779

[216] Chow A,Liu L.Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB.Sci Rep2014;4:5750 PMCID:PMC4102923

[217] Li X,Zhu R,Han Q.Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NFκB-TLR signaling pathway.J Hematol Oncol2016;9:42 PMCID:PMC4836087

[218] Ding G,Qian Y.Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p.Oncotarget2015;6:29877-88 PMCID:PMC4745769

[219] Zhang X,Yuan X,Qian H.Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration.Mol Cancer2018;17:146 PMCID:PMC6174070

[220] Pucci M,Urzì O.Tumor-derived small extracellular vesicles induce pro-inflammatory cytokine expression and PD-L1 regulation in M0 macrophages via IL-6/STAT3 and TLR4 signaling pathways.Int J Mol Sci2021;22:12118 PMCID:PMC8621495

[221] Zhang Y,Zhang L,Roy S.Extracellular vesicles with exosome-like features transfer TLRs between dendritic cells.Immunohorizons2019;3:186-93 PMCID:PMC8011940

[222] Fabbri M,Calore F.MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response.Proc Natl Acad Sci U S A2012;109:E2110-6 PMCID:PMC3412003

[223] Liu Y,Han Y.Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils.Cancer Cell2016;30:243-56

[224] Torralba D,Villarroya-Beltri C.Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts.Nat Commun2018;9:2658 PMCID:PMC6037695

[225] Kitai Y,Sueyoshi T.DNA-containing exosomes derived from cancer cells treated with topotecan activate a STING-dependent pathway and reinforce antitumor immunity.J Immunol2017;198:1649-59

[226] Nabet BY,Shabason JE.Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer.Cell2017;170:352-366.e13 PMCID:PMC6611169

[227] Wei X,Pei Y.Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway.J Extracell Vesicles2022;11:e12264 PMCID:PMC9448875