Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance

Abstract

Hypoxia is a common phenomenon in solid tumors as the poorly organized tumor vasculature cannot fulfill the increasing oxygen demand of rapidly expanding tumors. Under hypoxia, tumor cells reshape their microenvironment to sustain survival, promote metastasis, and develop resistance to therapy. Exosomes are extracellular vesicles secreted by most eukaryotic cells, including tumor cells. They are enriched with a selective collection of nucleic acids and proteins from the originating cells to mediate cell-to-cell communication. Accumulating evidence suggests that exosomes derived from tumor cells play critical roles in modulating the tumor microenvironment (TME). Hypoxia is known to stimulate the secretion of exosomes from tumor cells, thereby promoting intercellular communication of hypoxic tumors with the surrounding stromal tissues. Exosome-mediated signaling pathways under hypoxic conditions have been reported to cause angiogenesis, invasion, metastasis, drug resistance, and immune escape. Recently, the programmed cell death ligand-1 (PD-L1) has been reported to reside as a transmembrane protein in tumor exosomes. Exosomal PD-L1 was shown to suppress T cell effector function in the TME and cause drug resistance to immune checkpoint therapy. This review provides an update about the pivotal role of tumor-derived exosomes in drug resistance to chemotherapy and immunotherapy, particularly under hypoxic conditions. Emerging strategies that target the exosomes in the hypoxic TME to enhance the antitumor efficacy are discussed.

Keywords

Hypoxia / drug resistance / exosome / tumor microenvironment / immunotherapy / non-coding RNA

References

[1] Belisario DC,Pasino M.Hypoxia dictates metabolic rewiring of tumors: implications for chemoresistance.Cells2020;9:2598 PMCID:PMC7761956

[2] Kopecka J,Perez-Ruiz E.Hypoxia as a driver of resistance to immunotherapy.Drug Resist Updat2021;59:100787

[3] Shamis SAK,Edwards J.The relationship between hypoxia-inducible factor 1α (HIF-1α) and patient survival in breast cancer: Systematic review and meta-analysis.Crit Rev Oncol Hematol2021;159:103231

[4] Jadli AS,Edalat P.Inside(sight) of tiny communicator: exosome biogenesis, secretion, and uptake.Mol Cell Biochem2020;467:77-94

[5] Braicu C,Monroig P,Berindan-Neagoe I.Exosomes as divine messengers: are they the Hermes of modern molecular oncology?.Cell Death Differ2015;22:34-45 PMCID:PMC4262777

[6] Mathivanan S,Simpson RJ.Exosomes: extracellular organelles important in intercellular communication.J Proteomics2010;73:1907-20

[7] Samanta S,Drosos N,Dawn B.Exosomes: new molecular targets of diseases.Acta Pharmacol Sin2018;39:501-13 PMCID:PMC5888687

[8] Azmi AS,Sarkar FH.Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review.Cancer Metastasis Rev2013;32:623-42 PMCID:PMC3843988

[9] Santos P.Role of Exosomal miRNAs and the tumor microenvironment in drug resistance.Cells2020;9:1450 PMCID:PMC7349227

[10] Rai A,Chen M,Ji H.Exosomes derived from human primary and metastatic colorectal cancer cells contribute to functional heterogeneity of activated fibroblasts by reprogramming their proteome.Proteomics2019;19:e1800148

[11] Yekula A,Muralidharan K,Carter BS.Extracellular vesicles in glioblastoma tumor microenvironment.Front Immunol2019;10:3137 PMCID:PMC6990128

[12] He G,Wei S.Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications.Mol Cancer2022;21:19 PMCID:PMC8762953

[13] Laplane L,Larmonier N,Bikfalvi A.The multiple layers of the tumor environment.Trends Cancer2018;4:802-9

[14] Godet I,Wu F.Detection of hypoxia in cancer models: significance, challenges, and advances.Cells2022;11:686 PMCID:PMC8869817

[15] Bosco MC,Del Bufalo D.Targeting hypoxia in tumor: a new promising therapeutic strategy.J Exp Clin Cancer Res2020;39:8 PMCID:PMC6953227

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

[17] Möller A.The evolving translational potential of small extracellular vesicles in cancer.Nat Rev Cancer2020;20:697-709

[18] Kalluri R.The biology and function of exosomes in cancer.J Clin Invest2016;126:1208-15 PMCID:PMC4811149

[19] Wang Y,Tian J.Granulocytic myeloid-derived suppressor cells promote the stemness of colorectal cancer cells through exosomal S100A9.Adv Sci (Weinh)2019;6:1901278 PMCID:PMC6755519

[20] Jung KO,Yu JH,Pratx G.Development and MPI tracking of novel hypoxia-targeted theranostic exosomes.Biomaterials2018;177:139-48 PMCID:PMC6019194

[21] Ren R,Ma C,Wang H.Colon cancer cells secrete exosomes to promote self-proliferation by shortening mitosis duration and activation of STAT3 in a hypoxic environment.Cell Biosci2019;9:62 PMCID:PMC6683569

[22] Fu M,Jiang P,Xu W.Exosomes in gastric cancer: roles, mechanisms, and applications.Mol Cancer2019;18:41 PMCID:PMC6419325

[23] Li J,Xu H,Xiong N.Hypoxic cancer-secreted exosomal miR-182-5p promotes glioblastoma angiogenesis by targeting kruppel-like factor 2 and 4.Mol Cancer Res2020;18:1218-31

[24] Matsuura Y,Eguchi H.Exosomal miR-155 derived from hepatocellular carcinoma cells under hypoxia promotes angiogenesis in endothelial cells.Dig Dis Sci2019;64:792-802

[25] Patton MC,Khan MA,Singh AP.Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival.J Cell Biochem2020;121:828-39 PMCID:PMC6878126

[26] Liu W,Rong Y.Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126.Acta Biomater2020;103:196-212

[27] Zhang W,Yao Q,Zhang H.HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells.Am J Physiol Renal Physiol2017;313:F906-13 PMCID:PMC5668579

[28] Zhu LP,Wang JY.Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction.Theranostics2018;8:6163-77 PMCID:PMC6299684

[29] Ostrowski M,Krumeich S.Rab27a and Rab27b control different steps of the exosome secretion pathway.Nat Cell Biol2010;12:19-30; sup pp 1

[30] Rocha N,van der Kant R.Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning.J Cell Biol2009;185:1209-25 PMCID:PMC2712958

[31] Dorayappan KDP,Wallbillich JJ.Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins.Oncogene2018;37:3806-21 PMCID:PMC6043362

[32] 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

[33] Willms E,Mäger I,Vader P.Extracellular vesicle heterogeneity: subpopulations, isolation techniques, and diverse functions in cancer progression.Front Immunol2018;9:738 PMCID:PMC5936763

[34] Kucharzewska P,Welch JE.Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development.Proc Natl Acad Sci U S A2013;110:7312-7 PMCID:PMC3645587

[35] Pegtel DM.Exosomes.Annu Rev Biochem2019;88:487-514

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

[37] Navarro A,Marrades RM.Exosome analysis in tumor-draining pulmonary vein identifies NSCLC patients with higher risk of relapse after curative surgery.Cancers (Basel)2019;11:249 PMCID:PMC6407158

[38] Ramteke A,Agarwal C.Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules: hypoxic-exosomes role in pca aggressiveness.Mol Carcinog2015;54:554-65

[39] Caponnetto F,Skrap M.Size-dependent cellular uptake of exosomes.Nanomedicine2017;13:1011-20

[40] Kumar A.Exosomes in hypoxia-induced remodeling of the tumor microenvironment.Cancer Letters2020;488:1-8

[41] Wang W,Jo HA,Song YS.Non-coding RNAs shuttled via exosomes reshape the hypoxic tumor microenvironment.J Hematol Oncol2020;13:67 PMCID:PMC7275461

[42] Yang W,Zhou W,Zhou X.Reciprocal regulations between miRNAs and HIF-1a in human cancers.Cell Mol Life Sci2019; 76:453-71

[43] Bruning U,Neufeld Z.MicroRNA-155 promotes resolution of hypoxia-inducible factor 1alpha activity during prolonged hypoxia.Mol Cell Biol2011;31:4087-96 PMCID:PMC3187364

[44] Fabbiano F,Gurrieri E,Notarangelo M.RNA packaging into extracellular vesicles: an orchestra of RNA-binding proteins?.J Extracell Vesicles2020;10:e12043 PMCID:PMC7769857

[45] Santangelo L,Cicchini C.The RNA-binding protein SYNCRIP is a component of the hepatocyte exosomal machinery controlling microRNA sorting.Cell Rep2016;17:799-808

[46] Han J,Ho JC.Hypoxia is a key driver of alternative splicing in human breast cancer cells.Sci Rep2017;7:4108 PMCID:PMC5481333

[47] Farina AR,Sebastiano M,Guadagni S.Hypoxia-induced alternative splicing: the 11th Hallmark of cancer.J Exp Clin Cancer Res2020;39:110 PMCID:PMC7294618

[48] Nigita G,Romano G.microRNA editing in seed region aligns with cellular changes in hypoxic conditions.Nucleic Acids Res2016;44:6298-308 PMCID:PMC4994866

[49] Lin F,Song Y.YBX-1 mediated sorting of miR-133 into hypoxia/reoxygenation-induced EPC-derived exosomes to increase fibroblast angiogenesis and MEndoT.Stem Cell Res Ther2019;10:263 PMCID:PMC6708233

[50] Qiu W,Li B.Exosomal miR-1246 from glioma patient body fluids drives the differentiation and activation of myeloid-derived suppressor cells.Mol Ther2021;29:3449-64 PMCID:PMC8636176

[51] Nallamshetty S,Loscalzo J.Hypoxia: a master regulator of microRNA biogenesis and activity.Free Radic Biol Med2013;64:20-30 PMCID:PMC3762925

[52] Choudhry H.Advances in hypoxia-inducible factor biology.Cell Metab2018;27:281-98

[53] Xia X,Ni B.Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop.Oncogene2020;39:6231-44

[54] Zeng Z,Chen Q.Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis.Oncogene2021;40:5505-17

[55] Jeppesen DK,Franklin JL.Reassessment of exosome composition.Cell2019;177:428-445.e18 PMCID:PMC6664447

[56] Moreno-Gonzalo O,Sánchez-Madrid F.Post-translational modifications of exosomal proteins.Front Immunol2014;5:383 PMCID:PMC4128227

[57] Wade BE,Ma J,Sutliff RL.Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis.Pulm Circ2018;8:2045894018788267 PMCID:PMC6146334

[58] Sato A,Shimizu A.Cell-to-cell contact-mediated regulation of tumor behavior in the tumor microenvironment.Cancer Sci2021;112:4005-12 PMCID:PMC8486192

[59] Martins ÁM,Freitas D.Glycosylation of cancer extracellular vesicles: capture strategies, functional roles and potential clinical applications.Cells2021;10:109 PMCID:PMC7827205

[60] Weinhouse GL,Farber HW.Effect of hypoxia on endothelial cell surface glycoprotein expression: modulation of glycoprotein IIIa and other specific surface glycoproteins.Exp Cell Res1993;208:465-78

[61] Cerezo-magaña M,van Kuppevelt TH,Belting M.Hypoxic induction of exosome uptake through proteoglycan-dependent endocytosis fuels the lipid droplet phenotype in glioma.Molecular Cancer Research2021;19:528-40

[62] Hannafon BN,Xu YF,Calloway CL.Metastasis-associated protein 1 (MTA1) is transferred by exosomes and contributes to the regulation of hypoxia and estrogen signaling in breast cancer cells.Cell Commun Signal2019;17:13 PMCID:PMC6379974

[63] Trajkovic K,Chiantia S.Ceramide triggers budding of exosome vesicles into multivesicular endosomes.Science2008;319:1244-7

[64] Kajimoto T,Miya S,Nakamura S.Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes.Nat Commun2013;4:2712

[65] Namba Y,Okusha Y.Depletion of lipid efflux pump ABCG1 triggers the intracellular accumulation of extracellular vesicles and reduces aggregation and tumorigenesis of metastatic cancer cells.Front Oncol2018;8:376 PMCID:PMC6191470

[66] Wei X,Wang H.Surface phosphatidylserine is responsible for the internalization on microvesicles derived from hypoxia-induced human bone marrow mesenchymal stem cells into human endothelial cells.PLoS One2016;11:e0147360 PMCID:PMC4726621

[67] Schlaepfer IR,Ramteke A.Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation.Oncotarget2015;6:22836-56 PMCID:PMC4673203

[68] Xia QS,Wu F.New role for ceramide in hypoxia and insulin resistance.World J Gastroenterol2020;26:2177-86 PMCID:PMC7235208

[69] Ban JJ,Im W.Low pH increases the yield of exosome isolation.Biochem Biophys Res Commun2015;461:76-9

[70] Gong C,Shi M.Tumor exosomes reprogrammed by low pH are efficient targeting vehicles for smart drug delivery and personalized therapy against their homologous tumor.Adv Sci (Weinh)2021;8:2002787 PMCID:PMC8132050

[71] Wang Y,Xu C.Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1.Proc Natl Acad Sci USA2012;109:4892-7 PMCID:PMC3323978

[72] Mulcahy LA,Carter DR.Routes and mechanisms of extracellular vesicle uptake.J Extracell Vesicles2014;3:24641 PMCID:PMC4122821

[73] Dang K.The role of hypoxia-induced miR-210 in cancer progression.Int J Mol Sci2015;16:6353-72 PMCID:PMC4394536

[74] King HW,Gleadle JM.Hypoxic enhancement of exosome release by breast cancer cells.BMC Cancer2012;12:421 PMCID:PMC3488584

[75] Wozniak M,Czernek L.Analysis of the miRNA profiles of melanoma exosomes derived under normoxic and hypoxic culture conditions.Anticancer Res2017;37:6779-89

[76] Sharma KD,Kore RA.Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes.PLoS One2020;15:e0234614 PMCID:PMC7351166

[77] Dong C,Wang H.Hypoxic non-small-cell lung cancer cell-derived exosomal miR-21 promotes resistance of normoxic cell to cisplatin.Onco Targets Ther2019;12:1947-56 PMCID:PMC6420102

[78] Takahashi K,Kogure T,Patel T.Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer.FEBS Open Bio2014;4:458-67 PMCID:PMC4050189

[79] Zhu X,Yin X.Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer cells to elicit a chemoresistant phenotype.J Exp Clin Cancer Res2019;38:81 PMCID:PMC6377760

[80] Bebawy M,Lee E.Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells.Leukemia2009;23:1643-9

[81] Corcoran C,O'Brien K.Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.PLoS One2012;7:e50999 PMCID:PMC3519481

[82] Wei Y,Yu S.Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells.Breast Cancer Res Treat2014;147:423-31

[83] Zhang FF,Zhao QN.Microvesicles mediate transfer of P-glycoprotein to paclitaxel-sensitive A2780 human ovarian cancer cells, conferring paclitaxel-resistance.Eur J Pharmacol2014;738:83-90

[84] Sousa D,Vasconcelos MH.Intercellular transfer of cancer drug resistance traits by extracellular vesicles.Trends Mol Med2015;21:595-608

[85] Lv MM,Chen WX.Exosomes mediate drug resistance transfer in MCF-7 breast cancer cells and a probable mechanism is delivery of P-glycoprotein.Tumour Biol2014;35:10773-9

[86] Kato T,Kameyama K.Serum exosomal P-glycoprotein is a potential marker to diagnose docetaxel resistance and select a taxoid for patients with prostate cancer.Urol Oncol2015;33:385.e15-20

[87] Torreggiani E,Perut F,Baldini N.Multimodal transfer of MDR by exosomes in human osteosarcoma.Int J Oncol2016;49:189-96

[88] Safaei R,Cheng TC.Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells.Mol Cancer Ther2005;4:1595-604

[89] Ciravolo V,Ghedini GC.Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy.J Cell Physiol2012;227:658-67

[90] Schito L.Hypoxia-dependent angiogenesis and lymphangiogenesis in cancer. In: Gilkes DM, editor. Hypoxia and cancer metastasis. Cham: Springer International Publishing; 2019. pp. 71-85.

[91] Guo Z,Yang Y.Hypoxic tumor-derived exosomal long noncoding RNA UCA1 promotes angiogenesis via miR-96-5p/AMOTL2 in pancreatic cancer.Mol Ther Nucleic Acids2020;22:179-95 PMCID:PMC7498711

[92] Hsu YL,Chang WA.Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1.Oncogene2017;36:4929-42

[93] Umezu T,Azuma K,Ohyashiki K.Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1.Blood2014;124:3748-57 PMCID:PMC4263983

[94] Fisher L.Retraction: Exosomal miR-25-3p derived from hypoxia tumor mediates IL-6 secretion and stimulates cell viability and migration in breast cancer.RSC Adv2021;11:6257

[95] Xue M,Xiang A.Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1.Mol Cancer2017;16:143 PMCID:PMC5574139

[96] Li L,Wang S.Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype.Cancer Res2016;76:1770-80

[97] Zhang X,Wang F.Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT.Mol Cancer2019;18:40 PMCID:PMC6417285

[98] Liu Y.Characteristics and significance of the pre-metastatic niche.Cancer Cell2016;30:668-81

[99] Cole K,Talmadge JE.Role of myeloid-derived suppressor cells in metastasis.Cancer Metastasis Rev2021;40:391-411

[100] Arkhypov I,Petrova V.Myeloid cell modulation by tumor-derived extracellular vesicles.Int J Mol Sci2020;21:6319 PMCID:PMC7504548

[101] Olejarz W,Żołnierzak A,Lorenc T.Tumor-derived exosomes in immunosuppression and immunotherapy.J Immunol Res2020;2020:6272498 PMCID:PMC7261328

[102] Agnoletto C,Casciano F.Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3.Oncotarget2014;5:4347-60 PMCID:PMC4147328

[103] Ye SB,Cai TT.Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma.J Pathol2016;240:329-40

[104] Wang J,Xu J.Therapeutic development of immune checkpoint inhibitors. In: Xu J, editor. Regulation of cancer immune checkpoints. Singapore: Springer; 2020. pp. 619-49.

[105] Garcia-Diaz A,Moreno BH.Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression.Cell Rep2017;19:1189-201 PMCID:PMC6420824

[106] Yang Y,Chan LC.Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth.Cell Res2018;28:862-4 PMCID:PMC6082826

[107] Fan Y,Qu J.Exosomal PD-L1 retains immunosuppressive activity and is associated with gastric cancer prognosis.Ann Surg Oncol2019;26:3745-55

[108] Theodoraki MN,Hoffmann TK,Whiteside TL.Clinical significance of PD-L1⁺ exosomes in plasma of head and neck cancer patients.Clin Cancer Res2018;24:896-905 PMCID:PMC6126905

[109] Chen G,Zhang W.Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response.Nature2018;560:382-6 PMCID:PMC6095740

[110] Lux A,Grützmann R.c-Met and PD-L1 on circulating exosomes as diagnostic and prognostic markers for pancreatic cancer.Int J Mol Sci2019;20:3305 PMCID:PMC6651266

[111] Poggio M,Pai CC.Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory.Cell2019;177:414-427.e13 PMCID:PMC6499401

[112] Ostrand-Rosenberg S.Myeloid derived-suppressor cells: their role in cancer and obesity.Curr Opin Immunol2018;51:68-75 PMCID:PMC5943167

[113] Guo X,Liu Q.Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways.Oncogene2018;37:4239-59

[114] Messmer MN,Banik D.Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy.Cancer Immunol Immunother2015;64:1-13 PMCID:PMC4282948

[115] Li L,Liang X.Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes.Oncogene2019;38:2830-43

[116] 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

[117] Pan Y,Wang X.Tumor-associated macrophages in tumor immunity.Front Immunol2020;11:583084 PMCID:PMC7751482

[118] Wang X,Zhang K.Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis.Cancer Res2018;78:4586-98

[119] Chen X,Wang X,Zhu Q.Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization.Oncol Rep2017;38:522-8

[120] Chen X,Li X,Lin Y.Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype.Cancer Lett2018;435:80-91

[121] Park JE,Tse SW.Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift.Oncogene2019;38:5158-73

[122] Alix-Panabières C.Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy.Cancer Discov2016;6:479-91

[123] Yu W,Roberts D.Exosome-based liquid biopsies in cancer: opportunities and challenges.Ann Oncol2021;32:466-77 PMCID:PMC8268076

[124] Kizaka-Kondoh S.Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxia.Cancer Sci2009;100:1366-73

[125] Bjørnetrø T,Meltzer S.An experimental strategy unveiling exosomal microRNAs 486-5p, 181a-5p and 30d-5p from hypoxic tumour cells as circulating indicators of high-risk rectal cancer.J Extracell Vesicles2019;8:1567219 PMCID:PMC6352936

[126] He J,Wang W.Exosomal targeting and its potential clinical application.Drug Deliv Transl Res2021;

[127] Zhou X,Yao Q.Exosome production and its regulation of EGFR during wound healing in renal tubular cells.Am J Physiol Renal Physiol2017;312:F963-70 PMCID:PMC5495889

[128] Bobrie A,Reyal F.Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression.Cancer Res2012;72:4920-30

[129] Xie X,Zhou Y.Eliminating blood oncogenic exosomes into the small intestine with aptamer-functionalized nanoparticles.Nat Commun2019;10:5476 PMCID:PMC6889386

[130] Jiang Y,Wang K,Man X.Hypoxia enhances the production and antitumor effect of exosomes derived from natural killer cells.Ann Transl Med2021;9:473 PMCID:PMC8039676

[131] Bunggulawa EJ,Yin T.Recent advancements in the use of exosomes as drug delivery systems.J Nanobiotechnology2018;16:81 PMCID:PMC6190562

[132] Zhuang X,Grizzle W.Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain.Mol Ther2011;19:1769-79 PMCID:PMC3188748

[133] Aryani A.Exosomes as a nanodelivery system: a key to the future of neuromedicine?.Mol Neurobiol2016;53:818-34 PMCID:PMC4752585

[134] Jiang XC.Exosomes as novel bio-carriers for gene and drug delivery.Int J Pharm2017;521:167-75

[135] Alvarez-Erviti L,Yin H,Lakhal S.Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.Nat Biotechnol2011;29:341-5

[136] Coccè V,Brini AT.In vitro anticancer activity of extracellular vesicles (EVs) secreted by gingival mesenchymal stromal cells primed with paclitaxel.Pharmaceutics2019;11:61 PMCID:PMC6409699

[137] Huang Z,Li Y,Feng Y.Exosomes derived from hypoxic colorectal cancer cells transfer Wnt4 to normoxic cells to elicit a prometastatic phenotype.Int J Biol Sci2018;14:2094-102 PMCID:PMC6299371

[138] Kore RA,Jenkins SV.Hypoxia-derived exosomes induce putative altered pathways in biosynthesis and ion regulatory channels in glioblastoma cells.Biochem Biophys Rep2018;14:104-13 PMCID:PMC5986551

[139] Shan Y,Shi S.Hypoxia-induced matrix metalloproteinase-13 expression in exosomes from nasopharyngeal carcinoma enhances metastases.Cell Death Dis2018;9:382 PMCID:PMC5841433

[140] Aga M,Raffa S.Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes.Oncogene2014;33:4613-22 PMCID:PMC4162459

[141] Panigrahi GK,Peak TC.Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells.Sci Rep2018;8:3853 PMCID:PMC5832762