The role and clinical applications of exosomes in cancer drug resistance

Abstract

Tumor-secreted exosomes are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating intercellular crosstalk and activating signaling pathways. Distinct from previous reviews, we focus intently on exosome-therapeutic resistance dynamics and summarize the new findings about the regulation of cancer treatment resistance by exosomes, shedding light on the complex processes via which these nanovesicles facilitate therapeutic refractoriness across various malignancies. Future research in exosome biology can potentially transform diagnostic paradigms and therapeutic interventions for cancer management. This review synthesizes recent insights into the exosome-driven regulation of cancer drug resistance, illuminates the sophisticated mechanisms by which these nanovesicles facilitate therapeutic refractoriness across various malignancies, and summarizes some strategies to overcome drug resistance.

Keywords

Exosome / drug resistance / implications for clinical treatment

References

[1] Siegel RL,Wagle NS.Cancer statistics, 2023.CA Cancer J Clin2023;73:17-48

[2] Kocarnik JM, Compton K, Dean FE, et al; Global Burden of Disease 2019 Cancer Collaboration. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: a systematic analysis for the global burden of disease study 2019. JAMA Oncol 2022;8:420-44. PMCID:PMC8719276

[3] Namee NM.Extracellular vesicles and anti-cancer drug resistance.Biochim Biophys Acta Rev Cancer2018;1870:123-36

[4] Dong X,Ni J.Exosomes and breast cancer drug resistance.Cell Death Dis2020;11:987 PMCID:PMC7673022

[5] Lu Z,Luo W.Exosomes in genitourinary cancers: emerging mediators of drug resistance and promising biomarkers.Int J Biol Sci2023;19:167-82 PMCID:PMC9760437

[6] Hoshino A,Shen TL.Tumour exosome integrins determine organotropic metastasis.Nature2015;527:329-35 PMCID:PMC4788391

[7] Li XJ,Tang JH.Exosomal MicroRNA MiR-1246 promotes cell proliferation, invasion and drug resistance by targeting CCNG2 in breast cancer.Cell Physiol Biochem2017;44:1741-8

[8] Kreger BT,Cerione RA.The enrichment of survivin in exosomes from breast cancer cells treated with paclitaxel promotes cell survival and chemoresistance.Cancers2016;8:111 PMCID:PMC5187509

[9] Xuan Z,Tang W.Corrigendum: TKI-resistant renal cancer secretes low-level exosomal miR-549a to induce vascular permeability and angiogenesis to promote tumor metastasis.Front Cell Dev Biol2021;9:726535 PMCID:PMC8327907

[10] Milman N,Gil Z.Exosomes and their role in tumorigenesis and anticancer drug resistance.Drug Resist Updat2019;45:1-12

[11] Li S,Dong B,Luo S.The roles of exosomes in cancer drug resistance and its therapeutic application.Clin Transl Med2020;10:e257 PMCID:PMC7752167

[12] Klibi J,Riedel A.Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells.Blood2009;113:1957-66

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

[14] Chang WH,Antonyak MA.Extracellular vesicles and their roles in cancer progression.Methods Mol Biol2021;2174:143-70 PMCID:PMC8008708

[15] Rädler J,Zickler A.Exploiting the biogenesis of extracellular vesicles for bioengineering and therapeutic cargo loading.Mol Ther2023;31:1231-50 PMCID:PMC10188647

[16] Xu M,Jin D.The biogenesis and secretion of exosomes and multivesicular bodies (MVBs): intercellular shuttles and implications in human diseases.Genes Dis2023;10:1894-907 PMCID:PMC10363595

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

[18] Di Bella MA. Overview and update on extracellular vesicles: considerations on exosomes and their application in modern medicine.Biology2022;11:804 PMCID:PMC9220244

[19] Alia Moosavian S, Hashemi M, Etemad L, Daneshmand S, Salmasi Z. Melanoma-derived exosomes: versatile extracellular vesicles for diagnosis, metastasis, immune modulation, and treatment of melanoma.Int Immunopharmacol2022;113:109320

[20] Qiao L,Huang K.Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs.Theranostics2020;10:3474-87 PMCID:PMC7069079

[21] Tang MK.Exosomes: emerging biomarkers and targets for ovarian cancer.Cancer Lett2015;367:26-33

[22] Krylova SV.The machinery of exosomes: biogenesis, release, and uptake.Int J Mol Sci2023;24:1337 PMCID:PMC9865891

[23] Shahabi A,Ansarin K.The relationship between microRNAs and Rab family GTPases in human cancers.J Cell Physiol2019;234:12341-52

[24] Yang D,Zhang H.Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics.Theranostics2020;10:3684-707 PMCID:PMC7069071

[25] Rizwan MN,Nenkov M.Tumor-derived exosomes: key players in non-small cell lung cancer metastasis and their implication for targeted therapy.Mol Carcinog2022;61:269-80

[26] Runz S,Rupp C.Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM.Gynecol Oncol2007;107:563-71

[27] Movahedpour A,Karami N.Exosomal noncoding RNAs in prostate cancer.Clin Chim Acta2022;537:127-32

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

[29] Hallal S,Grau GE,Alexander KL.Understanding the extracellular vesicle surface for clinical molecular biology.J Extracell Vesicles2022;11:e12260 PMCID:PMC9563386

[30] Golchin A,Ardeshirylajimi A.The exosomes released from different cell types and their effects in wound healing.J Cell Biochem2018;119:5043-52

[31] Haraszti RA,Sapp E.High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources.J Extracell Vesicles2016;5:32570 PMCID:PMC5116062

[32] Kugeratski FG,Lilla S.Quantitative proteomics identifies the core proteome of exosomes with syntenin-1 as the highest abundant protein and a putative universal biomarker.Nat Cell Biol2021;23:631-41 PMCID:PMC9290189

[33] Hessvik NP.Current knowledge on exosome biogenesis and release.Cell Mol Life Sci2018;75:193-208 PMCID:PMC5756260

[34] Pathan M,Chitti SV.Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles.Nucleic Acids Res2019;47:D516-9 PMCID:PMC6323905

[35] De Sousa KP, Rossi I, Abdullahi M, Ramirez MI, Stratton D, Inal JM. Isolation and characterization of extracellular vesicles and future directions in diagnosis and therapy.Wiley Interdiscip Rev Nanomed Nanobiotechnol2023;15:e1835 PMCID:PMC10078256

[36] Paskeh MDA,Mirzaei S.Emerging role of exosomes in cancer progression and tumor microenvironment remodeling.J Hematol Oncol2022;15:83 PMCID:PMC9238168

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

[38] Yang Q,Gu J.Extracellular vesicles in cancer drug resistance: roles, mechanisms, and implications.Adv Sci2022;9:e2201609 PMCID:PMC9731723

[39] Wang Y,Xie Y.Nutrient availability regulates the secretion and function of immune cell-derived extracellular vesicles through metabolic rewiring.Sci Adv2024;10:eadj1290 PMCID:PMC10866539

[40] Buzas EI.The roles of extracellular vesicles in the immune system.Nat Rev Immunol2023;23:236-50 PMCID:PMC9361922

[41] Zhou X,Wang L.The function and clinical application of extracellular vesicles in innate immune regulation.Cell Mol Immunol2020;17:323-34 PMCID:PMC7109106

[42] Vahabi M,Franczak MA.Role of exosomes in transferring chemoresistance through modulation of cancer glycolytic cell metabolism.Cytokine Growth Factor Rev2023;73:163-72

[43] Gurung S,Touramanidou L.The exosome journey: from biogenesis to uptake and intracellular signalling.Cell Commun Signal2021;19:47 PMCID:PMC8063428

[44] Wang J,Hernot S.Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells.Blood2014;124:555-66

[45] Song Z,Ma P.Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis.Life Sci2021;276:119399

[46] Wu P,Yang H,Wang C.Exosomes derived from hypoxic glioma cells reduce the sensitivity of glioma cells to temozolomide through carrying miR-106a-5p.Drug Des Devel Ther2022;16:3589-98 PMCID:PMC9556335

[47] Yin J,Zhang Z,Yan W.Exosomal transfer of miR-1238 contributes to temozolomide-resistance in glioblastoma.EBioMedicine2019;42:238-51 PMCID:PMC6491393

[48] Liu J,Tang W,Mei Y.Exosomes from tamoxifen-resistant breast cancer cells transmit drug resistance partly by delivering miR-9-5p.Cancer Cell Int2021;21:55 PMCID:PMC7809732

[49] Chen WX,Zhu B.Exosomal miR-222 from adriamycin-resistant MCF-7 breast cancer cells promote macrophages M2 polarization via PTEN/Akt to induce tumor progression.Aging2021;13:10415-30 PMCID:PMC8064228

[50] Zhou C,Ma J.Cancer-secreted exosomal miR-1468-5p promotes tumor immune escape via the immunosuppressive reprogramming of lymphatic vessels.Mol Ther2022;30:976-7 PMCID:PMC8822128

[51] Wang M,Yu S.Paclitaxel-resistant gastric cancer MGC-803 cells promote epithelial-to-mesenchymal transition and chemoresistance in paclitaxel-sensitive cells via exosomal delivery of miR-155-5p.Int J Oncol2019;54:326-38 PMCID:PMC6254863

[52] Cao S,Cai J,Wang C.Linc00852 from cisplatin-resistant gastric cancer cell-derived exosomes regulates COMMD7 to promote cisplatin resistance of recipient cells through microRNA-514a-5p.Cell Biol Toxicol2023;39:483-96

[53] Li Z,Wu P.Glioblastoma cell-derived lncRNA-containing exosomes induce microglia to produce complement C5, promoting chemotherapy resistance.Cancer Immunol Res2021;9:1383-99

[54] Chen SW,Pei X.Cancer cell-derived exosomal circUSP7 induces CD8⁺ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC.Mol Cancer2021;20:144 PMCID:PMC8576933

[55] Shen T,Shi C.Pancreatic cancer-derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK-mediated endoplasmic reticulum stress.FASEB J2020;34:8442-58

[56] Wang D,Xu F.Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2.Theranostics2021;11:2860-75 PMCID:PMC7806469

[57] Zhang PF,Huang XY.Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma.Mol Cancer2020;19:110 PMCID:PMC7320583

[58] Liu J,Zheng X.Immune suppressed tumor microenvironment by exosomes derived from gastric cancer cells via modulating immune functions.Sci Rep2020;10:14749 PMCID:PMC7479614

[59] Yin Z,Ma T.Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1.J Immunother Cancer2021;9:e001698 PMCID:PMC7818841

[60] Najafi S,Mortezaee K.Extracellular vesicle-based drug delivery in cancer immunotherapy.Drug Deliv Transl Res2023;13:2790-806 PMCID:PMC10234250

[61] Shin S,Kim CH.Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy.Nat Mater2023;22:656-65

[62] Shan G,Gu J.Downregulated exosomal microRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/β-catenin pathway and upregulating PTEN.Cell Oncol2021;44:45-59 PMCID:PMC7906940

[63] Qin X,Wang X.Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5.Genome Biol2019;20:12 PMCID:PMC6332863

[64] Fang Y,Rong Y.Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer.Exp Cell Res2019;383:111543

[65] Gao Y,Zeng C.CD63⁺ cancer-associated fibroblasts confer tamoxifen resistance to breast cancer cells through exosomal miR-22.Adv Sci2020;7:2002518 PMCID:PMC7610308

[66] Qi R,Li K.Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs.Drug Resist Updat2023;68:100960

[67] Ham IH,Hur H.Cancer-associated fibroblast-induced resistance to chemotherapy and radiotherapy in gastrointestinal cancers.Cancers2021;13:1172 PMCID:PMC7963167

[68] Deng X,Zhang X.Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells.Int J Cancer2020;146:1700-16

[69] Zhou Y,Zhuo H.Cancer-associated fibroblast exosomes promote chemoresistance to cisplatin in hepatocellular carcinoma through circZFR targeting signal transducers and activators of transcription (STAT3)/ nuclear factor -kappa B (NF-κB) pathway.Bioengineered2022;13:4786-97 PMCID:PMC8973934

[70] Kunou S,Takai M.Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma.Oncogene2021;40:3989-4003 PMCID:PMC8195743

[71] Hu JL,Lan XL.CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer.Mol Cancer2019;18:91 PMCID:PMC6503554

[72] Richards KE,Fishel ML,Littlepage LE.Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells.Oncogene2017;36:1770-8 PMCID:PMC5366272

[73] Li C,Zhu HJ.Cancer associated-fibroblast-derived exosomes in cancer progression.Mol Cancer2021;20:154 PMCID:PMC8638446

[74] Ding C,Chen X.Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma.J Exp Clin Cancer Res2021;40:164 PMCID:PMC8111743

[75] Li Q,Jin P.New insights into the potential of exosomal circular RNAs in mediating cancer chemotherapy resistance and their clinical applications.Biomed Pharmacother2024;177:117027

[76] Hon KW,Abdullah NMA,Abu N.Extracellular vesicle-derived circular RNAs confers chemoresistance in colorectal cancer.Sci Rep2019;9:16497 PMCID:PMC6848089

[77] Wang X,Yang H.Exosome-delivered circRNA promotes glycolysis to induce chemoresistance through the miR-122-PKM2 axis in colorectal cancer.Mol Oncol2020;14:539-55 PMCID:PMC7053238

[78] Xie H,Wang Y.Exosome-transmitted circVMP1 facilitates the progression and cisplatin resistance of non-small cell lung cancer by targeting miR-524-5p-METTL3/SOX2 axis.Drug Deliv2022;29:1257-71 PMCID:PMC9045767

[79] Pan Z,Li B.EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3.Mol Cancer2022;21:16 PMCID:PMC8759291

[80] Guo X,Yang DH.Exosomal circular RNAs: a chief culprit in cancer chemotherapy resistance.Drug Resist Updat2023;67:100937

[81] Lu JC,Huang XY.Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma.J Hematol Oncol2021;14:200 PMCID:PMC8627086

[82] Si W,Zheng H.The role and mechanisms of action of microRNAs in cancer drug resistance.Clin Epigenetics2019;11:25 PMCID:PMC6371621

[83] Luo L,Rousuli Y.Exosome-mediated transfer of miR-3613-5p enhances doxorubicin resistance by suppression of PTEN expression in breast cancer cells.J Oncol2022;2022:9494910 PMCID:PMC9586760

[84] Zhao Z,Gao Y.Targeted delivery of exosomal miR-484 reprograms tumor vasculature for chemotherapy sensitization.Cancer Lett2022;530:45-58

[85] Santos JC,Sarian LO,Ribeiro ML.Exosome-mediated breast cancer chemoresistance via miR-155 transfer.Sci Rep2018;8:829 PMCID:PMC5770414

[86] Zhang X,Huang C,Wang J.Doxorubicin resistance in breast cancer xenografts and cell lines can be counterweighted by microRNA-140-3p, through PD-L1 suppression.Histol Histopathol2023;38:1193-204

[87] Liang G,Ali DJ.Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer.J Nanobiotechnology2020;18:10 PMCID:PMC6950820

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

[89] Li J,Ge P.FAM225B is a prognostic lncRNA for patients with recurrent glioblastoma.Dis Markers2020;2020:8888085 PMCID:PMC7704151

[90] Cheng Z,Zhu W,Guo Z.LEF1-AS1 accelerates tumorigenesis in glioma by sponging miR-489-3p to enhance HIGD1A.Cell Death Dis2020;11:690 PMCID:PMC7442828

[91] Arun G,Spector DL.MALAT1 long non-coding RNA: functional implications.Noncoding RNA2020;6:22 PMCID:PMC7344863

[92] Wang X,Huang X.The advancing roles of exosomes in breast cancer.Front Cell Dev Biol2021;9:731062 PMCID:PMC8591197

[93] Su K,Shao Q,Zhao B.The role of a ceRNA regulatory network based on lncRNA MALAT1 site in cancer progression.Biomed Pharmacother2021;137:111389

[94] Wang X,Chen W,Li Z.The updated role of exosomal proteins in the diagnosis, prognosis, and treatment of cancer.Exp Mol Med2022;54:1390-400 PMCID:PMC9535014

[95] Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities.Nat Rev Drug Discov2013;12:347-57

[96] Li W,Zhou T.Role of exosomal proteins in cancer diagnosis.Mol Cancer2017;16:145 PMCID:PMC5576100

[97] Wu H,Liu L.Bone marrow mesenchymal stem cells-derived exosomal microRNA-193a reduces cisplatin resistance of non-small cell lung cancer cells via targeting LRRC1.Cell Death Dis2020;11:801 PMCID:PMC7519084

[98] Li MY,Dong M.Progress on pivotal role and application of exosome in lung cancer carcinogenesis, diagnosis, therapy and prognosis.Mol Cancer2021;20:22 PMCID:PMC7839206

[99] Xu J,Liang Y.CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.Signal Transduct Target Ther2020;5:298 PMCID:PMC7762756

[100] Liu M,Yuan X.Role of exosomes in the development, diagnosis, prognosis and treatment of hepatocellular carcinoma.Mol Med2023;29:136 PMCID:PMC10580543

[101] Ghasempour E,Movahed E,Doroudian M.Mesenchymal stem cell-derived exosomes as a new therapeutic strategy in the brain tumors.Stem Cell Res Ther2022;13:527 PMCID:PMC9764546

[102] Long G,Shi R,Hu Z.Circular RNAs and drug resistance in genitourinary cancers: a literature review.Cancers2022;14:866 PMCID:PMC8869870

[103] Del Re M,Crucitta S.Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide.Prostate Cancer Prostatic Dis2021;24:524-31 PMCID:PMC8134038

[104] Rahmati S,Rezaei N.The multifaceted role of extracellular vesicles (EVs) in colorectal cancer: metastasis, immune suppression, therapy resistance, and autophagy crosstalk.J Transl Med2024;22:452 PMCID:PMC11092134

[105] Yi YW.Therapeutic implications of the drug resistance conferred by extracellular vesicles derived from triple-negative breast cancer cells.Int J Mol Sci2023;24:3704 PMCID:PMC9960576

[106] Kugeratski FG.Exosomes as mediators of immune regulation and immunotherapy in cancer.FEBS J2021;288:10-35 PMCID:PMC9116040

[107] Wang X,Lu J.Exosomes and cancer - diagnostic and prognostic biomarkers and therapeutic vehicle.Oncogenesis2022;11:54 PMCID:PMC9477829

[108] Witwer KW,Bemis LT.Standardization of sample collection, isolation and analysis methods in extracellular vesicle research.J Extracell Vesicles2013;2:20360 PMCID:PMC3760646

[109] Kim MS,Zhao Y.Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells.Nanomedicine2016;12:655-64 PMCID:PMC4809755