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Emerging role of exosomes and exosomal microRNA in cancer: pathophysiology and clinical potential

  • Review – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Exosomes are extracellular nanometric vesicles used by cells to communicate with each other. They are responsible for many pathological conditions, including tumors by transferring regulatory biomolecules that impact target cell activity. Because of their high concentration in exosomes compared with parental cells and the rest of exosomal content, specificity to the cell of origin, and their well-organized sorting mechanism, microRNAs (miRNAs) are thought to be the most potent exosomes cargo and used by scientists to track exosomes and to detect cell activity changes and prognosis in cancer early.

Purpose

In this review, the results of studies examining the role of exosomes in cancer pathophysiology and their clinical potential are discussed in detail.

Summary of the Findings

Tumor-derived exosomes (TDEs) mediate the dynamic changes of cancer growth and invasion, including local microenvironment remodeling, distance metastasis, angiogenesis, and tumor-associated immunosuppression. They also contribute to hypoxia-induced tumor progression and cancer cell drug resistance. As a result of exosomes being present in all body fluids, it is possible to have early accessible and less-invasive diagnostic and prognostic measures by forming a table for each cancer type and its matched specific miRNAs. Under testing, available therapeutic uses of exosomes include interference of exosomes biogenesis, secretion, or uptake, and recruitment of exosomes as target-specific drug delivery vehicles, and immunostimulatory agents for both cancer patients and healthy population to avoid cancer development from the start.

Conclusion

These data suggest that exosomes and exosomal microRNA are directly related to cancer progression mechanisms, and could be used in cancer early diagnosis, prognosis, and therapy.

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Data availability

All data generated or analyzed during this study are included in this published article.

References

  • Avan A, Tavakoly Sany SB, Ghayour-Mobarhan M, Rahimi HR, Tajfard M, Ferns G (2018) Serum C-reactive protein in the prediction of cardiovascular diseases: overview of the latest clinical studies and public health practice. J Cell Physiol 233(11):8508–8525

    Article  CAS  PubMed  Google Scholar 

  • Baglio SR, Lagerweij T, Pérez-Lanzón M, Ho XD, Léveillé N, Melo SA, Cleton-Jansen AM, Jordanova ES, Roncuzzi L, Greco M, Van Eijndhoven MA (2017) Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression. Clin Cancer Res 23(14):3721–3733

    Article  CAS  PubMed  Google Scholar 

  • Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, Skog J (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2(1):1–9

    Article  CAS  Google Scholar 

  • Banks WA, Sharma P, Bullock KM, Hansen KM, Ludwig N, Whiteside TL (2020) Transport of extracellular vesicles across the blood-brain barrier: brain pharmacokinetics and effects of inflammation. Int J Mol Sci 21(12):4407

    Article  CAS  PubMed Central  Google Scholar 

  • Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, Le Chevalier T, Livartoski A, Barlesi F, Laplanche A, Ploix S (2016) Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 5(4):e1071008

    Article  PubMed  CAS  Google Scholar 

  • Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, Mazzone M (2014) Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene 33(14):1743–1754

    Article  CAS  PubMed  Google Scholar 

  • Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, Tang JH (2014) Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS ONE 9(4):e95240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, Xia H (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560(7718):382–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chowdhury R, Webber JP, Gurney M, Mason MD, Tabi Z, Clayton A (2015) Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts. Oncotarget 6(2):715

    Article  PubMed  Google Scholar 

  • Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, Morelli D, Villa A, Mina PD, Menard S, Filipazzi P (2012) Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol 227(2):658–667

    Article  CAS  PubMed  Google Scholar 

  • Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, Xiang J (2015) Pancreatic cancer exosomes initiate premetastatic niche formation in the liver. Nat Cell Biol 17(6):816–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Del Re M, Biasco E, Crucitta S, Derosa L, Rofi E, Orlandini C, Miccoli M, Galli L, Falcone A, Jenster GW, van Schaik RH (2017) The detection of androgen receptor splice variant 7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. Eur Urol 71(4):680–687

    Article  PubMed  CAS  Google Scholar 

  • Du FENG et al (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11.5:675–687

    Google Scholar 

  • Fani M, Rezayi M, Meshkat Z, Rezaee SA, Makvandi M, Abouzari-Lotf E, Ferns GA (2019) Current approaches for detection of human T-lymphotropic virus Type 1: a systematic review. J Cell Physiol 234(8):12433–12441

    Article  CAS  PubMed  Google Scholar 

  • Goldie BJ, Dun MD, Lin M, Smith ND, Verrills NM, Dayas CV, Cairns MJ (2014) Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res 42(14):9195–9208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goradel NH, Mohammadi N, Haghi-Aminjan H, Farhood B, Negahdari B, Sahebkar A (2019) Regulation of tumor angiogenesis by microRNAs: state of the art. J Cell Physiol 234(2):1099–1110

    Article  CAS  PubMed  Google Scholar 

  • Guo X, Qiu W, Wang J, Liu Q, Qian M, Wang S, Zhang Z, Gao X, Chen Z, Guo Q, Xu J (2019) Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways. Int J Cancer 144(12):3111–3126

    Article  CAS  PubMed  Google Scholar 

  • Ha D, Yang N, Nadithe V (2016) Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharmaceutica Sinica B 6(4):287–296

    Article  PubMed  PubMed Central  Google Scholar 

  • Hessvik NP, Phuyal S, Brech A, Sandvig K, Llorente A (2021) Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochimica et Biophysica Acta (BBA) 1819(11–12):1154–1163

    Google Scholar 

  • Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Mark MT, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527(7578):329–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Rao SS, Wang ZX, Cao J, Tan YJ, Luo J, Li HM, Zhang WS, Chen CY, Xie H (2018) Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function. Theranostics 8(1):169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang T, Deng CX (2019) Current progresses of exosomes as cancer diagnostic and prognostic biomarkers. Int J Biol Sci 15(1):1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ikoma M, Gantt S, Casper C, Ogata Y, Zhang Q, Basom R, Dyen MR, Rose TM, Barcy S (2018) KSHV oral shedding and plasma viremia result in significant changes in the extracellular tumorigenic miRNA expression profile in individuals infected with the malaria parasite. PLoS ONE 13(2):e0192659

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kahlert C, Kalluri R (2013) Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med 91(4):431–437

    Article  CAS  PubMed  Google Scholar 

  • Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401

    Article  CAS  PubMed  Google Scholar 

  • Kang X, Zuo Z, Hong W, Tang H, Geng W (2019) Progress of research on exosomes in the protection against ischemic brain injury. Front Neurosci 13:1149

    Article  PubMed  PubMed Central  Google Scholar 

  • Le M, Fernandez-Palomo C, McNeill FE, Seymour CB, Rainbow AJ, Mothersill CE (2017) Exosomes are released by bystander cells exposed to radiation-induced biophoton signals: reconciling the mechanisms mediating the bystander effect. PLoS ONE 12(3):e0173685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li L, Cao B, Liang X, Lu S, Luo H, Wang Z, Wang S, Jiang J, Lang J, Zhu G (2019) Microenvironmental oxygen pressure orchestrates an anti-and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene 38(15):2830–2843

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Fan L, Yu H, Zhang J, He Y, Feng D, Wang F, Li X, Liu Q, Li Y, Guo Z (2019) Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages. Hepatology 70(1):241–258

    CAS  PubMed  Google Scholar 

  • Lu Y, Chen L, Li L, Cao Y (2020) Exosomes derived from brain metastatic breast cancer cells destroy the blood-brain barrier by carrying lncRNA GS1–600G8.5. Bio Med Res Int 2020

  • Marleau AM, Chen CS, Joyce JA, Tullis RH (2012) Exosome removal as a therapeutic adjuvant in cancer. J Transl Med 10(1):1–2

    Article  CAS  Google Scholar 

  • Mashreghi M, Azarpara H, Bazaz MR, Jafari A, Masoudifar A, Mirzaei H, Jaafari MR (2018) Angiogenesis biomarkers and their targeting ligands as potential targets for tumor angiogenesis. J Cell Physiol 233(4):2949–2965

    Article  CAS  PubMed  Google Scholar 

  • McAndrews KM, Kalluri R (2019) Mechanisms associated with biogenesis of exosomes in cancer. Mol Cancer 18(1):52

    Article  PubMed  PubMed Central  Google Scholar 

  • Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM (2015) Exosome mediated communication within the tumor microenvironment. J Control Release 10(219):278–294

    Article  CAS  Google Scholar 

  • Montecalvo A, Larregina AT, Shufesky WJ, Beer Stolz D, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z, Milosevic J (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119(3):756–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pattabiraman DR, Weinberg RA (2014) Tackling the cancer stem cells—what challenges do they pose? Nat Rev Drug Discov 13(7):497–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pavlyukov MS, Yu H, Bastola S, Minata M, Shender VO, Lee Y, Zhang S, Wang J, Komarova S, Wang J, Yamaguchi S (2018) Apoptotic cell-derived extracellular vesicles promote malignancy of glioblastoma via intercellular transfer of splicing factors. Cancer Cell 34(1):119–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar CM, Nitadori-Hoshino A (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R (2019) Suppression of exosomal PD-L1 induces systemic antitumor immunity and memory. Cell 177(2):414–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rana S, Yue S, Stadel D, Zöller M (2012) Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol 44(9):1574–1584

    Article  CAS  PubMed  Google Scholar 

  • Rasouli E, Basirun WJ, Rezayi M, Shameli K, Nourmohammadi E, Khandanlou R, Izadiyan Z, Sarkarizi HK (2018) Ultrasmall superparamagnetic Fe3O4 nanoparticles: honey-based green and facile synthesis and in vitro viability assay. Int J Nanomed 13:6903

    Article  CAS  Google Scholar 

  • Rezayi M, Farjami Z, Hosseini ZS, Ebrahimi N, Abouzari-Lotf E (2018) MicroRNA-based biosensors for early detection of cancers. Curr Pharm Des 24(39):4675–4680

    Article  CAS  PubMed  Google Scholar 

  • Ruivo CF, Adem B, Silva M, Melo SA (2017) The biology of cancer exosomes: insights and new perspectives. Can Res 77(23):6480–6488

    Article  CAS  Google Scholar 

  • Saari H, Lázaro-Ibáñez E, Viitala T, Vuorimaa-Laukkanen E, Siljander P, Yliperttula M (2015) Microvesicle-and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. J Control Release 28(220):727–737

    Article  CAS  Google Scholar 

  • Sahebi R, Langari H, Fathinezhad Z, Bahari Sani Z, Avan A, Ghayour Mobarhan M, Rezayi M (2020) Exosomes: new insights into cancer mechanisms. J Cell Biochem 121(1):7–16

    Article  CAS  PubMed  Google Scholar 

  • Sany SB, Hashim R, Rezayi M, Rahman MA, Razavizadeh BB, Abouzari-lotf E, Karlen DJ (2015) Integrated ecological risk assessment of dioxin compounds. Environ Sci Pollut Res 22(15):11193–11208

    Article  CAS  Google Scholar 

  • Shepard A (2017) Vesicles of the future: exosomes and cancer research | Fulbright EndCap 2017, from https://www.youtube.com/watch?v=wcuSysYNcaI

  • Sinha S, Hoshino D, Hong NH, Kirkbride KC, Grega-Larson NE, Seiki M, Tyska MJ, Weaver AM (2016) Cortactin promotes exosome secretion by controlling branched actin dynamics. J Cell Biol 214(2):197–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sund M, Kalluri R (2009) Tumor stroma derived biomarkers in cancer. Cancer Metastasis Rev 28(1–2):177–183

    Article  PubMed  PubMed Central  Google Scholar 

  • Svensson KJ, Kucharzewska P, Christianson HC, Sköld S, Löfstedt T, Johansson MC, Mörgelin M, Bengzon J, Ruf W, Belting M (2011) Hypoxia triggers a pro-angiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci 108(32):13147–13152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tai YL, Chen KC, Hsieh JT, Shen TL (2018) Exosomes in cancer development and clinical applications. Cancer Sci 109(8):2364–2374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamkovich SN, Tutanov OS, Laktionov PP (2016) Exosomes: Generation, structure, transport, biological activity, and diagnostic application. Biochem (Moscow) Supplement Ser A 10(3):163–173

    Article  Google Scholar 

  • Tang Z, Li D, Hou S, Zhu X (2020) The cancer exosomes: clinical implications, applications and challenges. Int J Cancer 146(11):2946–2959

    Article  CAS  PubMed  Google Scholar 

  • Tian T, Zhu YL, Zhou YY, Liang GF, Wang YY, Hu FH, Xiao ZD (2014) Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J Biol Chem 289(32):22258–22267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 9(6):654–659

    Article  CAS  PubMed  Google Scholar 

  • Xiao X, Yu S, Li S, Wu J, Ma R, Cao H, Zhu Y, Feng J (2014) Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS ONE 9(2):e89534

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu S, Wang J, Ding N, Hu W, Zhang X, Wang B, Hua J, Wei W, Zhu Q (2015) Exosome-mediated microRNA transfer plays a role in radiation-induced bystander effect. RNA Biol 12(12):1355–1363

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Li S, Li L, Li M, Guo C, Yao J, Mi S (2015) Exosome and exosomal microRNA: trafficking, sorting, and function. Genom Proteom Bioinf 13(1):17–24

    Article  CAS  Google Scholar 

  • Zhao H, Yang L, Baddour J, Achreja A, Bernard V, Moss T, Marini JC, Tudawe T, Seviour EG, San Lucas FA, Alvarez H (2016) Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. elife 5:e10250

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O’Connor ST, Chin AR, Yen Y (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25(4):501–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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“Not applicable.” This review is a collection of information and a result of individual’s work and not related to any institution.

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Authors and Affiliations

  1. Mansoura Manchester Medical Program, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Mohamed Ibrahim Elewaily

  2. Internal Medicine Department, Oncology Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Alyaa R. Elsergany

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  1. Mohamed Ibrahim Elewaily
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  2. Alyaa R. Elsergany
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Both ME and AS chose the article’s title. ME collected the data, then he wrote the manuscript and created the figures. He also made the modifications as suggested. AS supervised and scientifically guided ME.

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Correspondence to Mohamed Ibrahim Elewaily.

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Elewaily, M.I., Elsergany, A.R. Emerging role of exosomes and exosomal microRNA in cancer: pathophysiology and clinical potential. J Cancer Res Clin Oncol 147, 637–648 (2021). https://doi.org/10.1007/s00432-021-03534-5

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