The Role of Exosomes and its Cargos in Drug Resistance of Cancer

Authors

  • Yujie Xie State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Cancer Center, Sun Yat-sen University, Guangzhou 510060, China
  • Liwu Fu State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Cancer Center, Sun Yat-sen University, Guangzhou 510060, China

DOI:

https://doi.org/10.6000/1929-2279.2015.04.04.6

Keywords:

Exosomes, drug resistance, drug efflux, antibody, miRNAs, lncRNA, P-glycoprotein, EMT.

Abstract

 Chemotherapy is one of the main therapies in cancer and plays an important role in controlling tumor progression, which can offer a longer overall survival (OS) for patients. But as the accumulation of drugs used in vivo, cancer cells develop drug resistance, even multi-drug resistance (MDR), that can cause failure of the whole therapy. The similar phenomenon can be observed in vitro. There are several mechanisms of drug resistance such as drug efflux, mediated by extracellular vesicles. Exosomes, a subset of extracellular vesicles (EVs), can be secreted by many types of cells and transfer proteins, lipids, and miRNA/mRNA/DNAs between cells in vitro and in vivo. Particularly cancer cells secrete more exosomes than healthy cells and resistance cells secrete more exosomes than sensitive cells. Exosomes have function of intercellular communication and molecular transfer, both associated with tumor growth, invasion, metastasis, angiogenesis, and drug resistance. In this paper, we will review the current knowledge regarding the emerging roles of exosomes and its cargo in drug resistance.

References

Bebawy M, et al. Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells. Leukemia 2009; 23(9): 1643-9. http://dx.doi.org/10.1038/leu.2009.76

Longley DB, Johnston PG. Molecular mechanisms of drug resistance. The Journal of Pathology 2005; 205(2): 275-292. http://dx.doi.org/10.1002/path.1706

Morgan G, Ward R, Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin Oncol (R Coll Radiol) 2004; 16(8): 549-60. http://dx.doi.org/10.1016/j.clon.2004.06.007

Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev 2013; 32(3-4): 623-42. http://dx.doi.org/10.1007/s10555-013-9441-9

Li H, Yang BB. Friend or foe: the role of microRNA in chemotherapy resistance. Acta Pharmacol Sin 2013; 34(7): 870-9. http://dx.doi.org/10.1038/aps.2013.35

Holzel M, Bovier A, Tuting T. Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 2013; 13(5): 365-76. http://dx.doi.org/10.1038/nrc3498

McMillin DW, Negri JM, Mitsiades CS. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 2013; 12(3): 217-28. http://dx.doi.org/10.1038/nrd3870

Harding CV, Heuser JE, Stahl PD. Exosomes: looking back three decades and into the future. J Cell Biol 2013; 200(4): 367-71. http://dx.doi.org/10.1083/jcb.201212113

Dai S, et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 2008; 16(4): 782-90. http://dx.doi.org/10.1038/mt.2008.1

Staals RH, Pruijn GJ. The human exosome and disease. Adv Exp Med Biol 2011; 702: 132-42. http://dx.doi.org/10.1007/978-1-4419-7841-7_11

Schorey JS, Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic 2008; 9(6): 871-81. http://dx.doi.org/10.1111/j.1600-0854.2008.00734.x

Vlassov AV, et al. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 2012; 1820(7): 940-8. http://dx.doi.org/10.1016/j.bbagen.2012.03.017

Raposo G, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996; 183(3): 1161-72. http://dx.doi.org/10.1084/jem.183.3.1161

Fevrier B, et al. Exosomes: a bubble ride for prions? Traffic 2005; 6(1): 10-7. http://dx.doi.org/10.1111/j.1600-0854.2004.00247.x

Vinciguerra P, Stutz F. mRNA export: an assembly line from genes to nuclear pores. Curr Opin Cell Biol 2004; 16(3): 285-92. http://dx.doi.org/10.1016/j.ceb.2004.03.013

Gibbings DJ, et al. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 2009; 11(9): 1143-9. http://dx.doi.org/10.1038/ncb1929

Corrado C, et al. Exosome-mediated crosstalk between chronic myelogenous leukemia cells and human bone marrow stromal cells triggers an interleukin 8-dependent survival of leukemia cells. Cancer Lett 2014; 348(1-2): 71-6. http://dx.doi.org/10.1016/j.canlet.2014.03.009

Valadi H, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654-9. http://dx.doi.org/10.1038/ncb1596

Shedden K, et al. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res 2003; 63(15): 4331-7.

Corcoran C, et al. Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One 2012; 7(12): e50999. http://dx.doi.org/10.1371/journal.pone.0050999

Corcoran C, et al. Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One 2012; 7(12): e50999. http://dx.doi.org/10.1371/journal.pone.0050999

Lv MM, et al. Exosomes mediate drug resistance transfer in MCF-7 breast cancer cells and a probable mechanism is delivery of P-glycoprotein. Tumour Biol 2014; 35(11): 10773-9. http://dx.doi.org/10.1007/s13277-014-2377-z

Safaei R, et al. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 2005; 4(10): 1595-604. http://dx.doi.org/10.1158/1535-7163.MCT-05-0102

Chen KG, et al. Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas. Proc Natl Acad Sci U S A 2006; 103(26): 9903-7. http://dx.doi.org/10.1073/pnas.0600213103

McMillin DW, Negri JM, Mitsiades CS. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 2013; 12(3): 217-28. http://dx.doi.org/10.1038/nrd3870

Aung T, et al. Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proc Natl Acad Sci U S A 2011; 108(37): 15336-41. http://dx.doi.org/10.1073/pnas.1102855108

Pilzer D, Fishelson Z. Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. Int Immunol 2005; 17(9): 1239-48. http://dx.doi.org/10.1093/intimm/dxh300

Zhang HG, et al. A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. J Immunol 2006; 176(12): 7385-93. http://dx.doi.org/10.4049/jimmunol.176.12.7385

He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5(7): 522-31. http://dx.doi.org/10.1038/nrg1379

Mitchell PS, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008; 105(30): 10513-8. http://dx.doi.org/10.1073/pnas.0804549105

Jung T, et al. CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 2009; 11(10): 1093-105. http://dx.doi.org/10.1593/neo.09822

Skog J, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10(12): 1470-6. http://dx.doi.org/10.1038/ncb1800

Ogawa R, et al. Adipocyte-derived microvesicles contain RNA that is transported into macrophages and might be secreted into blood circulation. Biochem Biophys Res Commun 2010; 398(4): 723-9. http://dx.doi.org/10.1016/j.bbrc.2010.07.008

Zhang Y, et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 2010; 39(1): 133-44. http://dx.doi.org/10.1016/j.molcel.2010.06.010

Lasser C. Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors. Expert Opin Biol Ther 2012; 12 Suppl 1: S189-97. http://dx.doi.org/10.1517/14712598.2012.680018

Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol 2009; 21(4): 575-81. http://dx.doi.org/10.1016/j.ceb.2009.03.007

O'Brien K, et al. Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. Eur J Cancer 2013; 49(8): 1845-59. http://dx.doi.org/10.1016/j.ejca.2013.01.017

Chen WX, et al. Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One 2014; 9(4): e95240. http://dx.doi.org/10.1371/journal.pone.0095240

Chen WX, et al. MicroRNAs delivered by extracellular vesicles: an emerging resistance mechanism for breast cancer. Tumour Biol 2014; 35(4): 2883-92. http://dx.doi.org/10.1007/s13277-013-1417-4

Chen WX, et al. Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One 2014; 9(4): e95240. http://dx.doi.org/10.1371/journal.pone.0095240

Corcoran C, Rani S, O'Driscoll L. miR-34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression. Prostate 2014; 74(13): 1320-34. http://dx.doi.org/10.1002/pros.22848

Challagundla KB, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst 2015; 107(7). http://dx.doi.org/10.1093/jnci/djv135

Ariel I, et al. Imprinted H19 oncofetal RNA is a candidate tumour marker for hepatocellular carcinoma. Mol Pathol 1998; 51(1): 21-5. http://dx.doi.org/10.1136/mp.51.1.21

Lin R, et al. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 2007; 26(6): 851-8. http://dx.doi.org/10.1038/sj.onc.1209846

Panzitt K, et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 2007; 132(1): 330-42. http://dx.doi.org/10.1053/j.gastro.2006.08.026

Yang F, et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology 2011; 54(5): 1679-89. http://dx.doi.org/10.1002/hep.24563

Xiao X, et al. Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS One 2014; 9(2): e89534. http://dx.doi.org/10.1371/journal.pone.0089534

Qi P, Du X. The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine. Mod Pathol 2013; 26(2): 155-65. http://dx.doi.org/10.1038/modpathol.2012.160

Takahashi K, et al. Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio 2014; 4: 458-67. http://dx.doi.org/10.1016/j.fob.2014.04.007

Boyer LA, et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 2006; 441(7091): 349-53. http://dx.doi.org/10.1038/nature04733

Takahashi K, et al. Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Mol Cancer Res 2014; 12(10): 1377-87. http://dx.doi.org/10.1158/1541-7786.MCR-13-0636

Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003; 3(1): 46-54. http://dx.doi.org/10.1038/nrc968

Mita AC, et al. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res 2008; 14(16): 5000-5. http://dx.doi.org/10.1158/1078-0432.CCR-08-0746

Skog J, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10(12): 1470-6. http://dx.doi.org/10.1038/ncb1800

Valenzuela MM, et al. Exosomes Secreted from Human Cancer Cell Lines Contain Inhibitors of Apoptosis (IAP). Cancer Microenviron 2015; 8(2): 65-73. http://dx.doi.org/10.1007/s12307-015-0167-9

Munoz M, et al. Role of the MRP1/ABCC1 multidrug transporter protein in cancer. IUBMB Life 2007; 59(12): 752-7. http://dx.doi.org/10.1080/15216540701736285

Konieczna A, et al. Differential expression of ABC transporters (MDR1, MRP1, BCRP) in developing human embryos. J Mol Histol 2011; 42(6): 567-74. http://dx.doi.org/10.1007/s10735-011-9363-1

Ziemann C, et al. Reactive oxygen species participate in mdr1b mRNA and P-glycoprotein overexpression in primary rat hepatocyte cultures. Carcinogenesis 1999; 20(3): 407-14. http://dx.doi.org/10.1093/carcin/20.3.407

Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385-427. http://dx.doi.org/10.1146/annurev.bi.62.070193.002125

Szakacs G, et al. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006; 5(3): 219-34. http://dx.doi.org/10.1038/nrd1984

Gros P, Croop J, Housman D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 1986; 47(3): 371-80. http://dx.doi.org/10.1016/0092-8674(86)90594-5

Schinkel AH, et al. N-glycosylation and deletion mutants of the human MDR1 P-glycoprotein. J Biol Chem 1993; 268(10): 7474-81.

Wilkens S. Structure and mechanism of ABC transporters. F1000Prime Rep 2015; 7: 14. http://dx.doi.org/10.12703/P7-14

van Helvoort A, et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996; 87(3): 507-17. http://dx.doi.org/10.1016/S0092-8674(00)81370-7

Bebawy M, et al. Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells. Leukemia 2009; 23(9): 1643-9. http://dx.doi.org/10.1038/leu.2009.76

Jaiswal R, et al. Microparticle-associated nucleic acids mediate trait dominance in cancer. FASEB J 2012; 26(1): 420-9. http://dx.doi.org/10.1096/fj.11-186817

Pasquier J, et al. Different modalities of intercellular membrane exchanges mediate cell-to-cell p-glycoprotein transfers in MCF-7 breast cancer cells. J Biol Chem 2012; 287(10): 7374-87. http://dx.doi.org/10.1074/jbc.M111.312157

Zhu H, et al. Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol 2008; 76(5): 582-8. http://dx.doi.org/10.1016/j.bcp.2008.06.007

Zhang H, et al. Down-regulation of miR-27a might reverse multidrug resistance of esophageal squamous cell carcinoma. Dig Dis Sci 2010; 55(9): 2545-51. http://dx.doi.org/10.1007/s10620-009-1051-6

Kovalchuk O, et al. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther 2008; 7(7): 2152-9. http://dx.doi.org/10.1158/1535-7163.MCT-08-0021

Zhao X, Yang L, Hu J. Down-regulation of miR-27a might inhibit proliferation and drug resistance of gastric cancer cells. J Exp Clin Cancer Res 2011; 30: 55.

Jaiswal R, et al. Microparticle conferred microRNA profiles--implications in the transfer and dominance of cancer traits. Mol Cancer 2012; 11: 37.

Elhassan MO, Christie J, Duxbury MS. Homo sapiens systemic RNA interference-defective-1 transmembrane family member 1 (SIDT1) protein mediates contact-dependent small RNA transfer and microRNA-21-driven chemoresistance. J Biol Chem 2012; 287(8): 5267-77. http://dx.doi.org/10.1074/jbc.M111.318865

Ahmed N, et al. Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr Cancer Drug Targets 2010; 10(3): 268-78. http://dx.doi.org/10.2174/156800910791190175

Vella LJ. The emerging role of exosomes in epithelial-mesenchymal-transition in cancer. Front Oncol 2014; 4: 361.

Hakulinen J, et al. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J Cell Biochem 2008; 105(5): 1211-8. http://dx.doi.org/10.1002/jcb.21923

Mathias RA, et al. Extracellular remodelling during oncogenic Ras-induced epithelial-mesenchymal transition facilitates MDCK cell migration. J Proteome Res 2010; 9(2): 1007-19. http://dx.doi.org/10.1021/pr900907g

Chairoungdua A, et al. Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol 2010; 190(6): 1079-91. http://dx.doi.org/10.1083/jcb.201002049

Jeppesen DK, et al. Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors. Proteomics 2014; 14(6): 699-712. http://dx.doi.org/10.1002/pmic.201300452

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178-96. http://dx.doi.org/10.1038/nrm3758

Gross JC, et al. Active Wnt proteins are secreted on exosomes. Nat Cell Biol 2012; 14(10): 1036-45. http://dx.doi.org/10.1038/ncb2574

Luga V, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 2012; 151(7): 1542-56. http://dx.doi.org/10.1016/j.cell.2012.11.024

Menck K, et al. Induction and transport of Wnt 5a during macrophage-induced malignant invasion is mediated by two types of extracellular vesicles. Oncotarget 2013; 4(11): 2057-66. http://dx.doi.org/10.18632/oncotarget.1336

Aga M, et al. Exosomal HIF1alpha supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene 2014; 33(37): 4613-22. http://dx.doi.org/10.1038/onc.2014.66

Greening DW, et al. Emerging roles of exosomes during epithelial-mesenchymal transition and cancer progression. Semin Cell Dev Biol 2015; 40: 60-71. http://dx.doi.org/10.1016/j.semcdb.2015.02.008

Ji R, et al. Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer. Cell Cycle 2015; 14(15): 2473-83. http://dx.doi.org/10.1080/15384101.2015.1005530

Battke C, et al. Tumour exosomes inhibit binding of tumour-reactive antibodies to tumour cells and reduce ADCC. Cancer Immunol Immunother 2011; 60(5): 639-48. http://dx.doi.org/10.1007/s00262-011-0979-5

Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest 2011; 121(10): 3804-9. http://dx.doi.org/10.1172/JCI57099

Boelens MC, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 2014; 159(3): 499-513. http://dx.doi.org/10.1016/j.cell.2014.09.051

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2015-10-29

How to Cite

Yujie Xie, & Liwu Fu. (2015). The Role of Exosomes and its Cargos in Drug Resistance of Cancer. Journal of Cancer Research Updates, 4(4),  179–187. https://doi.org/10.6000/1929-2279.2015.04.04.6

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