Skip to main content

Advertisement

SpringerLink
Log in

Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering microRNAs

  • Research Article
  • Published:
Tumor Biology

Abstract

Breast cancer (BCa) remains chemo-unresponsive by inevitable progression of resistance to first-line treatment with docetaxel (doc). Emerging studies indicate that exosomes act as mediators of intercellular communication between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development. Such modulatory effects have been related to the constant shuttle of biologically active molecules including microRNAs (miRNAs). Here, we aimed to investigate the relevance of exosome-mediated miRNA delivery in resistance transmission of BCa subpopulations. Using microarray and polymerase chain reaction, we found that exosomes from doc-resistant BCa cells (D/exo) loaded cellular miRNAs. Following D/exo transfer to the fluorescent sensitive cells (GFP-S), some miRNAs were significantly increased in recipient GFP-S. Target gene prediction and pathway analysis revealed the involvement of the top 20 most abundant miRNAs of D/exo in pathways implicated in therapy failure. Coculture assays showed that miRNA-containing D/exo increased the overall resistance of GFP-S to doc exposure. Moreover, D/exo was able to alter gene expression in GFP-S. Our results open up an intriguing possibility that drug-resistant BCa cells may spread chemoresistance to sensitive ones by releasing exosomes and that the effects could be partly attributed to the intercellular transfer of specific miRNAs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. DeSantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J Clin. 2011;61(6):409–18. doi:10.3322/caac.20134.

    Article  PubMed  Google Scholar 

  2. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27. doi:10.1146/annurev.med.53.082901.103929.

    Article  CAS  PubMed  Google Scholar 

  3. Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, et al. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol. 2012;227(2):658–67. doi:10.1002/jcp.22773.

    Article  CAS  PubMed  Google Scholar 

  4. Corcoran C, Rani S, O'Brien K, O'Neill A, Prencipe M, Sheikh R, et al. Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One. 2012;7(12):e50999. doi:10.1371/journal.pone.0050999.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Safaei R, Larson BJ, Cheng TC, Gibson MA, Otani S, Naerdemann W, 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. doi:10.1158/1535-7163.mct-05-0102.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringner M, et al. 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 A. 2013;110(18):7312–7. doi:10.1073/pnas.1220998110.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Filipazzi P, Burdek M, Villa A, Rivoltini L, Huber V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol. 2012;22(4):342–9. doi:10.1016/j.semcancer.2012.02.005.

    Article  CAS  PubMed  Google Scholar 

  9. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151(7):1542–56. doi:10.1016/j.cell.2012.11.024.

    Article  CAS  PubMed  Google Scholar 

  10. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med. 2013;91(4):431–7. doi:10.1007/s00109-013-1020-6. Berlin, Germany.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. 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. doi:10.1007/s10555-013-9441-9.

    Article  CAS  PubMed  Google Scholar 

  12. Chen WX, Zhong SL, Ji MH, Pan M, Hu Q, Lv MM, et al. MicroRNAs delivered by extracellular vesicles: an emerging resistance mechanism for breast cancer. Tumour Biol: J Int Soc Oncodev Biol Med. 2014;35(4):2883–92. doi:10.1007/s13277-013-1417-4.

    Article  CAS  Google Scholar 

  13. Chiba M, Kimura M, Asari S. Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncol Rep. 2012;28(5):1551–8. doi:10.3892/or.2012.1967.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33. doi:10.1016/j.cell.2009.01.002.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9. doi:10.1038/ncb1596.

    Article  CAS  PubMed  Google Scholar 

  16. Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288(10):7105–16. doi:10.1074/jbc.M112.410944.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Xiao X, Yu S, Li S, Wu J, Ma R, Cao H, et al. Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS One. 2014;9(2):e89534. doi:10.1371/journal.pone.0089534.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P. Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids. 2013;2:e126. doi:10.1038/mtna.2013.60.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Knaust E, Porwit-MacDonald A, Gruber A, Xu D, Peterson C. Heterogeneity of isolated mononuclear cells from patients with acute myeloid leukemia affects cellular accumulation and efflux of daunorubicin. Haematologica. 2000;85(2):124–32.

    CAS  PubMed  Google Scholar 

  20. Li WJ, Zhong SL, Wu YJ, Xu WD, Xu JJ, Tang JH, et al. Systematic expression analysis of genes related to multidrug-resistance in isogenic docetaxel- and adriamycin-resistant breast cancer cell lines. Mol Biol Rep. 2013;40(11):6143–50. doi:10.1007/s11033-013-2725-x.

    Article  CAS  PubMed  Google Scholar 

  21. Zhong S, Li W, Chen Z, Xu J, Zhao J. MiR-222 and miR-29a contribute to the drug-resistance of breast cancer cells. Gene. 2013;531(1):8–14. doi:10.1016/j.gene.2013.08.062.

    Article  CAS  PubMed  Google Scholar 

  22. Li XJ, Ji MH, Zhong SL, Zha QB, Xu JJ, Zhao JH, et al. MicroRNA-34a modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1. Arch Med Res. 2012;43(7):514–21. doi:10.1016/j.arcmed.2012.09.007.

    Article  CAS  PubMed  Google Scholar 

  23. Hu Q, Chen WX, Zhong SL, Zhang JY, Ma TF, Ji H, et al. MicroRNA-452 contributes to the docetaxel resistance of breast cancer cells. Tumour Biol: J Int Soc Oncodev Biol Med. 2014. doi:10.1007/s13277-014-1834-z.

    Google Scholar 

  24. Miot S, Gianni-Barrera R, Pelttari K, Acharya C, Mainil-Varlet P, Juelke H, et al. In vitro and in vivo validation of human and goat chondrocyte labeling by green fluorescent protein lentivirus transduction. Tissue Eng C Methods. 2010;16(1):11–21. doi:10.1089/ten.TEC.2008.0698.

    Article  CAS  Google Scholar 

  25. Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009;4(3):e4722. doi:10.1371/journal.pone.0004722.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37(5):495–500. doi:10.1038/ng1536.

    Article  CAS  PubMed  Google Scholar 

  27. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120(1):15–20. doi:10.1016/j.cell.2004.12.035.

    Article  CAS  PubMed  Google Scholar 

  28. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36(Database issue):D154–8. doi:10.1093/nar/gkm952.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. Gene Ontol Consortium Nat Genet. 2000;25(1):25–9. doi:10.1038/75556.

    CAS  Google Scholar 

  30. Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res. 2008;36(Database issue):D480–4. doi:10.1093/nar/gkm882.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Huang da W, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007;35(Web Server issue):W169–75. doi:10.1093/nar/gkm415.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Gusev Y. Computational methods for analysis of cellular functions and pathways collectively targeted by differentially expressed microRNA. Methods. 2008;44(1):61–72. doi:10.1016/j.ymeth.2007.10.005. San Diego, Calif.

    Article  CAS  PubMed  Google Scholar 

  33. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4(12):937–47. doi:10.1038/nrc1503.

    Article  CAS  PubMed  Google Scholar 

  34. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  35. Harburg GC, Hinck L. Navigating breast cancer: axon guidance molecules as breast cancer tumor suppressors and oncogenes. J Mammary Gland Biol Neoplasia. 2011;16(3):257–70. doi:10.1007/s10911-011-9225-1.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Loh YN, Hedditch EL, Baker LA, Jary E, Ward RL, Ford CE. The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer. BMC Cancer. 2013;13:174. doi:10.1186/1471-2407-13-174.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Wang SE, Xiang B, Guix M, Olivares MG, Parker J, Chung CH, et al. Transforming growth factor beta engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab. Mol Cell Biol. 2008;28(18):5605–20. doi:10.1128/mcb.00787-08.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Li X, Liu X, Xu W, Zhou P, Gao P, Jiang S, et al. c-MYC-regulated miR-23a/24-2/27a cluster promotes mammary carcinoma cell invasion and hepatic metastasis by targeting Sprouty2. J Biol Chem. 2013;288(25):18121–33. doi:10.1074/jbc.M113.478560.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Koga Y, Yasunaga M, Moriya Y, Akasu T, Fujita S, Yamamoto S, et al. Exosome can prevent RNase from degrading microRNA in feces. J Gastrointest Oncol. 2011;2(4):215–22. doi:10.3978/j.issn.2078-6891.2011.015.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009;11(9):1143–9. doi:10.1038/ncb1929.

    Article  CAS  PubMed  Google Scholar 

  41. Kosaka N, Iguchi H, Ochiya T. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010;101(10):2087–92. doi:10.1111/j.1349-7006.2010.01650.x.

    Article  CAS  PubMed  Google Scholar 

  42. Chen X, Liang H, Zhang J, Zen K, Zhang CY. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012;22(3):125–32. doi:10.1016/j.tcb.2011.12.001.

    Article  CAS  PubMed  Google Scholar 

  43. Kogure T, Lin WL, Yan IK, Braconi C, Patel T. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology. 2011;54(4):1237–48. doi:10.1002/hep.24504. Baltimore, Md.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge the funding body for supporting this work: the National Natural Science Foundation of China provided to Jin-hai Tang (81272470). We also thank Jun Zhang, Hao Ji, and Xiao-hui Zhang for their discussion and help in our manuscript.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. The Fourth Clinical School, Nanjing Medical University, Nanjing, China

    Wei-xian Chen, Meng-meng Lv & Teng-fei Ma

  2. Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China

    Wei-xian Chen, Meng-meng Lv, Lin Chen & Jin-hai Tang

  3. Department of Thoracic Surgery, Nanjing Medical University Affiliated Huai’an First People’s Hospital, Huai’an, China

    Yan-qin Cai

  4. Graduate School, Xuzhou Medical College, Xuzhou, China

    Lin Chen

  5. Center of Clinical Laboratory, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China

    Shan-liang Zhong, Teng-fei Ma & Jian-hua Zhao

Authors
  1. Wei-xian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan-qin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng-meng Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shan-liang Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Teng-fei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-hua Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jin-hai Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jian-hua Zhao or Jin-hai Tang.

Additional information

Wei-xian Chen and Yan-qin Cai contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Wx., Cai, Yq., Lv, Mm. et al. Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering microRNAs. Tumor Biol. 35, 9649–9659 (2014). https://doi.org/10.1007/s13277-014-2242-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2242-0

Keywords

Search

Navigation