Skip to main content

Advertisement

SpringerLink
Log in

The roles and implications of exosomes in sarcoma

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Better diagnostic biomarkers and therapeutic options are still necessary for patients with sarcomas due to the current limitations of diagnosis and treatment. Exosomes are small extracellular membrane vesicles that are released by various cells and are found in most body fluids. Tumor-derived exosomes have been proven to mediate tumorigenesis, intercellular communication, microenvironment modulation, and metastasis in different cancers, including in sarcomas. Recently, exosomes have been considered as potential biomarkers for sarcoma diagnosis and prognosis, and as possible targets for sarcoma therapy. Moreover, due to their specific cell tropism and bioavailability, exosomes can also be engineered as vehicles for drug delivery. In this review, we discuss recent advances in the roles of tumor-derived exosomes in sarcoma and their potential clinical applications.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Riggi, N., et al. (2007). Sarcomas: genetics, signalling, and cellular origins. Part 1: the fellowship of TET. Journal of Pathology, 213(1), 4–20.

    Article  CAS  PubMed  Google Scholar 

  2. Harwood, J. L., et al. (2015). Targeted chemotherapy in bone and soft-tissue sarcoma. The Orthopedic Clinics of North America, 46(4), 587–608.

    Article  PubMed  Google Scholar 

  3. Hiniker, S. M., & Donaldson, S. S. (2015). Recent advances in understanding and managing rhabdomyosarcoma. F1000Prime Rep, 7, 59.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bielack, S. S., et al. (2009). Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients. Journal of Clinical Oncology, 27(4), 557–565.

    Article  PubMed  Google Scholar 

  5. Benjamin, R.S., et al. (2015). Chemotherapy for bone sarcomas in adults: the MD Anderson experience. American Society of Clinical Oncology Educational Book, p. e656-60.

  6. Yakkioui, Y., et al. (2014). Chordoma: the entity. Biochimica et Biophysica Acta, 1846(2), 655–669.

    CAS  PubMed  Google Scholar 

  7. Johnstone, R. M., et al. (1987). Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). Journal of Biological Chemistry, 262(19), 9412–9420.

    CAS  PubMed  Google Scholar 

  8. Rabinowits, G., et al. (2009). Exosomal microRNA: a diagnostic marker for lung cancer. Clinical Lung Cancer, 10(1), 42–46.

    Article  CAS  PubMed  Google Scholar 

  9. Silva, J., et al. (2012). Analysis of exosome release and its prognostic value in human colorectal cancer. Genes, Chromosomes & Cancer, 51(4), 409–418.

    Article  CAS  Google Scholar 

  10. Melo, S. A., et al. (2015). Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature, 523(7559), 177–182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Melo, S. A., et al. (2014). Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell, 26(5), 707–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zomer, A., et al. (2015). In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell, 161(5), 1046–1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ye, S. B., et al. (2014). Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget, 5(14), 5439–5452.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kim, M. S., et al. (2016). Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine, 12(3), 655–664.

    CAS  PubMed  Google Scholar 

  15. Rivoltini, L., et al. (2016). TNF-related apoptosis-inducing ligand (TRAIL)-armed exosomes deliver pro-apoptotic signals to tumor site. Clinical Cancer Research.

  16. Raposo, G., & Stoorvogel, W. (2013). Extracellular vesicles: exosomes, microvesicles, and friends. Journal of Cell Biology, 200(4), 373–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cocucci, E., & Meldolesi, J. (2015). Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends in Cell Biology, 25(6), 364–372.

    Article  CAS  PubMed  Google Scholar 

  18. Minciacchi, V. R., Freeman, M. R., & Di Vizio, D. (2015). Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Seminars in Cell and Developmental Biology, 40, 41–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. van der Pol, E., et al. (2012). Classification, functions, and clinical relevance of extracellular vesicles. Pharmacological Reviews, 64(3), 676–705.

    Article  PubMed  Google Scholar 

  20. Mathivanan, S., et al. (2012). ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Research, 40(Database issue), D1241–D1244.

    Article  CAS  PubMed  Google Scholar 

  21. Baietti, M. F., et al. (2012). Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nature Cell Biology, 14(7), 677–685.

    Article  CAS  PubMed  Google Scholar 

  22. Muralidharan-Chari, V., et al. (2009). ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Current Biology, 19(22), 1875–1885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Akers, J. C., et al. (2013). Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. Journal of Neuro-Oncology, 113(1), 1–11.

    Article  PubMed  Google Scholar 

  24. Turiak, L., et al. (2011). Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice. Journal of Proteomics, 74(10), 2025–2033.

    Article  CAS  PubMed  Google Scholar 

  25. Minciacchi, V. R., et al. (2015). Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles. Oncotarget, 6(13), 11327–11341.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Di Vizio, D., et al. (2012). Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. American Journal of Pathology, 181(5), 1573–1584.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ma, L., et al. (2015). Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Research, 25(1), 24–38.

    Article  CAS  PubMed  Google Scholar 

  28. Wright, P. K., et al. (2014). 17beta-estradiol regulates giant vesicle formation via estrogen receptor-alpha in human breast cancer cells. Oncotarget, 5(10), 3055–3065.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Colombo, M., Raposo, G., & Thery, C. (2014). Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annual Review of Cell and Developmental Biology, 30, 255–289.

    Article  CAS  PubMed  Google Scholar 

  30. Kowal, J., Tkach, M., & Thery, C. (2014). Biogenesis and secretion of exosomes. Current Opinion in Cell Biology, 29, 116–125.

    Article  CAS  PubMed  Google Scholar 

  31. Kruger, S., et al. (2014). Molecular characterization of exosome-like vesicles from breast cancer cells. BMC Cancer, 14, 44.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Thakur, B. K., et al. (2014). Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Research, 24(6), 766–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Takahashi, K., et al. (2014). Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio, 4, 458–467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gusachenko, O. N., Zenkova, M. A., & Vlassov, V. V. (2013). Nucleic acids in exosomes: disease markers and intercellular communication molecules. Biochemistry (Mosc), 78(1), 1–7.

    Article  CAS  Google Scholar 

  35. Gross, J. C., et al. (2012). Active Wnt proteins are secreted on exosomes. Nature Cell Biology, 14(10), 1036–1045.

    Article  CAS  PubMed  Google Scholar 

  36. Tsunemi, T., Hamada, K., & Krainc, D. (2014). ATP13A2/PARK9 regulates secretion of exosomes and alpha-synuclein. Journal of Neuroscience, 34(46), 15281–15287.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wei, J. X., et al. (2015). Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology, 61(4), 1284–1294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Savina, A., et al. (2003). Exosome release is regulated by a calcium-dependent mechanism in K562 cells. Journal of Biological Chemistry, 278(22), 20083–20090.

    Article  CAS  PubMed  Google Scholar 

  39. Li, J., et al. (2014). Beta-elemene against human lung cancer via up-regulation of P53 protein expression to promote the release of exosome. Lung Cancer, 86(2), 144–150.

    Article  PubMed  Google Scholar 

  40. Thompson, C. A., et al. (2013). Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. Journal of Biological Chemistry, 288(14), 10093–10099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tian, T., et al. (2010). Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. Journal of Cellular Biochemistry, 111(2), 488–496.

    Article  CAS  PubMed  Google Scholar 

  42. Feng, D., et al. (2010). Cellular internalization of exosomes occurs through phagocytosis. Traffic, 11(5), 675–687.

    Article  CAS  PubMed  Google Scholar 

  43. Escrevente, C., et al. (2011). Interaction and uptake of exosomes by ovarian cancer cells. BMC Cancer, 11, 108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Szatanek, R., et al. (2015). Isolation of extracellular vesicles: determining the correct approach (review). International Journal of Molecular Medicine, 36(1), 11–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Xu, R., et al. (2016). Extracellular vesicle isolation and characterization: toward clinical application. Journal of Clinical Investigation, 126(4), 1152–1162.

    Article  PubMed  Google Scholar 

  46. Abramowicz, A., Widlak P., Pietrowska, M. (2016). Proteomic analysis of exosomal cargo: the challenge of high purity vesicle isolation. Molecular Biosystems.

  47. Batrakova, E. V., & Kim, M. S. (2015). Using exosomes, naturally-equipped nanocarriers, for drug delivery. Journal of Controlled Release, 219, 396–405.

    Article  CAS  PubMed  Google Scholar 

  48. Zeringer, E., et al. (2015). Strategies for isolation of exosomes. Cold Spring Harbor Protocols, 2015(4), 319–323.

    Article  PubMed  Google Scholar 

  49. Ko, J., Carpenter, E., & Issadore, D. (2016). Detection and isolation of circulating exosomes and microvesicles for cancer monitoring and diagnostics using micro-/nano-based devices. Analyst, 141(2), 450–460.

    Article  CAS  PubMed  Google Scholar 

  50. Erdbrugger, U., & Lannigan, J. (2016). Analytical challenges of extracellular vesicle detection: a comparison of different techniques. Cytometry. Part A, 89(2), 123–134.

    Article  Google Scholar 

  51. Pope, S. M. & Lasser, C. (2013). Toxoplasma gondii infection of fibroblasts causes the production of exosome-like vesicles containing a unique array of mRNA and miRNA transcripts compared to serum starvation. Journal of Extracellular Vesicles, 2.

  52. Jorgensen, M. M., Baek, R., & Varming, K. (2015). Potentials and capabilities of the extracellular vesicle (EV) array. Journal of Extracellular Vesicles, 4, 26048.

    Article  PubMed  Google Scholar 

  53. Vlassov, A. V., et al. (2012). Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochimica et Biophysica Acta, 1820(7), 940–948.

    Article  CAS  PubMed  Google Scholar 

  54. Liang, B., et al. (2013). Characterization and proteomic analysis of ovarian cancer-derived exosomes. Journal of Proteomics, 80, 171–182.

    Article  CAS  PubMed  Google Scholar 

  55. Shimbo, K., et al. (2014). Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration. Biochemical and Biophysical Research Communications, 445(2), 381–387.

    Article  CAS  PubMed  Google Scholar 

  56. Ventura, S., et al. (2015). CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-kappaB signaling. Oncogene.

  57. Zeelenberg, I. S., et al. (2008). Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. Cancer Research, 68(4), 1228–1235.

    Article  CAS  PubMed  Google Scholar 

  58. Zeelenberg, I. S., et al. (2011). Antigen localization controls T cell-mediated tumor immunity. The Journal of Immunology, 187(3), 1281–1288.

    Article  CAS  PubMed  Google Scholar 

  59. Toda, Y., et al. (2015). Effective internalization of U251-MG-secreted exosomes into cancer cells and characterization of their lipid components. Biochemical and Biophysical Research Communications, 456(3), 768–773.

    Article  CAS  PubMed  Google Scholar 

  60. Mao, L., et al. (2016). Enterovirus 71 transmission by exosomes establishes a productive infection in human neuroblastoma cells. Virus Genes, 52(2), 189–194.

    Article  CAS  PubMed  Google Scholar 

  61. Atay, S., et al. (2014). Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proceedings of the National Academy of Sciences of the United States of America, 111(2), 711–716.

    Article  CAS  PubMed  Google Scholar 

  62. Tsuno, H., et al. (2016). Effects of methotrexate and salazosulfapyridine on protein profiles of exosomes derived from a human synovial sarcoma cell line of SW982. Proteomics Clinical Applications, 10(2), 164–171.

    Article  CAS  PubMed  Google Scholar 

  63. Sommer, G., et al. (2003). Gastrointestinal stromal tumors in a mouse model by targeted mutation of the kit receptor tyrosine kinase. Proceedings of the National Academy of Sciences of the United States of America, 100(11), 6706–6711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rubin, B. P., et al. (2005). A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E. Cancer Research, 65(15), 6631–6639.

    Article  CAS  PubMed  Google Scholar 

  65. Saleem, S. N., & Abdel-Mageed, A. B. (2015). Tumor-derived exosomes in oncogenic reprogramming and cancer progression. Cellular and Molecular Life Sciences, 72(1), 1–10.

    Article  CAS  PubMed  Google Scholar 

  66. Endo-Munoz, L., et al. (2015). Progression of osteosarcoma from a non-metastatic to a metastatic phenotype is causally associated with activation of an autocrine and paracrine uPA Axis. PLoS One, 10(8), e0133592.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hakulinen, J., et al. (2008). Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. Journal of Cellular Biochemistry, 105(5), 1211–1218.

    Article  CAS  PubMed  Google Scholar 

  68. Machado, E., et al. (2015). Regulated lysosomal exocytosis mediates cancer progression. Science Advances, 1(11), e1500603.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Miller, I. V., et al. (2013). First identification of Ewing’s sarcoma-derived extracellular vesicles and exploration of their biological and potential diagnostic implications. Biology of the Cell, 105(7), 289–303.

    Article  CAS  PubMed  Google Scholar 

  70. Remacle, A., Murphy, G., & Roghi, C. (2003). Membrane type I-matrix metalloproteinase (MT1-MMP) is internalised by two different pathways and is recycled to the cell surface. Journal of Cell Science, 116(Pt 19), 3905–3916.

    Article  CAS  PubMed  Google Scholar 

  71. Thery, C., Zitvogel, L., & Amigorena, S. (2002). Exosomes: composition, biogenesis and function. Nature Reviews Immunology, 2(8), 569–579.

    CAS  PubMed  Google Scholar 

  72. Taylor, D. D., & Gercel-Taylor, C. (2008). MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecologic Oncology, 110(1), 13–21.

    Article  CAS  PubMed  Google Scholar 

  73. Liao, J., et al. (2016). Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer. International Journal of Oncology, 48(6), 2567–2579.

    PubMed  Google Scholar 

  74. Meng, X., et al. (2016). Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget, 7(13), 16923–16935.

    PubMed  PubMed Central  Google Scholar 

  75. Munagala, R., Aqil, F., Gupta, R.C. (2016). Exosomal miRNAs as biomarkers of recurrent lung cancer. Tumour Biology.

  76. Berrondo, C., et al. (2016). Expression of the long non-coding RNA HOTAIR correlates with disease progression in bladder cancer and is contained in bladder cancer patient urinary exosomes. PLoS One, 11(1), e0147236.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ruiz-Martinez, M., et al. (2016). YKT6 expression, exosome release, and survival in non-small cell lung cancer. Oncotarget.

  78. Rodriguez, M., et al. (2015). Exosomes enriched in stemness/metastatic-related mRNAS promote oncogenic potential in breast cancer. Oncotarget, 6(38), 40575–40587.

    PubMed  PubMed Central  Google Scholar 

  79. van den Boorn, J. G., et al. (2013). Exosomes as nucleic acid nanocarriers. Advanced Drug Delivery Reviews, 65(3), 331–335.

    Article  PubMed  Google Scholar 

  80. Hood, J. L., San, R. S., & Wickline, S. A. (2011). Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Research, 71(11), 3792–3801.

    Article  CAS  PubMed  Google Scholar 

  81. Alvarez-Erviti, L., et al. (2011). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology, 29(4), 341–345.

    Article  CAS  PubMed  Google Scholar 

  82. Sun, D., et al. (2010). A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular Therapy, 18(9), 1606–1614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhuang, X., et al. (2011). Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Molecular Therapy, 19(10), 1769–1779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wahlgren, J., et al. (2012). Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Research, 40(17), e130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Katsuda, T., et al. (2013). The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics, 13(10-11), 1637–1653.

    Article  CAS  PubMed  Google Scholar 

  86. Fang, Y., et al. (2015). Expression and clinical significance of cyclooxygenase-2 and microRNA-143 in osteosarcoma. Experimental and Therapeutic Medicine, 9(6), 2374–2378.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhou, J., et al. (2015). microRNA-143 is associated with the survival of ALDH1+CD133+ osteosarcoma cells and the chemoresistance of osteosarcoma. Experimental Biology and Medicine (Maywood, N.J.), 240(7), 867–875.

    Article  CAS  Google Scholar 

  88. Arroyo, J. D., et al. (2011). Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proceedings of the National Academy of Sciences of the United States of America, 108(12), 5003–5008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported, in part, by the Gattegno and Wechsler funds, the Kenneth Stanton Fund, and the Jennifer Hunter Yates Foundation. Dr. Duan is supported, in part, by a grant from Sarcoma Foundation of America (SFA) and a grant from National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA151452-01.

Author information

Authors and Affiliations

  1. Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA, 02114, USA

    Li Min, Jacson Shen, Francis Hornicek & Zhenfeng Duan

  2. Department of Orthopedics, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, China

    Li Min & Chongqi Tu

Authors
  1. Li Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacson Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chongqi Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francis Hornicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhenfeng Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenfeng Duan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Min, L., Shen, J., Tu, C. et al. The roles and implications of exosomes in sarcoma. Cancer Metastasis Rev 35, 377–390 (2016). https://doi.org/10.1007/s10555-016-9630-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-016-9630-4

Keywords

Search

Navigation