Skip to main content

Advertisement

SpringerLink
Log in

Cancer-derived extracellular vesicles: the ‘soil conditioner’ in breast cancer metastasis?

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

It has been recognized that cancer-associated mortality is more often a result of the disrupted physiological functions in multiple organs following metastatic dissemination of cancer cells, rather than the presence and growth of the primary tumor. Despite advances in our understanding of the events leading to cancer initiation, growth, and acquisition of invasive properties, we are still unable to effectively treat metastatic disease. It is now being accepted that the secretion of extracellular vesicles, such as exosomes from cancer cells, has a profound impact on the initiation and propagation of metastatic breast cancer. These cancer-secreted vesicles differ from other means of cellular communication due to their capability of bulk delivery and organotropism. Here, we provide an overview of the role of extracellular vesicles in breast cancer metastasis and discuss key areas that may facilitate our understanding of metastatic breast cancer to guide our efforts towards providing better therapies.

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.

Similar content being viewed by others

References

  1. Villarroya-Beltri, C., Baixauli, F., et al. (2014). Sorting it out: regulation of exosome loading. Seminars in Cancer Biology , 28, 3–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hoshino, A., Costa-Silva, B., et al. (2015). Tumour exosome integrins determine organotropic metastasis. Nature , 527(7578), 329–335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Harris, D. A., Patel, S. H., et al. (2015). Exosomes released from breast cancer carcinomas stimulate cell movement. PloS One , 10(3), e0117495.

    Article  PubMed  PubMed Central  Google Scholar 

  4. McCready, J., Sims, J. D., et al. (2010). Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer , 10, 294.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Melo, S. A., Sugimoto, H., 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 

  6. O'Brien, K., Rani, S., et al. (2013). Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. European Journal of Cancer , 49(8), 1845–1859.

    Article  PubMed  Google Scholar 

  7. Singh, R., Pochampally, R., et al. (2014). Exosome-mediated transfer of miR-10b promotes cell invasion in breast cancer. Molecular Cancer , 13, 256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Le, M. T., Hamar, P., et al. (2014). miR-200-containing extracellular vesicles promote breast cancer cell metastasis. The Journal of Clinical Investigation , 124(12), 5109–5128.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Smith, Z. J., Lee, C., et al. (2015). Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content. J Extracell Vesicles , 4, 28533.

    Article  PubMed  Google Scholar 

  10. Su, J. (2015). Label-free single molecule detection using Microtoroid optical resonators. Journal of Visualized Experiments , 106, e53180.

    Google Scholar 

  11. Tauro, B. J., Greening, D. W., et al. (2013a). Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids. Molecular & Cellular Proteomics , 12(3), 587–598.

    Article  CAS  Google Scholar 

  12. Willms, E., Johansson, H. J., et al. (2016). Cells release subpopulations of exosomes with distinct molecular and biological properties. Scientific Reports , 6, 22519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Koumangoye, R. B., Sakwe, A. M., et al. (2011). Detachment of breast tumor cells induces rapid secretion of exosomes which subsequently mediate cellular adhesion and spreading. PloS One , 6(9), e24234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sung, B. H., Ketova, T., et al. (2015). Directional cell movement through tissues is controlled by exosome secretion. Nature Communications , 6, 7164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hoshino, D., Kirkbride, K. C., et al. (2013). Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Reports , 5(5), 1159–1168.

    Article  CAS  PubMed  Google Scholar 

  16. Purushothaman, A., Bandari, S. K., et al. (2016). Fibronectin on the surface of myeloma cell-derived exosomes mediates exosome-cell interactions. The Journal of Biological Chemistry , 291(4), 1652–1663.

    Article  CAS  PubMed  Google Scholar 

  17. Cho, J. A., Park, H., et al. (2012). Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. International Journal of Oncology , 40(1), 130–138.

    CAS  PubMed  Google Scholar 

  18. Luga, V., Zhang, L., et al. (2012). Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell , 151(7), 1542–1556.

    Article  CAS  PubMed  Google Scholar 

  19. Dutta, S., Warshall, C., et al. (2014). Interactions between exosomes from breast cancer cells and primary mammary epithelial cells leads to generation of reactive oxygen species which induce DNA damage response, stabilization of p53 and autophagy in epithelial cells. PloS One , 9(5), e97580.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yang, M., Chen, J., et al. (2011). Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Molecular Cancer , 10, 117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Seubert, B., Grunwald, B., et al. (2015). Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology , 61(1), 238–248.

    Article  CAS  PubMed  Google Scholar 

  22. Skog, J., Wurdinger, T., et al. (2008). Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biology , 10(12), 1470–1476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jung, K. K., Liu, X. W., et al. (2006). Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. The EMBO Journal , 25(17), 3934–3942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhou, W., Fong, M. Y., et al. (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 

  25. Tominaga, N., Kosaka, N., et al. (2015). Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nature Communications , 6, 6716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fong, M. Y., Zhou, W., et al. (2015). Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nature Cell Biology , 17(2), 183–194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang, L., Zhang, S., et al. (2015). Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature , 527(7576), 100–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xiang, X., Poliakov, A., et al. (2009). Induction of myeloid-derived suppressor cells by tumor exosomes. International Journal of Cancer , 124(11), 2621–2633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chow, A., Zhou, W., et al. (2014). Macrophage immunomodulation by breast cancer-derived exosomes requires toll-like receptor 2-mediated activation of NF-kappaB. Scientific Reports , 4, 5750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yu, S., Liu, C., et al. (2007). Tumor exosomes inhibit differentiation of bone marrow dendritic cells. Journal of Immunology , 178(11), 6867–6875.

    Article  CAS  Google Scholar 

  31. Clayton, A., Al-Taei, S., et al. (2011). Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. Journal of Immunology , 187(2), 676–683.

    Article  CAS  Google Scholar 

  32. Liu, C., Yu, S., et al. (2006). Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. Journal of Immunology , 176(3), 1375–1385.

    Article  CAS  Google Scholar 

  33. Kosaka, N., Iguchi, H., et al. (2013). Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. The Journal of Biological Chemistry , 288(15), 10849–10859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cogolludo, A., Moreno, L., et al. (2009). Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction. Cardiovascular Research , 82(2), 296–302.

    Article  CAS  PubMed  Google Scholar 

  35. King, H. W., Michael, M. Z., et al. (2012). Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer , 12, 421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wilson, W. R., & Hay, M. P. (2011). Targeting hypoxia in cancer therapy. Nature Reviews. Cancer , 11(6), 393–410.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao, H., Yang, L., et al. (2016). Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife , 5, e10250.

    PubMed  PubMed Central  Google Scholar 

  38. Wang, T., Gilkes, D. M., et al. (2014). Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proceedings of the National Academy of Sciences of the United States of America , 111(31), E3234–E3242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Parolini, I., Federici, C., et al. (2009). Microenvironmental pH is a key factor for exosome traffic in tumor cells. The Journal of Biological Chemistry , 284(49), 34211–34222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ban, J. J., Lee, M., et al. (2015). Low pH increases the yield of exosome isolation. Biochemical and Biophysical Research Communications , 461(1), 76–79.

    Article  CAS  PubMed  Google Scholar 

  41. Ostrowski, M., Carmo, N. B., et al. (2010). Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature Cell Biology , 12(1), 19–30 sup pp 11-13.

    Article  CAS  PubMed  Google Scholar 

  42. Bobrie, A., Krumeich, S., et al. (2012). Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Research , 72(19), 4920–4930.

    Article  CAS  PubMed  Google Scholar 

  43. Hendrix, A., Sormunen, R., et al. (2013). Vacuolar H+ ATPase expression and activity is required for Rab27B-dependent invasive growth and metastasis of breast cancer. International Journal of Cancer , 133(4), 843–854.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang, J. X., Huang, X. X., et al. (2012). Overexpression of the secretory small GTPase Rab27B in human breast cancer correlates closely with lymph node metastasis and predicts poor prognosis. Journal of Translational Medicine , 10, 242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tauro, B. J., Mathias, R. A., et al. (2013b). Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK)cell-derived exosomal proteins following epithelial-mesenchymal transition. Molecular & Cellular Proteomics , 12(8), 2148–2159.

  46. Garnier, D., Magnus, N., et al. (2012). Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor. The Journal of Biological Chemistry , 287(52), 43565–43572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gopal, S. K., Greening, D. W., et al. (2016). Oncogenic epithelial cell-derived exosomes containing Rac1 and PAK2 induce angiogenesis in recipient endothelial cells. Oncotarget , 7, 19709–19722.

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hendrix, A., Maynard, D., et al. (2010). Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. Journal of the National Cancer Institute , 102(12), 866–880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Peinado, H., Aleckovic, M., et al. (2012). Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine , 18(6), 883–891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Admyre, C., Johansson, S. M., et al. (2007). Exosomes with immune modulatory features are present in human breast milk. Journal of Immunology , 179(3), 1969–1978.

    Article  CAS  Google Scholar 

  52. Bissell, M. J., & Hines, W. C. (2011). Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nature Medicine , 17(3), 320–329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lim, P. K., Bliss, S. A., et al. (2011). Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Research , 71(5), 1550–1560.

    Article  CAS  PubMed  Google Scholar 

  54. Ono, M., Kosaka, N., et al. (2014). Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Science Signaling , 7(332), ra63.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We apologize to the authors of those excellent studies we are not able to include in this review due to the space limit. This work was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) grants R01CA166020 (SEW) and R01CA163586 (SEW), California Breast Cancer Research Program grant 20IB-0118 (SEW), and Breast Cancer Research Foundation-AACR grant 12-60-26-WANG (SEW).

Author information

Authors and Affiliations

  1. Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Andrew R. Chin & Shizhen Emily Wang

  2. City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, CA, 91010, USA

    Andrew R. Chin

Authors
  1. Andrew R. Chin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shizhen Emily Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shizhen Emily Wang.

Ethics declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chin, A.R., Wang, S.E. Cancer-derived extracellular vesicles: the ‘soil conditioner’ in breast cancer metastasis?. Cancer Metastasis Rev 35, 669–676 (2016). https://doi.org/10.1007/s10555-016-9639-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-016-9639-8

Keywords

Search

Navigation