Skip to main content

Advertisement

Log in

Exosomes as a storehouse of tissue remodeling proteases and mediators of cancer progression

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

Abstract

Rapidly increasing scientific reports of exosomes and their biological effects have improved our understanding of their cellular sources and their cell-to-cell communication. These nano-sized vesicles act as potent carriers of regulatory bio-macromolecules and can induce regulatory functions by delivering them from its source to recipient cells. The details of their communication network are less understood. Recent studies have shown that apart from delivering its cargo to the cells, it can directly act on extracellular matrix (ECM) proteins and growth factors and can induce various remodeling events. More importantly, exosomes carry many surface-bound proteases, which can cleave different ECM proteins and carbohydrates and can shed cell surface receptors. These local extracellular events can modulate signaling cascades, which consequently influences the whole tissue and organ. This review aims to highlight the critical roles of exosomal proteases and their mechanistic insights within the cellular and extracellular environment.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Nawaz, M., et al. (2018). Extracellular Vesicles and Matrix Remodeling Enzymes: The Emerging Roles in Extracellular Matrix Remodeling, Progression of Diseases and Tissue Repair. Cells, 7(10), 167.

    Article  CAS  PubMed Central  Google Scholar 

  3. Li, S. P., Lin, Z. X., Jiang, X. Y., & Yu, X. Y. (2018). Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools. Acta Pharmacologica Sinica, 39(4), 542–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Elsherbini, A., & Bieberich, E. (2018). Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy (Vol. 140). Elsevier Ltd.

  5. Williams, C., et al. (2018). Glycosylation of extracellular vesicles: current knowledge, tools and clinical perspectives. Journal of Extracellular Vesicles, 7(1).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Williams, C., et al. (2019). Assessing the role of surface glycans of extracellular vesicles on cellular uptake. Scientific Reports, 9(1), 11920.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9(6), 654–659.

    Article  CAS  PubMed  Google Scholar 

  8. Q. Liu et al., “Donor dendritic cell–derived exosomes promote allograft-targeting immune response,” vol. 126, no. 8, pp. 2805–2820, 2016.

  9. Fabbri, M., Paone, A., Calore, F., Galli, R., Croce, C. M., & Mediators, C. C. (2013). A new role for microRNAs, as ligands of Toll-like receptors Muller. RNA Biology, 10(2, no. February), 169–174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thakur, B. K., Zhang, H., Becker, A., Matei, I., Huang, Y., Costa-Silva, B., Zheng, Y., Hoshino, A., Brazier, H., Xiang, J., Williams, C., Rodriguez-Barrueco, R., Silva, J. M., Zhang, W., Hearn, S., Elemento, O., Paknejad, N., Manova-Todorova, K., Welte, K., Bromberg, J., Peinado, H., & Lyden, D. (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 

  11. Kalluri, R., & Lebleu, V. S. (2016). Discovery of double-stranded genomic DNA in circulating exosomes. Cold Spring Harbor Symposia on Quantitative Biology, 81(1), 275–280.

    Article  PubMed  Google Scholar 

  12. Dourado, M. R., et al. (2019). Extracellular vesicles derived from cancer-associated fibroblasts induce the migration and invasion of oral squamous cell carcinoma. Journal of Extracellular Vesicles, 8(1).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hamam, D., Abdouh, M., Gao, Z. H., Arena, V., Arena, M., & Arena, G. O. (2016). Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients. Journal of Experimental & Clinical Cancer Research, 35(1), 1–12.

    Article  CAS  Google Scholar 

  14. Minciacchi, V. R., et al. Extracellular Vesicles in Cancer: Exosomes, Microvesicles and the Emerging Role of Large Oncosomes. Seminars in Cell & Developmental Biology, 40, 41–51.

    Article  CAS  Google Scholar 

  15. McKelvey, K. J., Powell, K. L., Ashton, A. W., Morris, J. M., & McCracken, S. A. (2015). Exosomes: Mechanisms of uptake. Journal of Circulating Biomarkers, 4, 1–9.

    Article  CAS  Google Scholar 

  16. Gonda, A., Kabagwira, J., Senthil, G. N., & Wall, N. R. (2019). Internalization of exosomes through receptor-mediated endocytosis. Molecular Cancer Research, 17(2), 337–347.

    Article  CAS  PubMed  Google Scholar 

  17. Maas, S. L. N., Breakefield, X. O., & Weaver, A. M. (2017). Extracellular vesicles: Unique intercellular delivery vehicles. Trends in Cell Biology, 27(3), 172–188.

    Article  CAS  PubMed  Google Scholar 

  18. Duijvesz, D., et al. (2013). Proteomic profiling of exosomes leads to the identification of novel biomarkers for prostate cancer. PLoS One, 8(12), 1–10.

    Article  CAS  Google Scholar 

  19. Huang, T., & Deng, C. X. (2019). Current progresses of exosomes as cancer diagnostic and prognostic biomarkers. International Journal of Biological Sciences, 15(1), 1–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Shimoda, M., & Khokha, R. (2017). Metalloproteinases in extracellular vesicles. Biochimica et Biophysica Acta, Molecular Cell Research, 1864(11), 1989–2000.

    Article  CAS  PubMed  Google Scholar 

  21. Shimoda, M., & Khokha, R. (2013). Proteolytic factors in exosomes. Proteomics, 13(10–11), 1624–1636.

    Article  CAS  PubMed  Google Scholar 

  22. Das, A., Monteiro, M., Barai, A., Kumar, S., & Sen, S. (2017). MMP proteolytic activity regulates cancer invasiveness by modulating integrins. Scientific Reports, 7(1), 1–13.

    Article  CAS  Google Scholar 

  23. Das, S. S. A., Kapoor, A., Mehta, G. D., & Ghosh, S. K. (2013). Extracellular Matrix Density Regulates Extracellular Proteolysis via Modulation of Cellular Contractility. Journal of Carcinogenesis and Mutagenesis, S13.

  24. Kapoor, A., Barai, A., Thakur, B., Das, A., Patwardhan, S. R., Monteiro, M., Gaikwad, S., Bukhari, A. B., Mogha, P., Majumder, A., de, A., Ray, P., & Sen, S. (2018). Soft drug-resistant ovarian cancer cells migrate via two distinct mechanisms utilizing myosin II-based contractility. Biochimica et Biophysica Acta, Molecular Cell Research, 1865(2), 392–405.

    Article  CAS  PubMed  Google Scholar 

  25. A. Haage and I. C. Schneider, “Cellular contractility and extracellular matrix stiffness regulate matrix metalloproteinase activity in pancreatic cancer cells,” pp. 1–11, 2014.

  26. Gong, Y., Chippada-Venkata, U. D., & Oh, W. K. (2014). Roles of matrix metalloproteinases and their natural inhibitors in prostate cancer progression. Cancers (Basel), 6(3), 1298–1327.

    Article  CAS  Google Scholar 

  27. Jiao, Y., et al. (2012). Matrix metalloproteinase-2 promotes αvβ3 integrin-mediated adhesion and migration of human melanoma cells by cleaving fibronectin. PLoS One, 7(7), e41591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ginestra, A., Monea, S., Seghezzi, G., Dolo, V., Nagase, H., Mignatti, P., & Vittorelli, M. L. (1997). Urokinase plasminogen activator and gelatinases are associated with membrane vesicles shed by human HT1080 fibrosarcoma cells. The Journal of Biological Chemistry, 272(27), 17216–17222.

    Article  CAS  PubMed  Google Scholar 

  29. Sung, B. H., & Weaver, A. M. (2017). Exosome secretion promotes chemotaxis of cancer cells. Cell Adhesion & Migration, 11(2), 187–195.

    Article  CAS  Google Scholar 

  30. Dolo, V., et al. (1998). Selective localization of matrix metalloproteinase 9, β 1 integrins, and human lymphocyte antigen class I molecules on membrane vesicles shed by 8701-BC breast carcinoma cells. Cancer Research, 58(19), 4468–4474.

    CAS  PubMed  Google Scholar 

  31. van der Vorst, E. P. C., de Jong, R. J., & Donners, M. M. P. C. (2018). Message in a Microbottle: Modulation of Vascular Inflammation and Atherosclerosis by Extracellular Vesicles. Frontiers in Cardiovascular Medicine, 5(January), 1–8.

    Google Scholar 

  32. Li, H., Qiu, Z., Li, F., & Wang, C. (2017). The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis. Oncology Letters, 14(5), 5865–5870.

    PubMed  PubMed Central  Google Scholar 

  33. 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 & Developmental Biology, 40, 41–51.

    Article  CAS  Google Scholar 

  34. Runz, S., Keller, S., Rupp, C., Stoeck, A., Issa, Y., Koensgen, D., Mustea, A., Sehouli, J., Kristiansen, G., & Altevogt, P. (2007). Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. Gynecologic Oncology, 107(3), 563–571.

    Article  CAS  PubMed  Google Scholar 

  35. Han, K. Y., Dugas-Ford, J., Seiki, M., Chang, J. H., & Azar, D. T. (2015). Evidence for the involvement of MMP14 in MMP2 processing and recruitment in exosomes of corneal fibroblasts. Investigative Ophthalmology and Visual Science, 56(9), 5323–5329.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hakulinen, J., Sankkila, L., Sugiyama, N., Lehti, K., & Keski-Oja, J. (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 

  37. Meng, W., Hao, Y., He, C., Li, L., & Zhu, G. (2019). Exosome-orchestrated hypoxic tumor microenvironment. Molecular Cancer, 18(1), 1–14.

    Article  Google Scholar 

  38. Sung, B. H., Ketova, T., Hoshino, D., Zijlstra, A., & Weaver, A. M. (2015). Directional cell movement through tissues is controlled by exosome secretion. Nature Communications, 6(May), 1–14.

    Google Scholar 

  39. Shan, Y., et al. (2018). Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases. Cell Death & Disease, 9(3).

  40. Groth, E., Pruessmeyer, J., Babendreyer, A., Schumacher, J., Pasqualon, T., Dreymueller, D., Higashiyama, S., Lorenzen, I., Grötzinger, J., Cataldo, D., & Ludwig, A. (2016). Stimulated release and functional activity of surface expressed metalloproteinase ADAM17 in exosomes. Biochimica et Biophysica Acta, Molecular Cell Research, 1863(11), 2795–2808.

    Article  CAS  Google Scholar 

  41. Stoeck, A., Keller, S., Riedle, S., Sanderson, M. P., Runz, S., le Naour, F., Gutwein, P., Ludwig, A., Rubinstein, E., & Altevogt, P. (2006). A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. The Biochemical Journal, 393(3), 609–618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wanger, T. M., Dewitt, S., Collins, A., Maitland, N. J., Poghosyan, Z., & Knäuper, V. (2015). Differential regulation of TROP2 release by PKC isoforms through vesicles and ADAM17. Cellular Signalling, 27(7), 1325–1335.

    Article  CAS  PubMed  Google Scholar 

  43. Zaman, S., Jadid, H., Denson, A. C., & Gray, J. E. (2019). Targeting trop-2 in solid tumors: Future prospects. OncoTargets and Therapy, 12, 1781–1790.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tugutova, E. A., Tamkovich, S. N., Patysheva, M. R., Afanas’ev, S. G., Tsydenova, A. A., Grigor’eva, A. E., Kolegova, E. S., Kondakova, I. V., & Yunusova, N. V. (2019). Relation between tetraspanin- associated and tetraspanin- non- associated exosomal proteases and metabolic syndrome in colorectal cancer patients. Asian Pacific Journal of Cancer Prevention, 20(3), 809–815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shimoda, M., Principe, S., Jackson, H. W., Luga, V., Fang, H., Molyneux, S. D., Shao, Y. W., Aiken, A., Waterhouse, P. D., Karamboulas, C., Hess, F. M., Ohtsuka, T., Okada, Y., Ailles, L., Ludwig, A., Wrana, J. L., Kislinger, T., & Khokha, R. (2014). Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nature Cell Biology, 16(9), 889–901.

    Article  CAS  PubMed  Google Scholar 

  46. Hansen, H. P., et al. (2016). CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro. Oncotarget, 7(21), 30523–30535.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Tauro, B. J., Mathias, R. A., Greening, D. W., Gopal, S. K., Ji, H., Kapp, E. A., Coleman, B. M., Hill, A. F., Kusebauch, U., Hallows, J. L., Shteynberg, D., Moritz, R. L., Zhu, H. J., & Simpson, R. J. (2013). Oncogenic H-Ras reprograms madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Molecular & Cellular Proteomics, 12(8), 2148–2159.

    Article  CAS  Google Scholar 

  48. Yoneyama, T., Gorry, M., Sobo-Vujanovic, A., Lin, Y., Vujanovic, L., Gaither-Davis, A., Moss, M. L., Miller, M. A., Griffith, L. G., Lauffenburger, D. A., Stabile, L. P., Herman, J., & Vujanovic, N. L. (2018). ADAM10 sheddase activity is a potential lung-cancer biomarker. Journal of Cancer, 9(14), 2559–2570.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Yang, M., Li, Y., Chilukuri, K., Brady, O. A., Boulos, M. I., Kappes, J. C., & Galileo, D. S. (2011). L1 stimulation of human glioma cell motility correlates with FAK activation. Journal of Neuro-Oncology, 105(1), 27–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tamkovich, S. N., Yunusova, N. V., Tugutova, E., Somov, A. K., Proskura, K. V., Kolomiets, L. A., Stakheyeva, M. N., Grigor’eva, A. E., Laktionov, P. P., & Kondakova, I. V. (2019). Protease cargo in circulating exosomes of breast cancer and ovarian cancer patients. Asian Pacific Journal of Cancer Prevention, 20(1), 255–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lee, H. D., Koo, B. H., Kim, Y. H., Jeon, O. H., & Kim, D. S. (2012). Exosome release of ADAM15 and the functional implications of human macrophage-derived ADAM15 exosomes. The FASEB Journal, 26(7), 3084–3095.

    Article  CAS  PubMed  Google Scholar 

  52. Webber, J., Stone, T. C., Katilius, E., Smith, B. C., Gordon, B., Mason, M. D., Tabi, Z., Brewis, I. A., & Clayton, A. (2014). Proteomics analysis of cancer exosomes using a novel modified aptamer-based array (somascantm) platform. Molecular & Cellular Proteomics, 13(4), 1050–1064.

    Article  CAS  Google Scholar 

  53. Kato, T., et al. (2014). Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Research & Therapy, 16(4), 1–11.

    Article  Google Scholar 

  54. Rana, S., Malinowska, K., & Zöller, M. (2013). Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia (United States), 15(3), 281–295.

    Article  CAS  Google Scholar 

  55. McAtee, C. O., et al. (2019). Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling. Matrix Biology, 78–79, 165–179.

    Article  PubMed  CAS  Google Scholar 

  56. Hong, Y., et al. (2018). Exosome as a vehicle for delivery of membrane protein therapeutics, PH20, for enhanced tumor penetration and antitumor efficacy. Advanced Functional Materials, 28(5), 1–9.

    Article  CAS  Google Scholar 

  57. Genschmer, K. R., et al. (2019). Activated PMN Exosomes: Pathogenic Entities Causing Matrix Destruction and Disease in the Lung. Cell, 176(1–2), 113–126.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bulloj, A., Leal, M. C., Xu, H., Castaño, E. M., & Morelli, L. (2010). Insulin-degrading enzyme sorting in exosomes: A secretory pathway for a key brain amyloid-β degrading protease. Journal of Alzheimer's Disease, 19(1), 79–95.

    Article  PubMed  CAS  Google Scholar 

  59. Sanderson, R. D., Bandari, S. K., & Vlodavsky, I. (2019). Proteases and glycosidases on the surface of exosomes: Newly discovered mechanisms for extracellular remodeling. Matrix Biology, 75–76, 160–169.

    Article  PubMed  CAS  Google Scholar 

  60. Thompson, C. A., Purushothaman, A., Ramani, V. C., Vlodavsky, I., & Sanderson, R. D. (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 

  61. Murayama, T., Kataoka, H., Koita, H., Nabeshima, K., & Koono, M. (1991). Glycocalyceal bodies in a human rectal carcinoma cell line and their interstitial collagenolytic activities. Virchows Archiv. B, Cell Pathology Including Molecular Pathology, 60(1), 263–270.

    Article  CAS  PubMed  Google Scholar 

  62. Harris, D. A., Patel, S. H., Gucek, M., Hendrix, A., Westbroek, W., & Taraska, J. W. (2015). Exosomes released from breast cancer carcinomas stimulate cell movement. PLoS One, 10(3), 1–18.

    CAS  Google Scholar 

  63. Cocucci, E., Racchetti, G., & Meldolesi, J. (2009). Shedding microvesicles: Artefacts no more. Trends in Cell Biology, 19(2), 43–51.

    Article  CAS  PubMed  Google Scholar 

  64. Whiteside, T. L. (2016). Tumor-Derived Exosomes and Their Role in Cancer Progression (Vol. 74, 1st ed.). Elsevier Inc..

  65. Edwards, D. R., Handsley, M. M., & Pennington, C. J. (2009). The ADAM metalloproteinases. Molecular Aspects of Medicine, 29(5), 258–289.

    Article  CAS  Google Scholar 

  66. Wetzel, S., Seipold, L., & Saftig, P. (2017). The metalloproteinase ADAM10: A useful therapeutic target? Biochimica et Biophysica Acta, Molecular Cell Research, 1864(11), 2071–2081.

    Article  CAS  PubMed  Google Scholar 

  67. Levin, M., Udi, Y., Solomonov, I., & Sagi, I. (2017). Next generation matrix metalloproteinase inhibitors — Novel strategies bring new prospects. Biochimica et Biophysica Acta, Molecular Cell Research, 1864(11), 1927–1939.

    Article  CAS  PubMed  Google Scholar 

  68. Thathiah, A., Blobel, C. P., & Carson, D. D. (2003). Tumor necrosis factor-α converting enzyme/ADAM 17 mediates MUC1 shedding. The Journal of Biological Chemistry, 278(5), 3386–3394.

    Article  CAS  PubMed  Google Scholar 

  69. Gooz, M. (2010). ADAM-17: The enzyme that does it all. Critical Reviews in Biochemistry and Molecular Biology, 45(2), 146–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mishra, H. K., Ma, J., & Walcheck, B. (2017). Ectodomain shedding by ADAM17: Its ole in neutrophil recruitment and the Impairment of this process during sepsis. Frontiers in Cellular and Infection Microbiology, 7(APR), 1–10.

    Google Scholar 

  71. Lambrecht, B. N., Vanderkerken, M., & Hammad, H. (2018). The emerging role of ADAM metalloproteinases in immunity. Nature Reviews. Immunology, 18(12), 745–758.

    Article  CAS  PubMed  Google Scholar 

  72. Chalaris, A., Adam, N., Sina, C., Rosenstiel, P., Lehmann-Koch, J., Schirmacher, P., Hartmann, D., Cichy, J., Gavrilova, O., Schreiber, S., Jostock, T., Matthews, V., Häsler, R., Becker, C., Neurath, M. F., Reiß, K., Saftig, P., Scheller, J., & Rose-John, S. (2010). Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice. The Journal of Experimental Medicine, 207(8), 1617–1624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hartmann, D. (2002). The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Human Molecular Genetics, 11(21), 2615–2624.

    Article  CAS  PubMed  Google Scholar 

  74. Purow, B. (2012). Notch signaling in embryology and Cancer. Advances in Experimental Medicine and Biology, 727, 174–315.

    Article  Google Scholar 

  75. Mullooly, M., McGowan, P. M., Kennedy, S. A., Madden, S. F., Crown, J., O' Donovan, N., & Duffy, M. J. (2015). ADAM10: A new player in breast cancer progression? British Journal of Cancer, 113(6), 945–951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, B. X., et al. (2011). Effects of RNA interference-mediated gene silencing of JMJD2A on human breast cancer cell line MDA-MB-231 in vitro. Journal of Experimental & Clinical Cancer Research, 30(1), 1–9.

    Article  CAS  Google Scholar 

  77. Feldinger, K., Generali, D., Kramer-Marek, G., Gijsen, M., Ng, T. B., Wong, J. H., Strina, C., Cappelletti, M., Andreis, D., Li, J. L., Bridges, E., Turley, H., Leek, R., Roxanis, I., Capala, J., Murphy, G., Harris, A. L., & Kong, A. (2014). ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer. Oncotarget, 5(16), 6633–6646.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wozniak, J., & Ludwig, A. (2018). Novel role of APP cleavage by ADAM10 for breast cancer metastasis. EBioMedicine, 38, 5–6.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Duffy, M. J., et al. (2011). The ADAMs family of proteases: New biomarkers and therapeutic targets for cancer? Clinical Proteomics, 8(1), 1–13.

    Article  CAS  Google Scholar 

  80. “The ADAMTS metalloproteinases,” Biochem. J., vol. 27, pp. 15–27, 2011.

  81. Cal, S., & López-Otín, C. (2015). ADAMTS proteases and cancer. Matrix Biology, 44–46, 77–85.

    Article  PubMed  CAS  Google Scholar 

  82. Kelwick, R., Desanlis, I., Wheeler, G. N., & Edwards, D. R. (2015). The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family. Genome Biology, 16(1).

  83. Mead, T. J., du, Y., Nelson, C. M., Gueye, N. A., Drazba, J., Dancevic, C. M., Vankemmelbeke, M., Buttle, D. J., & Apte, S. S. (2018). ADAMTS9-regulated Pericellular matrix dynamics governs focal adhesion-dependent smooth muscle differentiation. Cell Reports, 23(2), 485–498.

    Article  CAS  PubMed  Google Scholar 

  84. El-Safory, N. S., Fazary, A. E., & Lee, C. K. (2010). Hyaluronidases, a group of glycosidases: Current and future perspectives. Carbohydrate Polymers, 81(2), 165–181.

    Article  CAS  Google Scholar 

  85. McAtee, C. O., Barycki, J. J., & Simpson, M. A. (2014). Emerging roles for hyaluronidase in cancer metastasis and therapy. Advances in Cancer Research, 123(402), 1–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Josefsson, A., Adamo, H., Hammarsten, P., Granfors, T., Stattin, P., Egevad, L., Laurent, A. E., Wikström, P., & Bergh, A. (2011). Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome. The American Journal of Pathology, 179(4), 1961–1968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tan, J. X., et al. (2011). Upregulation of HYAL1 expression in breast cancer promoted tumor cell proliferation, migration, invasion and angiogenesis. PLoS One, 6(7).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kikuchi, S., Yoshioka, Y., Prieto-Vila, M., & Ochiya, T. (2019). Involvement of extracellular vesicles in vascular-related functions in cancer progression and metastasis. International Journal of Molecular Sciences, 20(10), 1–17.

    Article  Google Scholar 

  89. Shao, C., et al. (2018). Role of hypoxia-induced exosomes in tumor biology. Molecular Cancer, 17(1), 1–8.

    Article  CAS  Google Scholar 

  90. Lee, J. K., et al. (2013). Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One, (8, 12).

  91. Gopal, S. K., Greening, D. W., Hanssen, E. G., Zhu, H. J., Simpson, R. J., & Mathias, R. A. (2016). Oncogenic epithelial cell-derived exosomes containing Rac1 and PAK2 induce angiogenesis in recipient endothelial cells. Oncotarget, 7(15), 19709–19722.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Poggio, M., et al. (2019). Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory. Cell, 177(2), 414–427.e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zeng, Z., et al. (2018). Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nature Communications, 9(1).

  94. Tang, M. K. S., et al. (2018). Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface. Nature Communications, 9(1), 1–15.

    Article  CAS  Google Scholar 

  95. Mao, Y., Keller, E. T., Garfield, D. H., Shen, K., & Wang, J. (2013). Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Reviews, 32(1–2), 303–315.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Ludwig, N., & Whiteside, T. L. (2018). Potential roles of tumor-derived exosomes in angiogenesis. Expert Opinion on Therapeutic Targets, 22(5), 409–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Paggetti, J., Haderk, F., Seiffert, M., Janji, B., Distler, U., Ammerlaan, W., Kim, Y. J., Adam, J., Lichter, P., Solary, E., Berchem, G., & Moussay, E. (2015). Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood, 126(9), 1106–1117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Corrado, C., Saieva, L., Raimondo, S., Santoro, A., De Leo, G., & Alessandro, R. (2016). Chronic myelogenous leukaemia exosomes modulate bone marrow microenvironment through activation of epidermal growth factor receptor. Journal of Cellular and Molecular Medicine, 20(10), 1829–1839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Javidi-Sharifi, N., et al. (2019). Fgf2-fgfr1 signaling regulates release of leukemia-protective exosomes from bone marrow stromal cells. Elife, 8, 1–23.

    Google Scholar 

  100. Purushothaman, A., Bandari, S. K., Liu, J., Mobley, J. A., Brown, E. A., & Sanderson, R. D. (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 

  101. Yang, L., & Zhang, Y. (2017). Tumor-associated macrophages: from basic research to clinical application. Journal of Hematology & Oncology, 10(1), 58.

    Article  CAS  Google Scholar 

  102. Zhang, W., Zhang, J., Cheng, L., Ni, H., You, B., Shan, Y., Bao, L., Wu, D., Zhang, T., Yue, H., & Chen, J. (2018). A disintegrin and metalloprotease 10-containing exosomes derived from nasal polyps promote angiogenesis and vascular permeability. Molecular Medicine Reports, 17(4), 5921–5927.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen, W., Xiao, M., Zhang, J., & Chen, W. (2018). M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma. Journal of Experimental & Clinical Cancer Research, 37(1), 1–15.

    Article  CAS  Google Scholar 

  104. Plebanek, M. P., et al. (2017). Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nature Communications, 8(1).

  105. Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., Reinhart-King, C. A., Margulies, S. S., Dembo, M., Boettiger, D., Hammer, D. A., & Weaver, V. M. (2005). Tensional homeostasis and the malignant phenotype. Cancer Cell, 8(3), 241–254.

    Article  CAS  PubMed  Google Scholar 

  106. Lu, P., Weaver, V. M., & Werb, Z. (Feb. 2012). The extracellular matrix: A dynamic niche in cancer progression. The Journal of Cell Biology, 196(4), 395–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kumar, S., Das, A., & Sen, S. (2018). Multicompartment cell-based modeling of confined migration: Regulation by cell intrinsic and extrinsic factors. Molecular Biology of the Cell, 29(13), 1599–1610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Das, A., Barai, A., Monteiro, M., Kumar, S., & Sen, S. (2019). Nuclear softening is essential for protease-independent migration. Matrix Biology, 82, 4–19.

    Article  CAS  PubMed  Google Scholar 

  109. Petrova, V., Annicchiarico-Petruzzelli, M., Melino, G., & Amelio, I. (2018). The hypoxic tumour microenvironment. Oncogenesis, 7(1).

  110. de Jong, O. G., van Balkom, B. W. M., Gremmels, H., & Verhaar, M. C. (2016). Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2. Journal of Cellular and Molecular Medicine, 20(2), 342–350.

    Article  PubMed  CAS  Google Scholar 

  111. Li, R., et al. (2019). Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis. Molecular Cancer, 18(1), 1–19.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hoshino, D., Kirkbride, K. C., Costello, K., Clark, E. S., Sinha, S., Grega-Larson, N., Tyska, M. J., & Weaver, A. M. (2013). Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Reports, 5(5), 1159–1168.

    Article  CAS  PubMed  Google Scholar 

  113. Fu, M., Gu, J., Jiang, P., Qian, H., Xu, W., & Zhang, X. (2019). Exosomes in gastric cancer: Roles, mechanisms, and applications. Molecular Cancer, 18(1), 1–12.

    Article  Google Scholar 

  114. Zhang, W., Gu, J., Chen, J., Zhang, P., Ji, R., Qian, H., Xu, W., & Zhang, X. (2017). Interaction with neutrophils promotes gastric cancer cell migration and invasion by inducing epithelial-mesenchymal transition. Oncology Reports, 38(5), 2959–2966.

    Article  CAS  PubMed  Google Scholar 

  115. Chen, L., et al. (2018). Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA. Nature Communications, 9(1).

  116. Fedele, C., Singh, A., Zerlanko, B. J., Iozzo, R. V., & Languino, L. R. (2015). The alphavbeta6 integrin is transferred Intercellularly via exosomes. The Journal of Biological Chemistry, 290(8), 4545–4551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Helmink, B. A., Khan, M. A. W., Hermann, A., Gopalakrishnan, V., & Wargo, J. A. (2019). The microbiome, cancer, and cancer therapy. Nature Medicine, 25(3), 377–388.

    Article  CAS  PubMed  Google Scholar 

  118. Urbaniak, C., Gloor, G. B., Brackstone, M., Scott, L., Tangney, M., & Reida, G. (2016). The microbiota of breast tissue and its association with breast cancer. Applied and Environmental Microbiology, 82(16), 5039–5048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wei, M. Y., et al. (2019). The microbiota and microbiome in pancreatic cancer: More influential than expected. Molecular Cancer, 18(1), 1–15.

    Article  CAS  Google Scholar 

  120. L. T. Geller et al., “Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine Leore T. Geller,1* Michal Barzily-Rokni,2* Tal Danino,3† Oliver H. Jonas,4,5 Noam Shental,6 Deborah Nejman,1 Nancy Gavert,1 Yaara Zwang,1 Zachary ,” vol. 1160, no. September, pp. 1156–1160, 2017.

  121. Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., Mohan, N., Aykut, B., Usyk, M., Torres, L. E., Werba, G., Zhang, K., Guo, Y., Li, Q., Akkad, N., Lall, S., Wadowski, B., Gutierrez, J., Kochen Rossi, J. A., Herzog, J. W., Diskin, B., Torres-Hernandez, A., Leinwand, J., Wang, W., Taunk, P. S., Savadkar, S., Janal, M., Saxena, A., Li, X., Cohen, D., Sartor, R. B., Saxena, D., & Miller, G. (2018). The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discovery, 8(4), 403–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Schwechheimer, C., & Kuehn, M. J. (2015). Outer-membrane vesicles from gram-negative bacteria: Biogenesis and functions. Nature Reviews. Microbiology, 13(10), 605–619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yu, Y. J., Wang, X. H., & Fan, G. C. (2018). Versatile effects of bacterium-released membrane vesicles on mammalian cells and infectious/inflammatory diseases. Acta Pharmacologica Sinica, 39(4), 514–533.

    Article  CAS  PubMed  Google Scholar 

  124. Sieber, K. B., Bromley, R. E., & Dunning Hotopp, J. C. (2017). Lateral gene transfer between prokaryotes and eukaryotes. Experimental Cell Research, 358(2), 421–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chang, A. H., & Parsonnet, J. (2010). Role of bacteria in oncogenesis. Clinical Microbiology Reviews, 23(4), 837–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Robinson, K. M., Crabtree, J., Mattick, J. S. A., Anderson, K. E., & Hotopp, J. C. D. (2017). Distinguishing potential bacteria-tumor associations from contamination in a secondary data analysis of public cancer genome sequence data. Microbiome, 5(1), 1–17.

    Article  Google Scholar 

  127. Surve, M. V., et al. (2016). Membrane vesicles of group B Streptococcus disrupt Feto-maternal barrier leading to preterm birth. PLoS Pathogens, 12(9), 1–23.

    Article  CAS  Google Scholar 

  128. Barteneva, N. S., Baiken, Y., Fasler-Kan, E., Alibek, K., Wang, S., Maltsev, N., Ponomarev, E. D., Sautbayeva, Z., Kauanova, S., Moore, A., Beglinger, C., & Vorobjev, I. A. (2017). Extracellular vesicles in gastrointestinal cancer in conjunction with microbiota: On the border of kingdoms. Biochimica et Biophysica Acta, Reviews on Cancer, 1868(2), 372–393.

    Article  CAS  PubMed  Google Scholar 

  129. Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., & Sarkar, S. (2014). Drug resistance in cancer: An overview. Cancers (Basel), 6(3), 1769–1792.

    Article  CAS  Google Scholar 

  130. Zhang, J., Gu, Y., & Chen, B. (2019). Mechanisms of drug resistance in acute myeloid leukemia. OncoTargets and Therapy, 12, 1937–1945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bandari, S. K., Purushothaman, A., Ramani, V. C., Brinkley, G. J., Chandrashekar, D. S., Varambally, S., Mobley, J. A., Zhang, Y., Brown, E. E., Vlodavsky, I., & Sanderson, R. D. (2018). Chemotherapy induces secretion of exosomes loaded with heparanase that degrades extracellular matrix and impacts tumor and host cell behavior. Matrix Biology, 65(2018), 104–118.

    Article  CAS  PubMed  Google Scholar 

  132. Vlodavsky, I., Gross-Cohen, M., Weissmann, M., Ilan, N., & Sanderson, R. D. (2018). Opposing functions of Heparanase-1 and Heparanase-2 in Cancer progression. Trends in Biochemical Sciences, 43(1), 18–31.

    Article  CAS  PubMed  Google Scholar 

  133. Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017). Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 546(7659), 498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Dimou, A., Syrigos, K. N., & Saif, M. W. (2012). Overcoming the stromal barrier: Technologies to optimize drug delivery in pancreatic cancer. Therapeutic Advances in Medical Oncology, 4(5), 271–279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hoshino, A., Costa-Silva, B., Shen, T. L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., Molina, H., Kohsaka, S., di Giannatale, A., Ceder, S., Singh, S., Williams, C., Soplop, N., Uryu, K., Pharmer, L., King, T., Bojmar, L., Davies, A. E., Ararso, Y., Zhang, T., Zhang, H., Hernandez, J., Weiss, J. M., Dumont-Cole, V. D., Kramer, K., Wexler, L. H., Narendran, A., Schwartz, G. K., Healey, J. H., Sandstrom, P., Jørgen Labori, K., Kure, E. H., Grandgenett, P. M., Hollingsworth, M. A., de Sousa, M., Kaur, S., Jain, M., Mallya, K., Batra, S. K., Jarnagin, W. R., Brady, M. S., Fodstad, O., Muller, V., Pantel, K., Minn, A. J., Bissell, M. J., Garcia, B. A., Kang, Y., Rajasekhar, V. K., Ghajar, C. M., Matei, I., Peinado, H., Bromberg, J., & Lyden, D. (2015). Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578), 329–335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sagar, G., et al. (2017). Pathogenesis of pancreatic Cancer exosome-induced lipolysis in adipose tissue. Gut, 65(7), 1165–1174.

    Article  CAS  Google Scholar 

  137. Zhou, M., Chen, J., Zhou, L., Chen, W., Ding, G., & Cao, L. (2014). Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cellular Immunology, 292(1–2), 65–69.

    Article  CAS  PubMed  Google Scholar 

  138. Li, Z., Jiang, P., Li, J., Peng, M., Zhao, X., Zhang, X., Chen, K., Zhang, Y., Liu, H., Gan, L., Bi, H., Zhen, P., Zhu, J., & Li, X. (2018). Tumor-derived exosomal lnc-Sox2ot promotes EMT and stemness by acting as a ceRNA in pancreatic ductal adenocarcinoma. Oncogene, 37(28), 3822–3838.

    Article  CAS  PubMed  Google Scholar 

  139. Wang, X., Luo, G., Zhang, K., Cao, J., Huang, C., Jiang, T., Liu, B., Su, L., & Qiu, Z. (2018). Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kg to promote pancreatic cancer metastasis. Cancer Research, 78(16), 4586–4598.

    Article  CAS  PubMed  Google Scholar 

  140. Chiba, M., Kubota, S., Sato, K., & Monzen, S. (2018). Exosomes released from pancreatic cancer cells enhance angiogenic activities via dynamin-dependent endocytosis in endothelial cells in vitro. Scientific Reports, 8(1), 1–9.

    Article  CAS  Google Scholar 

  141. Melo, S. A., Luecke, L. B., Kahlert, C., Fernandez, A. F., Gammon, S. T., Kaye, J., LeBleu, V. S., Mittendorf, E. A., Weitz, J., Rahbari, N., Reissfelder, C., Pilarsky, C., Fraga, M. F., Piwnica-Worms, D., & Kalluri, R. (2015). Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature, 523(7559), 177–182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lau, C., et al. (2013). Role of pancreatic cancer-derived exosomes in salivary biomarker development. The Journal of Biological Chemistry, 288(37), 2688–2697.

    Article  CAS  Google Scholar 

  143. Mendt, M., et al. (2018). Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight, 3(8).

  144. Holland, E. C. (2000). Glioblastoma multiforme: The terminator. Proceedings of the National Academy of Sciences of the United States of America, 97(12), 6242–6244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Graner, M. W., Cumming, R. I., & Bigner, D. D. (2007). The heat shock response and chaperones/heat shock proteins in brain tumors: Surface expression, release, and possible immune consequences. The Journal of Neuroscience, 27(42), 11214–11227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kore, R. A., & Abraham, E. C. (2014). Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells. Biochemical and Biophysical Research Communications, 453(3), 326–331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Challagundla, K. B., et al. (2015). Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. Journal of the National Cancer Institute, 107(7), 1–13.

    Article  CAS  Google Scholar 

  148. Marimpietri, D., et al. (2013). Proteome Profiling of Neuroblastoma-Derived Exosomes Reveal the Expression of Proteins Potentially Involved in Tumor Progression. PLoS One, 8(9).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Fong, M. Y., Zhou, W., Liu, L., Alontaga, A. Y., Chandra, M., Ashby, J., Chow, A., O’Connor, S. T. F., Li, S., Chin, A. R., Somlo, G., Palomares, M., Li, Z., Tremblay, J. R., Tsuyada, A., Sun, G., Reid, M. A., Wu, X., Swiderski, P., Ren, X., Shi, Y., Kong, M., Zhong, W., Chen, Y., & Wang, S. E. (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 

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

Download references

Acknowledgements

Irit Sagi is an Incumbent of the Maurizio Pontecorvo Professorial Chair and wants to acknowledge European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 695437), Israel Science Foundation (1800/19), the USA-Israel Binational Science Foundation (712506-01) and The Rising Tide Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Irit Sagi.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Das, A., Mohan, V., Krishnaswamy, V.R. et al. Exosomes as a storehouse of tissue remodeling proteases and mediators of cancer progression. Cancer Metastasis Rev 38, 455–468 (2019). https://doi.org/10.1007/s10555-019-09813-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-019-09813-5

Keywords

Navigation