Skip to main content
SpringerLink
Log in

The Role of Microvesicles in Malignancies

  • Chapter
  • First Online:
Cell Fusion in Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 950))

Abstract

Microvesicles are membrane-covered cell fragments whose size varies between 30 and 1,000 nm. They are generated by all cell types, constituvely and in response to activation signals. Their importance in intercellular communication has been only recently discovered. They seem to enhance the potential of information transfer between cells, displaying a large number of proteins and lipids as membrane constituents and as components of the inner vesicular content. The content reflects the phenotype of the donor cell and allows the identification of the microvesicular origine as well. Complex “packets” of molecules are transmitted to the target cells this way, modifying their cellular physiology. Additionally, epigenetic changes may be induced by transmitted DNA and RNAs, that have also been identified in these vesicles. The vesicles can act in close and far distances as well. Microvesicles have been implicated in several physiological and pathological processes. There is an increasing evidence, that they play a pivotal role in tumorigenesis. Vesicles shedding from tumor cells reflect the special potential of the tumor for survival and expansion, independently from cell-to-cell contact. Tumor derived vesicles are fully equipped to facilitate the escape of tumor cells from immune surveillance through their protein and RNA content, at the same time they are involved in the establishment of an optimal environment for newly formed and metastatic tumor cells, influencing angiogenesis and the reorganization of the extracellular matrix. As immune cells, endothels, platelets and stem cells also release microvesicles, a multilevel communication network draws up, allowing a complex interplay between the cells. The concentration of tumor derived vesicles increases in blood plasma and other body fluids with the progression of the disease; therefor they may serve as prognostic markers. The microvesicular approach can offer new perspectives: interfering with the formation, release and propagation of these vesicles, they can be considered as new targets in tumor therapy.

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

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579

    PubMed  CAS  Google Scholar 

  2. Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9(8):581–593

    Article  PubMed  Google Scholar 

  3. Johnstone RM (2006) Exosomes biological significance: a concise review. Blood Cells Mol Dis 36:315–321

    Article  PubMed  CAS  Google Scholar 

  4. Ratajczak J, Wysoczynski M, Hayek F et al (2006) Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20:1487–1495

    Article  PubMed  CAS  Google Scholar 

  5. Kramer B, Pelchen-Matthews A, Deneka M et al (2005) HIV interaction with endosomes in macrophages and dendritic cells. Blood Cells Mol Dis 35:136–142

    Article  PubMed  CAS  Google Scholar 

  6. Valenti R, Huber V, Iero M et al (2007) Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 67:2912–2915

    Article  PubMed  CAS  Google Scholar 

  7. Valenti R, Huber V, Filipazzi P et al (2006) Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66:9290–9298

    Article  PubMed  CAS  Google Scholar 

  8. Iero M, Valenti R, Huber V et al (2008) Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ 1:80–88

    Article  Google Scholar 

  9. Shedden K, Xie XT, Chandaroy P et al (2003) Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res 63(15):4331–4337

    PubMed  CAS  Google Scholar 

  10. Chaput N, Taieb J, Schartz NE et al (2004) Exosome-based immunotherapy. Cancer Immunol Immunother 53: 234–239

    Article  PubMed  CAS  Google Scholar 

  11. Wieckowski E, Whiteside TL (2006) Human tumor-derived vs dendritic cell-derived exosomes have distinct biologic roles and molecular profiles. Immunol Res 36:247–254

    Article  PubMed  CAS  Google Scholar 

  12. VanWijk MJ, VanBavel E, Sturk A et al (2003) Microparticles in cardiovascular diseases. Cardiovasc Res 59: 277–287

    Article  PubMed  CAS  Google Scholar 

  13. Pap E, Pallinger E, Falus A et al (2008) T lymphocytes are targets for platelet- and trophoblast-derived microvesicles during pregnancy. Placenta 29:826–832

    Article  PubMed  CAS  Google Scholar 

  14. Distler JH, Pisetsky DS, Huber LC et al (2005) Microparticles as regulators of inflammation: novel players of cellular crosstalk in the rheumatic diseases. Arthritis Rheum 52:3337–3348

    Article  PubMed  CAS  Google Scholar 

  15. Piccin A, Murphy WG, Smith OP et al (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171

    Article  PubMed  CAS  Google Scholar 

  16. Freyssinet JM (2003) Cellular microparticles: what are they bad or good for? J Thromb Haemost 1:1655–1662

    Article  PubMed  CAS  Google Scholar 

  17. Jimenez JJ, Jy W, Mauro LM et al (2003) Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis. Thromb Res 109:175–180

    Article  PubMed  CAS  Google Scholar 

  18. Pap E, Pállinger E, Pásztói M et al (2009) Highlights of a new type of intercellular communication: microvesicle-based information transfer. Inflamm Res 58(1):1–8

    Article  PubMed  CAS  Google Scholar 

  19. Valadi H, Ekstrom K, Bossios A et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    Article  PubMed  CAS  Google Scholar 

  20. Bergsmedh A, Szeles A, Henriksson M, et al. (2001) Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci USA 98:6407–6411

    Article  PubMed  CAS  Google Scholar 

  21. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K et al (2006) Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother 55(7):808–818

    Article  PubMed  CAS  Google Scholar 

  22. Clayton A, Mitchell JP, Court J et al (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67(15):7458–7466

    Article  PubMed  CAS  Google Scholar 

  23. Van Blitterswijk WJ, De Veer G, Krol JH et al (1982) Comparative lipid analysis of purified plasma membranes and shed extracellular membrane vesicles from normal murine thymocytes and leukemic GRSL cells. Biochim Biophys Acta 688(2):495–504

    Article  PubMed  Google Scholar 

  24. Van Blitterswijk WJ, Emmelot P, Hilkmann HA, et al. (1979) Rigid plasma-membrane-derived vesicles, enriched in tumour-associated surface antigens (MLr), occurring in the ascites fluid of a murine leukaemia (GRSL). Int J Cancer 23(1):62–70

    Article  PubMed  Google Scholar 

  25. Kim CW, Lee HM, Lee TH et al (2002) Extracellular membrane vesicles from tumor cells promote angiogenesis via sphingomyelin. Cancer Res 62(21):6312–6317

    PubMed  CAS  Google Scholar 

  26. Dahiya R, Boyle B, Goldberg BC et al (1992) Blumenfeld W, narayan P. Metastasis-Associated alterations in phospholipids and fatty acids of human prostatic adenocarcinoma cell lines. Biochem Cell Biol 70(7):548–554

    Article  PubMed  CAS  Google Scholar 

  27. Miyanishi M, Tada K, Koike M et al (2007) Identification of tim4 as a phosphatidylserine receptor. Nature 450(7168):435–439

    Article  PubMed  CAS  Google Scholar 

  28. Trajkovic K, Hsu C, Chiantia S et al (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319(5867):1244–1247

    Article  PubMed  CAS  Google Scholar 

  29. Thery C, Boussac M, Veron P, et al. (2001) Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 166:7309–7318

    PubMed  CAS  Google Scholar 

  30. Raposo G, Nijman HW, Stoorvogel W, et al (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161

    Article  PubMed  CAS  Google Scholar 

  31. Sims PJ, Faioni EM, Wiedmer T, et al. (1988) Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor va and express prothrombinase activity. J Biol Chem 263:18205–18212

    PubMed  CAS  Google Scholar 

  32. Théry C, Amigorena S, Raposo G et al (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol Chapter 3:Unit 3.22

    Google Scholar 

  33. Poutsiaka DD, Schroder EW, Taylor DD et al (1985) Membrane vesicles shed by murine melanoma cells selectively inhibit the expression of ia antigen by macrophages. J Immunol 134(1):138–144

    PubMed  CAS  Google Scholar 

  34. Huber V, Fais S, Iero M et al (2005) Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology 128:1796–1804

    Article  PubMed  CAS  Google Scholar 

  35. Taylor DD, Lyons KS, Gerçel-Taylor C (2002) Shed membrane fragment-associated markers for endometrial and ovarian cancers. Gynecol Oncol 84(3):443–448

    Article  PubMed  Google Scholar 

  36. Kim HK, Song KS, Park YS et al (2003) Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur J Cancer 39(2):184–191

    Article  PubMed  CAS  Google Scholar 

  37. Ginestra A, Miceli D, Dolo V et al (1999) Membrane vesicles in ovarian cancer fluids: a new potential marker. Anticancer Res 19(4C):3439–3445

    PubMed  CAS  Google Scholar 

  38. Taraboletti G, D’Ascenzo S, Borsotti P et al (2002) Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle- associated components by endothelial cells. Am J Pathol 160(2):673–680

    Article  PubMed  CAS  Google Scholar 

  39. Andre F, Schartz NE, Movassagh M et al (2002) Malignant effusions and immunogenic tumour-derived exosomes. Lancet 360(9329):295–305

    Article  PubMed  CAS  Google Scholar 

  40. Trosko JE (2009) Review paper: cancer stem cells and cancer nonstem cells: from adult stem cells or from reprogramming of differentiated somatic cells. Vet Pathol 46(2):176–193

    PubMed  CAS  Google Scholar 

  41. Riteau B, Faure F, Menier C et al (2003) Exosomes bearing HLA-G are released by melanoma cells. Hum Immunol 64(11):1064–1072

    Article  PubMed  CAS  Google Scholar 

  42. Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19(2):43–51

    Article  PubMed  CAS  Google Scholar 

  43. Ostroukhova M, Qi Z, Oriss TB et al (2006) Treg-mediated immunosuppression involves activation of the notch-HES1 axis by membrane-bound TGF-beta. J Clin Invest 116(4):996–1004

    Article  PubMed  CAS  Google Scholar 

  44. Ichim TE, Zhong Z, Kaushal S et al (2008) Exosomes as a tumor immune escape mechanism: possible therapeutic implications. J Transl Med 6:37

    Article  PubMed  Google Scholar 

  45. Abusamra AJ, Zhong Z, Zheng X et al (2005) Tumor exosomes expressing fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis 35(2):169–173

    Article  PubMed  CAS  Google Scholar 

  46. Andreola G, Rivoltini L, Castelli C et al (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195:1303–1316

    Article  PubMed  CAS  Google Scholar 

  47. Kim JW, Wieckowski E, Taylor DD et al (2005) Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin Cancer Res 11(3):1010–1020

    PubMed  CAS  Google Scholar 

  48. Taylor DD, Gerçel-Taylor C (2005) Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br J Cancer 92(2):305–311

    PubMed  CAS  Google Scholar 

  49. Pilzer D, Fishelson Z (2005) Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. Int Immunol 17(9):1239–1248

    Article  PubMed  CAS  Google Scholar 

  50. Böing AN, Hau CM, Sturk A et al (2008) Platelet microparticles contain active caspase 3. Platelets 19(2):96–103

    Article  PubMed  Google Scholar 

  51. Sapet C, Simoncini S, Loriod B et al (2006) Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2. Blood 108(6):1868–1876

    Article  PubMed  CAS  Google Scholar 

  52. Abid Hussein MN, Böing AN, Sturk A et al (2007) Inhibition of microparticle release triggers endothelial cell apoptosis and detachment. Thromb Haemost 98(5): 1096–1107

    PubMed  Google Scholar 

  53. Jänicke RU, Sprengart ML, Wati MR et al (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273(16):9357–9360

    Article  PubMed  Google Scholar 

  54. Ambudkar SV, Sauna ZE, Gottesman MM et al (2005) A novel way to spread drug resistance in tumor cells: functional intercellular transfer of P-glycoprotein (ABCB1). Trends Pharmacol Sci 26(8):385–387

    Article  PubMed  CAS  Google Scholar 

  55. Levchenko A, Mehta BM, Niu X et al (2005) Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells. Proc Natl Acad Sci USA 102:1933–1938

    Article  PubMed  CAS  Google Scholar 

  56. Skog J, Würdinger T, van Rijn S et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476

    Article  PubMed  CAS  Google Scholar 

  57. Al-Nedawi K, Meehan B, Micallef J et al (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10(5):619–624

    Article  PubMed  CAS  Google Scholar 

  58. Al-Nedawi K, Meehan B, Kerbel RS et al (2009) Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci USA 106(10):3794–3799

    Article  PubMed  Google Scholar 

  59. Janowska-Wieczorek A, Marquez-Curtis LA, Wysoczynski M et al (2006) Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion 46(7):1199–1209

    Article  PubMed  Google Scholar 

  60. Janowska-Wieczorek A, Wysoczynski M, Kijowski J et al (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113(5):752–760

    Article  PubMed  CAS  Google Scholar 

  61. Sidhu SS, Mengistab AT, Tauscher AN et al (2004) The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions. Oncogene 23(4):956–963

    Article  PubMed  CAS  Google Scholar 

  62. Dolo V, Ginestra A, Cassarà D, et al (1998) Selective localization of matrix metalloproteinase 9, beta1 integrins, and human lymphocyte antigen class I molecules on membrane vesicles shed by 8701-BC breast carcinoma cells. Cancer Res 58(19):4468–4474

    PubMed  CAS  Google Scholar 

  63. Silberberg JM, Gordon S, Zucker S (1989) Identification of tissue factor in two human pancreatic cancer cell lines. Cancer Res 49(19):5443–5447

    PubMed  CAS  Google Scholar 

  64. Giusti I, D’Ascenzo S, Millimaggi D et al (2008) Cathepsin B mediates the pH-dependent proinvasive activity of tumor-shed microvesicles. Neoplasia 10(5):481–488

    PubMed  CAS  Google Scholar 

  65. Wysoczynski M, Ratajczak MZ (2009) Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors. Int J Cancer 125(7):1595–1603

    Article  PubMed  CAS  Google Scholar 

  66. Rak J, Milsom C, Magnus N et al (2009) Tissue factor in tumour progression. Best Pract Res Clin Haematol 22(1):71–83

    Article  PubMed  CAS  Google Scholar 

  67. Castellana D, Zobairi F, Martinez MC et al (2009) Membrane microvesicles as actors in the establishment of a favorable prostatic tumoral niche: a role for activated fibroblasts and CX3CL1-CX3CR1 axis. Cancer Res 69(3):785–793

    Article  PubMed  CAS  Google Scholar 

  68. Lima LG, Chammas R, Monteiro RQ et al (2009) Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner. Cancer Lett 283(2):168–175

    Article  PubMed  CAS  Google Scholar 

  69. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K et al (2007) Tumour-derived microvesicles modulate biological activity of human monocytes. Immunol Lett 113(2):76–82

    Article  PubMed  CAS  Google Scholar 

  70. Sims PJ, Faioni EM, Wiedmer T et al (1988) Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor va and express prothrombinase activity. J Biol Chem 263:18205–18212

    PubMed  CAS  Google Scholar 

  71. Weyrich AS, Lindemann S, Zimmerman GA (2003) The evolving role of platelets in inflammation. J Thromb Haemost 1:1897–1905

    Article  PubMed  CAS  Google Scholar 

  72. Wang HB, Wang JT, Zhang L et al (2007) P-selectin primes leukocyte integrin activation during inflammation. Nat Immunol 8:882–892

    Article  PubMed  CAS  Google Scholar 

  73. Barry OP, Pratico D, Savani RC et al (1998) Modulation of monocyte-endothelial cell interactions by platelet microparticles. J Clin Invest 102:136–144

    Article  PubMed  CAS  Google Scholar 

  74. Bizios R, Lai LC, Cooper JA et al (1988) Thrombininduced adherence of neutrophils to cultured endothelial monolayers: increased endothelial adhesiveness. J Cell Physiol 134:275–280

    Article  PubMed  CAS  Google Scholar 

  75. Wright PK (2008) Targeting vesicle trafficking: an important approach to cancer chemotherapy. Recent Pat Anticancer Drug Discov 3(2):137–147

    Article  PubMed  CAS  Google Scholar 

  76. Jordens I, Marsman M, Kuijl C et al (2005) Rab proteins, connecting transport and vesicle fusion. Traffic 6(12):1070–1077

    Article  PubMed  CAS  Google Scholar 

  77. Cheng KW, Lahad JP, Kuo WL et al (2004) The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med 10(11):1251–1256

    Article  PubMed  CAS  Google Scholar 

  78. Cheng KW, Lahad JP, Gray JW et al (2005) Emerging role of RAB GTPases in cancer and human disease. Cancer Res 65(7):2516–2519

    Article  PubMed  CAS  Google Scholar 

  79. Ostrowski M, Carmo NB, Krumeich S et al (2010) Rab27a and rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12(1):19–30, suppp 1–13

    Article  PubMed  CAS  Google Scholar 

  80. Wolfers J, Lozier A, Raposo G et al (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7(3):297–303

    Article  PubMed  CAS  Google Scholar 

  81. Chaput N, Schartz NE, André F et al (2004) Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive tc1 lymphocytes leading to tumor rejection. J Immunol 172(4):2137–2146

    PubMed  CAS  Google Scholar 

  82. Dai S, Wei D, Wu Z et al (2008) Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 16(4):782–790

    Article  PubMed  CAS  Google Scholar 

  83. Liu C, Yu S, Zinn K et al (2006) Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol 176(3):1375–1385

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genetics, Cell- and Immunobiology, Semmelweis University, 1089, Budapest, Hungary

    Erna Pap

Authors
  1. Erna Pap
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erna Pap .

Editor information

Editors and Affiliations

  1. Inst. Immunologie, Universität Witten/Herdecke, Stockumer Str. 10, Witten, 58448, Germany

    Thomas Dittmar

  2. Institute of Immunologie, University of Witten/Herdecke, Stockumer Str. 10, Witten, 58448, Germany

    Kurt S. Zänker

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Pap, E. (2011). The Role of Microvesicles in Malignancies. In: Dittmar, T., Zänker, K. (eds) Cell Fusion in Health and Disease. Advances in Experimental Medicine and Biology, vol 950. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0782-5_10

Download citation

Publish with us

Policies and ethics

Search

Navigation