Background. Cancer has traditionally been considered as a disease resulting from gene mutations. New findings in biology are challenging gene-centered explanations of cancer progression and redirecting them to the non-genetic origins of tumorigenicity. It has become clear that intercellular communication plays a crucial role in cancer progression. Among the most intriguing ways of intercellular communication is that via extracellular vesicles (EVs). EVs are membrane structures released from various types of cells. After separation from the mother membrane, EVs become mobile and may travel from the extracellular space to blood and other body fluids.
Conclusions. Recently it has been shown that tumour cells are particularly prone to vesiculation and that tumour-derived EVs can carry proteins, lipids and nucleic acids causative of cancer progression. The uptake of tumour-derived EVs by noncancerous cells can change their normal phenotype to cancerous. The suppression of vesiculation could slow down tumour growth and the spread of metastases. The purpose of this review is to highlight examples of EVmediated cancer phenotypic transformation in the light of possible therapeutic applications.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Al-Nedawi K Meehan B Rak J. Microvesicles: messengers and mediators of tumor progression. Cell Cycle 2009; 8: 2014-18.
2. Rak J. Microparticles in cancer. Semin Thromb Hemost 2010; 36: 888-906.
3. Pap E. The role of microvesicles in malignancies. Adv Exp Med Biol 2011; 714: 183-199.
4. Camussi G Deregibus MC Bruno S Grange C Fonsato V Tetta C. Exosome/ microvesicle-mediated epigenetic reprogramming of cells. Am J Cancer Res 2011; 1: 98-110.
5. Veranic P Lokar M Schutz GJ Weghuber J Wieser S Hagerstrand H et al. Different types of cell-to-cell connections mediated by nanotubular structures. Biophys J 2008; 95: 4416-25.
6. Sustar V Bedina-Zavec A Stukelj R Frank M Bobojevic G Jansa R et al. Nanoparticles isolated from blood: a reflection of vesiculability of blood cells during the isolation process. Int J Nanomedicine 2011; 6: 2737-48.
7. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967; 13: 269-88.
8. Junkar I Sustar V Frank M Jansa V Bedina Zavec A Rozman B et al. Blood and synovial microparticles as revealed by atomic force and scanning electron microscope. Open Autoimmun J 2009; 1: 50-58.
9. Pisitkun T Shen RF Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci USA 2004; 101: 13368-73.
10. Gonzales P Pisitkun T Knepper MA. Urinary exosomes: is there a future? Nephrol Dial Transplant 2008; 23: 1799-801.
11. Graves LE Ariztia EV Navari JR Matzel HJ Stack MS Fishman DA. Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Res 2004; 64: 7045-9.
12. Mrvar-Brecko A Sustar V Jansa V Stukelj R Jansa R Mujagic E et al. Isolated microvesicles from peripheral blood and body fluids as observed by scanning electron microscope. Blood Cells Mol Dis 2010; 44: 307-12.
13. Skriner K Adolph K Jungblut PR Burmester GR. Association of citrullinated proteins with synovial exosomes. Arthritis Rheum 2006; 54: 3809-14.
14. Bard MP Hegmans JP Hemmes A Luider TM Willemsen R Severijnen LA et al. Proteomic analysis of exosomes isolated from human malignant pleural effusions. Am J Respir Cell Mol Biol 2004; 31: 114-21.
15. Admyre C Grunewald J Thyberg J Gripenback S Tornling G Eklund A et al. Exosomes with major histocompatibility complex class II and costimulatory molecules are present in human BAL fluid. Eur Respir J 2003; 22: 578-583.
16. Sullivan R Saez F Girouard J Frenette G. Role of exosomes in sperm maturation during the transit along the male reproductive tract. Blood Cells MolDis 2005; 35: 1-10.
17. Admyre C Johansson SM Qazi KR Filen JJ Lahesmaa R Norman M et al. Exosomes with immune modulatory features are present in human breast milk. J Immunol 2007; 179: 1969-78.
18. Taylor DD Akyol S Gercel-Taylor C. Pregnancy-associated exosomes and their modulation of T cell signaling. J Immunol 2006; 176: 1534-42.
19. Asea A Jean-Pierre C Kaur P Rao P Linhares IM Skupski D et al. Heat shock protein-containing exosomes in mid-trimester amniotic fluids. JReprod Immunol 2008; 79: 12-7.
20. Perkumas KM Hoffman EA McKay BS Allingham RR Stamer WD. Myocilin-associated exosomes in human ocular samples. Exp Eye Res 2007; 84: 209-12.
21. Ogawa Y Kanai-Azuma M Akimoto Y Kawakami H Yanoshita R. Exosomelike vesicles with dipeptidyl peptidase IV in human saliva. Biol Pharm Bull 2008; 31: 1059-62.
22. Ratajczak J Wysoczynski M Hayek F Janowska-Wieczorek A Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 2006; 20:1487-95.
23. van der Vos KE Balaj L Skog J Breakefield XO. Brain Tumor Microvesicles: Insights into Intercellular Communication in the Nervous System. Cell MolNeurobiol 2011; 31: 949-59.
24. Skog J Wurdinger T van Rijn S Meijer DH Gainche L Sena-Esteves M et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10: 1470-U1209.
25. Janowska-Wieczorek A Wysoczynski M Kijowski J Marquez-Curtis L Machalinski B Ratajczak J et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 2005; 113: 752-60.
26. Safaei R Larson BJ Cheng TC Gibson MA Otani S Naerdemann W et al. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 2005; 4: 1595-604.
27. Shedden K Xie XT Chandaroy P Chang YT Rosania GR. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res 2003; 63: 4331-7.
28. Hakulinen J Junnikkala S Sorsa T Meri S. Complement inhibitor membrane cofactor protein (MCP; CD46) is constitutively shed from cancer cell membranes in vesicles and converted by a metalloproteinase to a functionally active soluble form. Eur J Immunol 2004; 34: 2620-9.
29. Valenti R Huber V Filipazzi P Pilla L Sovena G Villa A et al. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 2006; 66: 9290-8.
30. Abid Hussein MN Boing AN Sturk A Hau CM Nieuwland R. Inhibition of microparticle release triggers endothelial cell apoptosis and detachment. Thromb Haemost 2007; 98: 1096-107.
31. Kim HK Song KS Park YS Kang YH Lee YJ Lee KR et al. 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 2003; 39: 184-91.
32. Jansa R Sustar V Frank M Susanj P Bester J Mancek-Keber M et al. Number of microvesicles in peripheral blood and ability of plasma to induce adhesion between phospholipid membranes in 19 patients with gastrointestinal diseases. Blood Cells Mol Dis 2008; 41: 124-32.
33. Baran J Baj-Krzyworzeka M Weglarczyk K Szatanek R Zembala M Barbasz J et al. Circulating tumour-derived microvesicles in plasma of gastric cancer patients. Cancer Immunol Immunother 2010; 59: 841-50.
34. Lipowsky R. The conformation of membranes. Nature 1991; 349: 475-81.
35. Kralj-Iglic V Babnik B Gauger DR May S Iglic A. Quadrupolar ordering of phospholipid molecules in narrow necks of phospholipid vesicles. J StatPhys 2006; 125: 727-52.
36. Hagerstrand H Isomaa B. Morphological characterization of exovesicles and endovesicles released from human erythrocytes following treatment with amphiphiles. Biochim Biophys Acta 1992; 1109: 117-26.
37. Black PH. Shedding from Normal and Cancer-Cell Surfaces. New Engl J Med 1980; 303: 1415-6.
38. Kralj-Iglic V Batista U Hägerstrand H Iglic A Majhenc J Sok M. On mechanisms of cell plasma membrane vesiculation. Radiol Oncol 1998; 32: 119-23.
39. Kralj-Iglic V Veranic P. Curvature-Induced Sorting of Bilayer Membrane Constituents and Formation of Membrane Rafts. In: A. Leitmannova Liu editor. Advances in planar lipid bilayers and liposomes Vol. 5 Elsevier; 2007. p. 129-49.
40. Kralj-Iglic V Iglic A Hagerstrand H Peterlin P. Stable tubular microexovesicles of the erythrocyte membrane induced by dimeric amphiphiles. PhysRev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 2000; 61: 4230-4.
41. Sheetz MP Singer SJ. Biological-membranes as bilayer couples - molecular mechanism of drug-erythrocyte interactions. Proc Natl Acad Sci USA 1974; 71: 4457-61.
42. Helfrich W. Blocked lipid exchange in bilayers and its possible influence on the shape of vesicles. Z. Naturforsch. 1974; 29c: 510.
43. Evans EA. Bending resistance and chemically induced moments in membrane bilayers. Biophys J 1974; 14: 923-31.
44. Kralj-Iglic V. Stability of membranous nanostructures: a possible key mechanism in cancer progression. Int J Nanomedicine 2012; 7: 3579-96.
45. Zachowski A Devaux PF. Transmembrane movements of lipids. Experientia 1990; 46: 644-56
46. Sims PJ Wiedmer T. Unraveling the mysteries of phospholipid scrambling. Thromb Haemost 2001; 86: 266-75.
47. Wydro P Hac-Wydro K. Thermodynamic description of the interactions between lipids in ternary Langmuir monolayers: the study of cholesterol distribution in membranes. J Phys Chem B 2007; 111: 2495-502.
48. Pap E Pallinger E Pasztoi M Falus A. Highlights of a new type of intercellular communication: microvesicle-based information transfer. InflammRes 2009; 58: 1-8.
49. van Meer G. Dynamic transbilayer lipid asymmetry. Csh Perspect Biol 2011; 3.
50. Camussi G Deregibus MC Bruno S Cantaluppi V Biancone L. Exosomes/ microvesicles as a mechanism of cell-to-cell communication. Kidney Int2010; 78: 838-48.
51. Davizon P Lopez JA. Microparticles and thrombotic disease. Curr OpinHematol 2009; 16: 334-41.
52. Mrówczyńska L Salzer U Iglič A Hägerstrand H. Curvature factor and membrane solubilisation with particular reference to membrane rafts. CellBiol Int 2011; 35: 991-5.
53. Simons K Ikonen E. Functional rafts in cell membranes. Nature 1997; 387: 569-72.
54. Brown DA London E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Bi 1998; 14: 111-36.
55. Ikonen E. Roles of lipid rafts in membrane transport. Curr Opin Cell Biol 2001; 13: 470-7.
56. Flaumenhaft R. Formation and fate of platelet microparticles. Blood CellsMol Dis 2006; 36: 182-7.
57. Huttner WB Zimmerberg J. Implications of lipid microdomains for membrane curvature budding and fission. Curr Opin Cell Biol 2001; 13: 478-84.
58. Schmidt A Wolde M Thiele C Fest W Kratzin H Podtelejnikov AV et al. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature 1999; 401: 133-41.
59. Kozlov MM. Fission of biological membranes: interplay between dynamin and lipids. Traffic 2001; 2: 51-65.
60. Heijnen HFG Schiel AE Fijnheer R Geuze HJ Sixma JJ. Activated platelets release two types of membrane vesicles: Microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 1999; 94: 3791-9.
61. Pap E Pallinger E Falus A. The role of membrane vesicles in tumorigenesis. Crit Rev Oncol Hematol 2011; 79: 213-23.
62. Di Vizio D Kim J Hager MH Morello M Yang W Lafargue CJ et al. Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease. Cancer Res 2009; 69: 5601-9.
63. Del Conde I Shrimpton CN Thiagarajan P Lopez JA. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005; 106: 1604-11.
64. Kharaziha P Ceder S Li Q Panaretakis T. Tumor cell-derived exosomes: A message in a bottle. Biochim Biophys Acta 2012; 1826: 103-11.
65. Miyanishi M Tada K Koike M Uchiyama Y Kitamura T Nagata S. Identification of Tim4 as a phosphatidylserine receptor. Nature 2007; 450: 435-9.
66. Segura E Nicco C Lombard B Veron P Raposo G Batteux F et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood 2005; 106: 216-23.
67. Feng D Zhao WL Ye YY Bai XC Liu RQ Chang LF et al. Cellular Internalization of exosomes occurs through phagocytosis. Traffic 2010; 11: 675-87.
68. Teissier E Pecheur EI. Lipids as modulators of membrane fusion mediated by viral fusion proteins. Eur Biophys J 2007; 36: 887-99.
69. Parolini I Federici C Raggi C Lugini L Palleschi S De Milito A et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. JBiol Chem 2009; 284: 34211-22.
70. Escrevente C Keller S Altevogt P Costa J. Interaction and uptake of exosomes by ovarian cancer cells. BMC Cancer 2011; 11: 108.
71. Taraboletti G D’Ascenzo S Giusti I Marchetti D Borsotti P Millimaggi D et al. Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH. Neoplasia 2006; 8: 96-103.
72. Cocucci E Racchetti G Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol 2009; 19: 43-51.
73. Rak J Guha A. Extracellular vesicles - vehicles that spread cancer genes. Bioessays 2012; 34: 489-97.
74. Lee TH D’Asti E Magnus N Al-Nedawi K Meehan B Rak J. Microvesicles as mediators of intercellular communication in cancer - the emerging science of cellular ‘debris’. Semin Immunopathol 2011; 33: 455-67.
75. Al-Nedawi K Meehan B Micallef J Lhotak V May L Guha A et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008; 10: 619-24.
76. Peinado H Aleckovic M Lavotshkin S Matei I Costa-Silva B Moreno- Bueno G et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012; 18: 883-91.
77. Sidhu SS Mengistab AT Tauscher AN LaVail J Basbaum C. The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions. Oncogene 2004; 23: 956-963.
78. McCready J Sims JD Chan D Jay DG. Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer 2010; 10: 294.
79. Andre F Schartz NE Movassagh M Flament C Pautier P Morice P. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 2002; 360: 295-305.
80. Koga K Matsumoto K Akiyoshi T Kubo M Yamanaka N Tasaki A et al. Purification characterization and biological significance of tumor-derived exosomes. Anticancer Res 2005; 25: 3703-7.
81. Dinger ME Mercer TR Mattick JS. RNAs as extracellular signaling molecules. J Mol Endocrinol 2008; 40: 151-9.
82. Lagos-Quintana M Rauhut R Lendeckel W Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 2001; 294: 853-8.
83. Esquela-Kerscher A Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006; 6: 259-69.
84. Tsui NB Ng EK Lo YM. Stability of endogenous and added RNA in blood specimens serum and plasma. Clin Chem 2002; 48: 1647-53.
85. Tsui NB Ng EK Lo YM. Molecular analysis of circulating RNA in plasma. Methods Mol Biol 2006; 336: 123-34.
86. Valadi H Ekstrom K Bossios A Sjostrand M Lee JJ Lotvall JO. Exosomemediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9: 654-9.
87. Hong BS Cho JH Kim H Choi EJ Rho S Kim J et al. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genomics 2009; 10: 556.
88. Baj-Krzyworzeka M Szatanek R Weglarczyk K Baran J Urbanowicz B Branski P et al. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother 2006; 55: 808-18.
89. Kogure T Lin WL Yan IK Braconi C Patel T. Intercellular nanovesiclemediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 2011; 54: 1237-48.
90. Ohshima K Inoue K Fujiwara A Hatakeyama K Kanto K Watanabe Y et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoSOne 2010; 5: e13247.
91. Taylor DD Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008; 110:13-21.
92. Bergsmedh A Szeles A Henriksson M Bratt A Folkman MJ Spetz AL et al. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc NatlAcad Sci USA 2001; 98: 6407-11.
93. Balaj L Lessard R Dai L Cho YJ Pomeroy SL Breakefield XO et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2011; 2: 180.
94. Desler C Marcker ML Singh KK Rasmussen LJ. The importance of mitochondrial DNA in aging and cancer. J Aging Res 2011; 2011: 407536.
95. Guescini M Genedani S Stocchi V Agnati LF. Astrocytes and Glioblastoma cells release exosomes carrying mtDNA. J Neural Transm 2010; 117: 1-4.
96. Bannert N Kurth R. Retroelements and the human genome: new perspectives on an old relation. Proc Natl Acad Sci USA 2004; 101: 14572-9.
97. Cordaux R Batzer MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet 2009; 10: 691-703.
98. Wiemels JL Hofmann J Kang M Selzer R Green R Zhou M et al. Chromosome 12p deletions in TEL-AML1 childhood acute lymphoblastic leukemia are associated with retrotransposon elements and occur postnatally. Cancer Res 2008; 68: 9935-44.
99. Bretscher MS. Membrane structure: some general principles. Science 1973; 181: 622-9.
100. Dahiya R Boyle B Goldberg BC Yoon WH Konety B Chen K et al. Metastasis-associated alterations in phospholipids and fatty acids of human prostatic adenocarcinoma cell lines. Biochem Cell Biol 1992; 70: 548-54.
101. Kim CW Lee HM Lee TH Kang C Kleinman HK Gho YS. Extracellular membrane vesicles from tumor cells promote angiogenesis via sphingomyelin. Cancer Res 2002; 62: 6312-7.
102. McGarry LJ Thompson D. Retrospective database analysis of the prevention of venous thromboembolism with low-molecular-weight heparin in acutely III medical inpatients in community practice. Clin Ther 2004; 26: 419-30.
103. Smorenburg SM Hettiarachchi RJ Vink R Buller HR. The effects of unfractionated heparin on survival in patients with malignancy-a systematic review. Thromb Haemost 1999; 82: 1600-4.
104. Stevenson JL Choi SH Wahrenbrock M Varki A Varki NM. Heparin effects in metastasis and Trouseeau syndrome: anticoagulation is not the primary mechanism. Haem Rep 2005; 1: 59-60.
105. Sustar V Jansa R Frank M Hagerstrand H Krzan M Iglic A et al. Suppression of membrane microvesiculation - a possible anticoagulant and anti-tumor progression effect of heparin. Blood Cells Mol Dis 2009; 42: 223-7.
106. Urbanija J Tomsic N Lokar M Ambrozic A Cucnik S Rozman B et al. Coalescence of phospholipid membranes as a possible origin of anticoagulant effect of serum proteins. Chem Phys Lipids 2007; 150: 49-57.
107. Urbanija J Babnik B Frank M Tomsic N Rozman B Kralj-Iglic V et al. Attachment of beta 2-glycoprotein I to negatively charged liposomes may prevent the release of daughter vesicles from the parent membrane. EurBiophys J 2008; 37: 1085-95.
108. May S Iglič A Reščič J Maset S. Bohinc K. Bridging like-charged macroions through long divalent rod-like ions. J Phys Chem B 2008; 112: 1685-92.
109. Velikonja A Perutkova Š Gongadze E Kramar P Polak A Maček-Lebar A Iglič A. Monovalent ions and water dipoles in contact with dipolar zwitterionic lipid headroups - theory and MD simulations Int J Mol Sci 2013; 14: 2846-61.
110. Gongadze E Iglič A. Excluded volume effect of counterions and water dipoles near a highly charged surface due to a rotationally averaged Boltzmann factor for water dipoles. Gen Phys Biophys 2013; 21: 143-5..
111. Ambrožič A Čučnik S Tomšič N Urbanija J Lokar M Babnik B et al. Interaction of giant phospholipid vesicles containing cardiolipin and cholesterol with beta 2-glycoprotein-I and anti-beta2-glycoprotein-I antibodies. Autoimmun Rev 2006; 6: 10-5.