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Microvesicles as Mediators of Intercellular Communication in Cancer

  • Marc A. Antonyak
  • Richard A. CerioneEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1165)

Abstract

The discovery that cancer cells generate large membrane-enclosed packets of epigenetic information, known as microvesicles (MVs), that can be transferred to other cells and influence their behavior (Antonyak et al., Small GTPases 3:219–224, 2012; Cocucci et al., Trends Cell Biol 19:43–51, 2009; Rak, Semin Thromb Hemost 36:888–906, 2010; Skog et al., Nat Cell Biol 10:1470–1476, 2008) has added a unique perspective to the classical paracrine signaling paradigm. This is largely because, in addition to growth factors and cytokines, MVs contain a variety of components that are not usually thought to be released into the extracellular environment by viable cells including plasma membrane-associated proteins, cytosolic- and nuclear-localized proteins, as well as nucleic acids, particularly RNA transcripts and micro-RNAs (Skog et al., Nat Cell Biol 10:1470–1476, 2008; Al-Nedawi et al., Nat Cell Biol 10:619–624, 2008; Antonyak et al., Proc Natl Acad Sci U S A 108:4852–4857, 2011; Balaj et al., Nat Commun 2:180, 2011; Choi et al., J Proteome Res 6:4646–4655, 2007; Del Conde et al., Blood 106:1604–1611, 2005; Gallo et al., PLoS One 7:e30679, 2012; Graner et al., FASEB J 23:1541–1557, 2009; Grange et al., Cancer Res 71:5346–5356, 2011; Hosseini-Beheshti et al., Mol Cell Proteomics 11:863–885, 2012; Martins et al., Curr Opin Oncol 25:66–75, 2013; Noerholm et al., BMC Cancer 12:22, 2012; Zhuang et al., EMBO J 31:3513–3523, 2012). When transferred between cancer cells, MVs have been shown to stimulate signaling events that promote cell growth and survival (Al-Nedawi et al., Nat Cell Biol 10:619–624, 2008). Cancer cell-derived MVs can also be taken up by normal cell types that surround the tumor, an outcome that helps shape the tumor microenvironment, trigger tumor vascularization, and even confer upon normal recipient cells the transformed characteristics of a cancer cell (Antonyak et al., Proc Natl Acad Sci U S A 108:4852–4857, 2011; Martins et al., Curr Opin Oncol 25:66–75, 2013; Al-Nedawi et al., Proc Natl Acad Sci U S A 106:3794–3799, 2009; Ge et al., Cancer Microenviron 5:323–332, 2012). Thus, the production of MVs by cancer cells plays crucial roles in driving the expansion of the primary tumor. However, it is now becoming increasingly clear that MVs are also stable in the circulation of cancer patients, where they can mediate long-range effects and contribute to the formation of the pre-metastatic niche, an essential step in metastasis (Skog et al., Nat Cell Biol 10:1470–1476, 2008; Noerholm et al., BMC Cancer 12:22, 2012; Peinado et al., Nat Med 18:883–891, 2012; Piccin et al., Blood Rev 21:157–171, 2007; van der Vos et al., Cell Mol Neurobiol 31:949–959, 2011). These findings, when taken together with the fact that MVs are being aggressively pursued as diagnostic markers, as well as being considered as potential targets for intervention against cancer (Antonyak et al., Small GTPases 3:219–224, 2012; Hosseini-Beheshti et al., Mol Cell Proteomics 11:863–885, 2012; Martins et al., Curr Opin Oncol 25:66–75, 2013; Ge et al., Cancer Microenviron 5:323–332, 2012; Peinado et al., Nat Med 18:883–891, 2012; Piccin et al., Blood Rev 21:157–171, 2007; Al-Nedawi et al., Cell Cycle 8:2014–2018, 2009; Cocucci and Meldolesi, Curr Biol 21:R940–R941, 2011; D’Souza-Schorey and Clancy, Genes Dev 26:1287–1299, 2012; Shao et al., Nat Med 18:1835–1840, 2012), point to critically important roles for MVs in human cancer progression that can potentially be exploited to develop new targeted approaches for treating this disease.

Key words

Microvesicles Shedding vesicles Microparticles Oncosomes Exosomes Intercellular communication ARF6 RhoA EGF-receptor Extracellular matrix Cytoskeleton Tumor microenvironment Angiogenesis Metastasis 

References

  1. 1.
    Baraniak PR, McDevitt TC (2010) Stem cell paracrine actions and tissue regeneration. Regen Med 5:121–143PubMedCentralPubMedGoogle Scholar
  2. 2.
    Perrimon N, Pitsouli C, Shilo BZ (2012) Signaling mechanisms controlling cell fate and embryonic patterning. Cold Spring Harb Perspect Biol 4:a005975PubMedCentralPubMedGoogle Scholar
  3. 3.
    Wilson KJ, Mill C, Lambert S et al (2012) EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors 30:107–116PubMedCentralPubMedGoogle Scholar
  4. 4.
    Seshacharyulu P, Ponnusamy MP, Haridas D et al (2012) Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 16:15–31PubMedCentralPubMedGoogle Scholar
  5. 5.
    Shilo BZ (2005) Regulating the dynamics of EGF receptor signaling in space and time. Development 132:4017–4027PubMedGoogle Scholar
  6. 6.
    Han W, Lo HW (2012) Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett 318: 124–134PubMedCentralPubMedGoogle Scholar
  7. 7.
    Hopkins S, Linderoth E, Hantschel O et al (2012) Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis. Dev Cell 23:547–559PubMedCentralPubMedGoogle Scholar
  8. 8.
    Moscatello DK, Montgomery RB, Sundareshan P et al (1996) Transformational and altered signal transduction by a naturally occurring mutant EGF receptor. Oncogene 13:85–96PubMedGoogle Scholar
  9. 9.
    Moscatello DK, Ramirez G, Wong AJ (1997) A naturally occurring mutant human epidermal growth factor receptor as a target for peptide vaccine immunotherapy of tumors. Cancer Res 57:1419–1424PubMedGoogle Scholar
  10. 10.
    Miettinen PJ, Berger JE, Meneses J et al (1995) Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376:337–341PubMedGoogle Scholar
  11. 11.
    Miettinen PJ, Chin JR, Shum L et al (1999) Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nat Genet 22:69–73PubMedGoogle Scholar
  12. 12.
    Threadgill DW, Dlugosz AA, Hansen LA et al (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269:230–234PubMedGoogle Scholar
  13. 13.
    Kramer C, Klasmeyer K, Bojar H et al (2007) Heparin-binding epidermal growth factor-like growth factor isoforms and epidermal growth factor receptor/ErbB1 expression in bladder cancer and their relation to clinical outcome. Cancer 109:2016–2024PubMedGoogle Scholar
  14. 14.
    Moscatello DK, Holgado-Madruga M, Godwin AK et al (1995) Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 55:5536–5539PubMedGoogle Scholar
  15. 15.
    Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedGoogle Scholar
  16. 16.
    Verhaak RG, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110PubMedCentralPubMedGoogle Scholar
  17. 17.
    Antonyak MA, Kenyon LC, Godwin AK et al (2002) Elevated JNK activation contributes to the pathogenesis of human brain tumors. Oncogene 21:5038–5046PubMedGoogle Scholar
  18. 18.
    Boroughs LK, Antonyak MA, Johnson JL et al (2011) A unique role for heat shock protein 70 and its binding partner tissue transglutaminase in cancer cell migration. J Biol Chem 286:37094–37107PubMedCentralPubMedGoogle Scholar
  19. 19.
    Antonyak MA, Wilson KF, Cerione RA (2012) R(h)oads to microvesicles. Small GTPases 3:219–224PubMedCentralPubMedGoogle Scholar
  20. 20.
    Al-Nedawi K, Meehan B, Rak J (2009) Microvesicles: messengers and mediators of tumor progression. Cell Cycle 8:2014–2018PubMedGoogle Scholar
  21. 21.
    Cocucci E, Meldolesi J (2011) Ectosomes. Curr Biol 21:R940–R941PubMedGoogle Scholar
  22. 22.
    D’Souza-Schorey C, Clancy JW (2012) Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev 26:1287–1299PubMedCentralPubMedGoogle Scholar
  23. 23.
    Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19:43–51PubMedGoogle Scholar
  24. 24.
    Di Vizio D, Kim J, Hager MH et al (2009) Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease. Cancer Res 69:5601–5609PubMedCentralPubMedGoogle Scholar
  25. 25.
    Varon D, Shai E (2009) Role of platelet-derived microparticles in angiogenesis and tumor progression. Discov Med 8:237–241PubMedGoogle Scholar
  26. 26.
    Skog J, Wurdinger T, van Rijn S et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476PubMedCentralPubMedGoogle Scholar
  27. 27.
    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 10:619–624PubMedGoogle Scholar
  28. 28.
    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 U S A 106:3794–3799PubMedCentralPubMedGoogle Scholar
  29. 29.
    van der Vos KE, Balaj L, Skog J et al (2011) Brain tumor microvesicles: insights into intercellular communication in the nervous system. Cell Mol Neurobiol 31:949–959PubMedCentralPubMedGoogle Scholar
  30. 30.
    Wysoczynski M, Ratajczak MZ (2009) Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors. Int J Cancer 125:1595–1603PubMedCentralPubMedGoogle Scholar
  31. 31.
    Antonyak MA, Li B, Boroughs LK et al (2011) Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. Proc Natl Acad Sci U S A 108:4852–4857PubMedCentralPubMedGoogle Scholar
  32. 32.
    Tian T, Wang Y, Wang H et al (2010) Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J Cell Biochem 111:488–496PubMedGoogle Scholar
  33. 33.
    Rak J (2010) Microparticles in cancer. Semin Thromb Hemost 36:888–906PubMedGoogle Scholar
  34. 34.
    Ge R, Tan E, Sharghi-Namini S et al (2012) Exosomes in cancer microenvironment and beyond: have we overlooked these extracellular messengers? Cancer Microenviron 5:323–332PubMedCentralPubMedGoogle Scholar
  35. 35.
    Di Vizio D, Morello M, Dudley AC et al (2012) Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am J Pathol 181:1573–1584PubMedCentralPubMedGoogle Scholar
  36. 36.
    Ginestra A, La Placa MD, Saladino F et al (1998) The amount and proteolytic content of vesicles shed by human cancer cell lines correlates with their in vitro invasiveness. Anticancer Res 18:3433–3437PubMedGoogle Scholar
  37. 37.
    Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteomics 73:1907–1920PubMedGoogle Scholar
  38. 38.
    Teis D, Saksena S, Emr SD (2009) SnapShot: the ESCRT machinery. Cell 137:182–182 e181Google Scholar
  39. 39.
    Ceruti S, Colombo L, Magni G et al (2011) Oxygen-glucose deprivation increases the enzymatic activity and the microvesicle-mediated release of ectonucleotidases in the cells composing the blood–brain barrier. Neurochem Int 59:259–271PubMedGoogle Scholar
  40. 40.
    Hanson PI, Cashikar A (2012) Multivesicular body morphogenesis. Annu Rev Cell Dev Biol 28:337–362PubMedGoogle Scholar
  41. 41.
    Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171PubMedGoogle Scholar
  42. 42.
    Muralidharan-Chari V, Clancy JW, Sedgwick A et al (2010) Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci 123:1603–1611PubMedCentralPubMedGoogle Scholar
  43. 43.
    Muralidharan-Chari V, Clancy J, Plou C et al (2009) ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr Biol 19:1875–1885PubMedCentralPubMedGoogle Scholar
  44. 44.
    Hosseini-Beheshti E, Pham S, Adomat H et al (2012) Exosomes as biomarker enriched microvesicles: characterization of exosomal proteins derived from a panel of prostate cell lines with distinct AR phenotypes. Mol Cell Proteomics 11:863–885PubMedCentralPubMedGoogle Scholar
  45. 45.
    Li B, Antonyak MA, Zhang J et al (2012) RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells. Oncogene 31:4740–4749PubMedCentralPubMedGoogle Scholar
  46. 46.
    Scott G (2012) Demonstration of melanosome transfer by a shedding microvesicle mechanism. J Invest Dermatol 132:1073–1074PubMedGoogle Scholar
  47. 47.
    Shen B, Wu N, Yang JM et al (2011) Protein targeting to exosomes/microvesicles by plasma membrane anchors. J Biol Chem 286:14383–14395PubMedCentralPubMedGoogle Scholar
  48. 48.
    Balaj L, Lessard R, Dai L et al (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2:180PubMedCentralPubMedGoogle Scholar
  49. 49.
    Choi DS, Lee JM, Park GW et al (2007) Proteomic analysis of microvesicles derived from human colorectal cancer cells. J Proteome Res 6:4646–4655PubMedGoogle Scholar
  50. 50.
    Gallo A, Tandon M, Alevizos I et al (2012) The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One 7:e30679PubMedCentralPubMedGoogle Scholar
  51. 51.
    Graner MW, Alzate O, Dechkovskaia AM et al (2009) Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 23:1541–1557PubMedCentralPubMedGoogle Scholar
  52. 52.
    Grange C, Tapparo M, Collino F et al (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71:5346–5356PubMedGoogle Scholar
  53. 53.
    Noerholm M, Balaj L, Limperg T et al (2012) RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. BMC Cancer 12:22PubMedCentralPubMedGoogle Scholar
  54. 54.
    Zhuang G, Wu X, Jiang Z et al (2012) Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J 31:3513–3523PubMedCentralPubMedGoogle Scholar
  55. 55.
    Baran J, Baj-Krzyworzeka M, Weglarczyk K et al (2010) Circulating tumour-derived microvesicles in plasma of gastric cancer patients. Cancer Immunol Immunother 59:841–850PubMedGoogle Scholar
  56. 56.
    Marcucci G, Mrozek K, Radmacher MD et al (2009) MicroRNA expression profiling in acute myeloid and chronic lymphocytic leukaemias. Best Pract Res Clin Haematol 22:239–248PubMedGoogle Scholar
  57. 57.
    Sandvig K, Llorente A (2012) Proteomic analysis of microvesicles released by the human prostate cancer cell line PC-3. Mol Cell Proteomics 11:M111.012914PubMedCentralPubMedGoogle Scholar
  58. 58.
    Zhou Q, Souba WW, Croce CM et al (2010) MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome. Gut 59:775–784PubMedCentralPubMedGoogle Scholar
  59. 59.
    Del Conde I, Bharwani LD, Dietzen DJ et al (2007) Microvesicle-associated tissue factor and Trousseau’s syndrome. J Thromb Haemost 5:70–74PubMedCentralPubMedGoogle Scholar
  60. 60.
    Graves LE, Ariztia EV, Navari JR et al (2004) Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Res 64:7045–7049PubMedGoogle Scholar
  61. 61.
    Chen C, Skog J, Hsu CH et al (2010) Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 10:505–511PubMedCentralPubMedGoogle Scholar
  62. 62.
    Owen DM, Magenau A, Williamson D et al (2012) The lipid raft hypothesis revisited: new insights on raft composition and function from super-resolution fluorescence microscopy. Bioessays 34:739–747PubMedGoogle Scholar
  63. 63.
    Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572PubMedGoogle Scholar
  64. 64.
    Gangalum RK, Atanasov IC, Zhou ZH et al (2011) AlphaB-crystallin is found in detergent-resistant membrane microdomains and is secreted via exosomes from human retinal pigment epithelial cells. J Biol Chem 286:3261–3269PubMedCentralPubMedGoogle Scholar
  65. 65.
    Lopez JA, del Conde I, Shrimpton CN (2005) Receptors, rafts, and microvesicles in thrombosis and inflammation. J Thromb Haemost 3:1737–1744PubMedGoogle Scholar
  66. 66.
    Mairhofer M, Steiner M, Mosgoeller W et al (2002) Stomatin is a major lipid-raft component of platelet alpha granules. Blood 100:897–904PubMedGoogle Scholar
  67. 67.
    Del Conde I, Shrimpton CN, Thiagarajan P et al (2005) Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106:1604–1611PubMedGoogle Scholar
  68. 68.
    Liu ML, Scalia R, Mehta JL et al (2012) Cholesterol-induced membrane microvesicles as novel carriers of damage-associated molecular patterns: mechanisms of formation, action, and detoxification. Arterioscler Thromb Vasc Biol 32:2113–2121PubMedGoogle Scholar
  69. 69.
    Pomorski T, Menon AK (2006) Lipid flippases and their biological functions. Cell Mol Life Sci 63:2908–2921PubMedGoogle Scholar
  70. 70.
    Seigneuret M, Devaux PF (1984) ATP-dependent asymmetric distribution of spin-labeled phospholipids in the erythrocyte membrane: relation to shape changes. Proc Natl Acad Sci U S A 81:3751–3755PubMedCentralPubMedGoogle Scholar
  71. 71.
    Contreras FX, Sanchez-Magraner L, Alonso A et al (2010) Transbilayer (flip-flop) lipid motion and lipid scrambling in membranes. FEBS Lett 584:1779–1786PubMedGoogle Scholar
  72. 72.
    Dasgupta SK, Abdel-Monem H, Niravath P et al (2009) Lactadherin and clearance of platelet-derived microvesicles. Blood 113:1332–1339PubMedCentralPubMedGoogle Scholar
  73. 73.
    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 283:168–175PubMedGoogle Scholar
  74. 74.
    Collino F, Deregibus MC, Bruno S et al (2010) Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One 5:e11803PubMedCentralPubMedGoogle Scholar
  75. 75.
    Meng Y, Kang S, Fishman DA (2005) Lysophosphatidic acid stimulates fas ligand microvesicle release from ovarian cancer cells. Cancer Immunol Immunother 54:807–814PubMedGoogle Scholar
  76. 76.
    Charras GT, Hu CK, Coughlin M et al (2006) Reassembly of contractile actin cortex in cell blebs. J Cell Biol 175:477–490PubMedCentralPubMedGoogle Scholar
  77. 77.
    Fackler OT, Grosse R (2008) Cell motility through plasma membrane blebbing. J Cell Biol 181:879–884PubMedCentralPubMedGoogle Scholar
  78. 78.
    Heasman SJ, Ridley AJ (2008) Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 9:690–701PubMedGoogle Scholar
  79. 79.
    Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7:737–749PubMedGoogle Scholar
  80. 80.
    Hahmann C, Schroeter T (2010) Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity. Cell Mol Life Sci 67:171–177PubMedGoogle Scholar
  81. 81.
    Mizuno K (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cell Signal 25: 457–469PubMedGoogle Scholar
  82. 82.
    Narumiya S, Ishizaki T, Uehata M (2000) Use and properties of ROCK-specific inhibitor Y-27632. Methods Enzymol 325:273–284PubMedGoogle Scholar
  83. 83.
    Narumiya S, Tanji M, Ishizaki T (2009) Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 28:65–76PubMedGoogle Scholar
  84. 84.
    Sahai E, Ishizaki T, Narumiya S et al (1999) Transformation mediated by RhoA requires activity of ROCK kinases. Curr Biol 9:136–145PubMedGoogle Scholar
  85. 85.
    Del Vecchio CA, Li G, Wong AJ (2012) Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev Vaccines 11:133–144PubMedGoogle Scholar
  86. 86.
    Corcoran C, Rani S, O’Brien K et al (2012) Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One 7:e50999PubMedCentralPubMedGoogle Scholar
  87. 87.
    Lehmann BD, Paine MS, Brooks AM et al (2008) Senescence-associated exosome release from human prostate cancer cells. Cancer Res 68:7864–7871PubMedGoogle Scholar
  88. 88.
    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 63:4331–4337PubMedGoogle Scholar
  89. 89.
    Svensson KJ, Kucharzewska P, Christianson HC et al (2011) Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci U S A 108:13147–13152PubMedCentralPubMedGoogle Scholar
  90. 90.
    Erickson JW, Cerione RA (2010) Glutaminase: a hot spot for regulation of cancer cell metabolism? Oncotarget 1:734–740PubMedCentralPubMedGoogle Scholar
  91. 91.
    Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11:325–337PubMedGoogle Scholar
  92. 92.
    Wilson KF, Erickson JW, Antonyak MA et al (2013) Rho GTPases and their roles in cancer metabolism. Trends Mol Med 19:74–82PubMedCentralPubMedGoogle Scholar
  93. 93.
    Altieri DC (2008) New wirings in the survivin networks. Oncogene 27:6276–6284PubMedCentralPubMedGoogle Scholar
  94. 94.
    Cheung CH, Cheng L, Chang KY et al (2011) Investigations of survivin: the past, present and future. Front Biosci 16:952–961Google Scholar
  95. 95.
    Honegger A, Leitz J, Bulkescher J et al (2013) Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and amounts of extracellular microvesicles released from HPV-positive cancer cells. Int J Cancer 133:1631–1642. doi: 10.1002/ijc.28164 PubMedGoogle Scholar
  96. 96.
    Khan S, Jutzy JM, Aspe JR et al (2011) Survivin is released from cancer cells via exosomes. Apoptosis 16:1–12PubMedCentralPubMedGoogle Scholar
  97. 97.
    Khan S, Jutzy JM, Valenzuela MM et al (2012) Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. PLoS One 7:e46737PubMedCentralPubMedGoogle Scholar
  98. 98.
    Taylor DD, Gercel-Taylor C, Parker LP (2009) Patient-derived tumor-reactive antibodies as diagnostic markers for ovarian cancer. Gynecol Oncol 115:112–120PubMedCentralPubMedGoogle Scholar
  99. 99.
    Fujita M, Kinoshita T (2012) GPI-anchor remodeling: potential functions of GPI-anchors in intracellular trafficking and membrane dynamics. Biochim Biophys Acta 1821: 1050–1058PubMedGoogle Scholar
  100. 100.
    Muller G, Schneider M, Biemer-Daub G et al (2011) Microvesicles released from rat adipocytes and harboring glycosylphosphatidylinositol-anchored proteins transfer RNA stimulating lipid synthesis. Cell Signal 23: 1207–1223PubMedGoogle Scholar
  101. 101.
    Hao S, Ye Z, Li F et al (2006) Epigenetic transfer of metastatic activity by uptake of highly metastatic B16 melanoma cell-released exosomes. Exp Oncol 28:126–131PubMedGoogle Scholar
  102. 102.
    Hessvik NP, Phuyal S, Brech A et al (2012) Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochim Biophys Acta 1819:1154–1163PubMedGoogle Scholar
  103. 103.
    Chiba M, Kimura M, Asari S (2012) Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncol Rep 28:1551–1558PubMedCentralPubMedGoogle Scholar
  104. 104.
    Bolukbasi MF, Mizrak A, Ozdener GB et al (2012) miR-1289 and “Zipcode”-like sequence enrich mRNAs in microvesicles. Mol Ther Nucleic Acids 1:e10PubMedCentralPubMedGoogle Scholar
  105. 105.
    Faini M, Beck R, Wieland FT et al (2013) Vesicle coats: structure, function, and general principles of assembly. Trends Cell Biol 23:279–288. doi: 10.1016/j.tcb.2013.01.005 PubMedGoogle Scholar
  106. 106.
    Donaldson JG, Jackson CL (2011) ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat Rev Mol Cell Biol 12:362–375PubMedCentralPubMedGoogle Scholar
  107. 107.
    Martins VR, Dias MS, Hainaut P (2013) Tumor-cell-derived microvesicles as carriers of molecular information in cancer. Curr Opin Oncol 25:66–75PubMedGoogle Scholar
  108. 108.
    Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18: 884–901PubMedCentralPubMedGoogle Scholar
  109. 109.
    Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337PubMedCentralPubMedGoogle Scholar
  110. 110.
    Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedGoogle Scholar
  111. 111.
    Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481:306–313PubMedCentralPubMedGoogle Scholar
  112. 112.
    Redmond KM, Wilson TR, Johnston PG et al (2008) Resistance mechanisms to cancer chemotherapy. Front Biosci 13:5138–5154PubMedGoogle Scholar
  113. 113.
    Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310PubMedGoogle Scholar
  114. 114.
    Campanella C, Bucchieri F, Merendino AM et al (2012) The odyssey of Hsp60 from tumor cells to other destinations includes plasma membrane-associated stages and Golgi and exosomal protein-trafficking modalities. PLoS One 7:e42008PubMedCentralPubMedGoogle Scholar
  115. 115.
    Chalmin F, Ladoire S, Mignot G et al (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471PubMedCentralPubMedGoogle Scholar
  116. 116.
    McCready J, Sims JD, Chan D et al (2010) Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer 10:294PubMedCentralPubMedGoogle Scholar
  117. 117.
    Morimoto RI (2011) The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb Symp Quant Biol 76:91–99PubMedGoogle Scholar
  118. 118.
    Rappa F, Farina F, Zummo G et al (2012) HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview. Anticancer Res 32:5139–5150PubMedGoogle Scholar
  119. 119.
    Safaei R, Larson BJ, Cheng TC et al (2005) Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 4:1595–1604PubMedGoogle Scholar
  120. 120.
    Boing AN, Hau CM, Sturk A et al (2008) Platelet microparticles contain active caspase 3. Platelets 19:96–103PubMedGoogle Scholar
  121. 121.
    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 108:1868–1876PubMedGoogle Scholar
  122. 122.
    Abid Hussein MN, Boing AN, Sturk A et al (2007) Inhibition of microparticle release triggers endothelial cell apoptosis and detachment. Thromb Haemost 98:1096–1107PubMedGoogle Scholar
  123. 123.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410PubMedGoogle Scholar
  124. 124.
    Gialeli C, Theocharis AD, Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278:16–27PubMedGoogle Scholar
  125. 125.
    Dolo V, D’Ascenzo S, Violini S et al (1999) Matrix-degrading proteinases are shed in membrane vesicles by ovarian cancer cells in vivo and in vitro. Clin Exp Metastasis 17:131–140PubMedGoogle Scholar
  126. 126.
    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 46:1199–1209PubMedGoogle Scholar
  127. 127.
    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 113:752–760PubMedGoogle Scholar
  128. 128.
    Braundmeier AG, Dayger CA, Mehrotra P et al (2012) EMMPRIN is secreted by human uterine epithelial cells in microvesicles and stimulates metalloproteinase production by human uterine fibroblast cells. Reprod Sci 19:1292–1301PubMedGoogle Scholar
  129. 129.
    Millimaggi D, Mari M, D’Ascenzo S et al (2007) Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia 9:349–357PubMedCentralPubMedGoogle Scholar
  130. 130.
    Abe T, Okamura K, Ono M et al (1993) Induction of vascular endothelial tubular morphogenesis by human glioma cells. A model system for tumor angiogenesis. J Clin Invest 92:54–61PubMedCentralPubMedGoogle Scholar
  131. 131.
    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 55:808–818PubMedGoogle Scholar
  132. 132.
    Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107:1047–1057PubMedGoogle Scholar
  133. 133.
    Joosse SA, Pantel K (2013) Biologic challenges in the detection of circulating tumor cells. Cancer Res 73:8–11PubMedGoogle Scholar
  134. 134.
    Peinado H, Aleckovic M, Lavotshkin S et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891PubMedCentralPubMedGoogle Scholar
  135. 135.
    Shao H, Chung J, Balaj L et al (2012) Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med 18:1835–1840PubMedCentralPubMedGoogle Scholar
  136. 136.
    Aliotta JM, Pereira M, Johnson KW et al (2010) Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp Hematol 38:233–245PubMedCentralPubMedGoogle Scholar
  137. 137.
    Nilsson J, Skog J, Nordstrand A et al (2009) Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer 100:1603–1607PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Molecular MedicineCornell UniversityIthacaUSA
  2. 2.Department of Molecular Medicine, C3-155 Veterinary Medical CenterCornell UniversityIthacaUSA

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