Advertisement

Clinical and Translational Oncology

, Volume 19, Issue 8, pp 921–930 | Cite as

The role of pancreatic cancer-derived exosomes in cancer progress and their potential application as biomarkers

  • H. Jin
  • Y. Wu
  • X. TanEmail author
Review Article

Abstract

Pancreatic cancer is one of the most deadly cancers, with dismal prognosis due to its poor early detection rate and high metastatic rate. Thus, elucidation of the molecular mechanisms accounting for its metastasis and discovery of competent biomarkers is required. Exosomes are multivesicular body-derived small extracellular vesicles released by various cell types that serve as important message carriers during intercellular communication. They are also known to play critical roles during cancer-genesis, cancer-related immune reactions, and metastasis. They also possess promising potential as novel biomarkers for cancer early detection. Therefore, extensive studies on pancreatic cancer-derived exosomes are currently being performed because they hold the promising potential of elevating the overall survival rate of patients with pancreatic cancer. In the present review, we focus on the role of exosomes in pancreatic cancer-related immune reactions, metastasis, and complications, and on their potential application as pancreatic cancer biomarkers.

Keywords

Cancer biomarker Exosomes Immunology Metastasis Pancreatic cancer 

Abbreviations

AFM

Atomic force microscopy

BM

Bone marrow

CAFs

Cancer-associated fibroblasts

crExos

Circulating exosomes

CP

Chronic pancreatitis

CSC

Cancer stem cell

DCs

Dendritic cells

ESCRT

Endosomal sorting complex required for transport

EMT

Epithelial mesenchymal transition

exoDNA

Exosomal DNA

exoRNA

Exosomal RNA

EVs

Extracellular vesicles

FACS

Fluorescence-activated cell sorting

GPC1

Glypican-1

ISEV

International Society for Extracellular Vesicles

ILVs

Intraluminal vesicles

LSPR

Localized surface plasmon resonance

MIF

Macrophage migration inhibitory factor

MVB

Multivesicular body

NK cells

Nature-killing cells

PaCa

Pancreatic cancer

PDAC

Pancreatic ductal adenocarcinomas

PMs

Plasma membranes

PEG

Polyethylene glycol

PKM

Pyruvate kinase

SNARE

Soluble N-ethylmaleimide-sensitive fusion attachment protein receptors

SAW

Surface acoustic wave

TGF-β

Transforming growth factor β

TEM

Transmission electron microscopy

UC

Ultracentrifugation

Notes

Compliance with ethical standards

This study was funded by the Outstanding Scientific Fund of Shengjing Hospital (grant number M731).

Conflict of interest

The authors have no potential conflicts of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17(6):816–26. doi: 10.1038/ncb3169.CrossRefPubMedGoogle Scholar
  2. 2.
    Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–23. doi: 10.1016/j.stem.2007.06.002.CrossRefPubMedGoogle Scholar
  3. 3.
    Li CW, Heidt DG, Dalerba P, Burant CF, Zhang LJ, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030–7. doi: 10.1158/0008-5472.CAN-06-2030.CrossRefPubMedGoogle Scholar
  4. 4.
    Lonardo E, Hermann PC, Heeschen C. Pancreatic cancer stem cells—update and future perspectives. Mol Oncol. 2010;4(5):431–42. doi: 10.1016/j.molonc.2010.06.002.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang H, Rana S, Giese N, Buchler MW, Zoller M. Tspan8, CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer-initiating cells. Int J Cancer. 2013;133(2):416–26. doi: 10.1002/ijc.28044.CrossRefPubMedGoogle Scholar
  6. 6.
    Madhavan B, Yue S, Galli U, Rana S, Gross W, Muller M, et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer. 2015;136(11):2616–27. doi: 10.1002/ijc.29324.CrossRefPubMedGoogle Scholar
  7. 7.
    Heiler S, Wang Z, Zoller M. Pancreatic cancer stem cell markers and exosomes—the incentive push. World J Gastroenterol. 2016;22(26):5971–6007. doi: 10.3748/wjg.v22.i26.5971.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164(6):1226–32. doi: 10.1016/j.cell.2016.01.043.CrossRefPubMedGoogle Scholar
  9. 9.
    Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93. doi: 10.1038/nri2567.CrossRefPubMedGoogle Scholar
  10. 10.
    Chaput N, Thery C. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol. 2011;33(5):419–40. doi: 10.1007/s00281-010-0233-9.CrossRefPubMedGoogle Scholar
  11. 11.
    Rak J. Extracellular vesicles—biomarkers and effectors of the cellular interactome in cancer. Front Pharmacol. 2013;4:21. doi: 10.3389/fphar.2013.00021.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9. doi: 10.1038/ncb1596.CrossRefPubMedGoogle Scholar
  13. 13.
    Bobrie A, Colombo M, Raposo G, Thery C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic. 2011;12(12):1659–68. doi: 10.1111/j.1600-0854.2011.01225.x.CrossRefPubMedGoogle Scholar
  14. 14.
    Marques-Garcia F, Isidoro-Garcia M. Protocols for exosome isolation and RNA profiling. Methods Mol Biol. 2016;1434:153–67. doi: 10.1007/978-1-4939-3652-6_11.CrossRefPubMedGoogle Scholar
  15. 15.
    Min L, Shen J, Tu C, Hornicek F, Duan Z. The roles and implications of exosomes in sarcoma. Cancer Metastasis Rev. 2016;. doi: 10.1007/s10555-016-9630-4.PubMedGoogle Scholar
  16. 16.
    Greening DW, Gopal SK, Mathias RA, Liu L, Sheng J, Zhu HJ, et al. Emerging roles of exosomes during epithelial–mesenchymal transition and cancer progression. Semin Cell Dev Biol. 2015;40:60–71. doi: 10.1016/j.semcdb.2015.02.008.CrossRefPubMedGoogle Scholar
  17. 17.
    Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM. Exosome mediated communication within the tumor microenvironment. J Control Release. 2015;219:278–94. doi: 10.1016/j.jconrel.2015.06.029.CrossRefPubMedGoogle Scholar
  18. 18.
    An T, Qin S, Xu Y, Tang Y, Huang Y, Situ B, et al. Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. J Extracell Vesicles. 2015;4:27522. doi: 10.3402/jev.v4.27522.CrossRefPubMedGoogle Scholar
  19. 19.
    Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3:26913. doi: 10.3402/jev.v3.26913.CrossRefPubMedGoogle Scholar
  20. 20.
    Lener T, Gimona M, Aigner L, Borger V, Buzas E, Camussi G, et al. Applying extracellular vesicles based therapeutics in clinical trials—an ISEV position paper. J Extracell Vesicles. 2015;4:30087. doi: 10.3402/jev.v4.30087.CrossRefPubMedGoogle Scholar
  21. 21.
    Cheung KH, Keerthikumar S, Roncaglia P, Subramanian SL, Roth ME, Samuel M, et al. Extending gene ontology in the context of extracellular RNA and vesicle communication. J Biomed Semant. 2016;7:19. doi: 10.1186/s13326-016-0061-5.CrossRefGoogle Scholar
  22. 22.
    Dreyer F, Baur A. Biogenesis and functions of exosomes and extracellular vesicles. Methods Mol Biol. 2016;1448:201–16. doi: 10.1007/978-1-4939-3753-0_15.CrossRefPubMedGoogle Scholar
  23. 23.
    Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89. doi: 10.1146/annurev-cellbio-101512-122326.CrossRefPubMedGoogle Scholar
  24. 24.
    Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2. doi: 10.3402/jev.v2i0.20360.
  25. 25.
    Kowal J, Tkach M, Thery C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–25. doi: 10.1016/j.ceb.2014.05.004.CrossRefPubMedGoogle Scholar
  26. 26.
    Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24(6):766–9. doi: 10.1038/cr.2014.44.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hill AF, Pegtel DM, Lambertz U, Leonardi T, O’Driscoll L, Pluchino S, et al. ISEV position paper: extracellular vesicle RNA analysis and bioinformatics. J Extracell Vesicles. 2013;2. doi: 10.3402/jev.v2i0.22859.
  28. 28.
    Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA. 2016;113(8):E968–77. doi: 10.1073/pnas.1521230113.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Szatanek R, Baran J, Siedlar M, Baj-Krzyworzeka M. Isolation of extracellular vesicles: determining the correct approach (Review). Int J Mol Med. 2015;36(1):11–7. doi: 10.3892/ijmm.2015.2194.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Nolte-’t Hoen E, Cremer T, Gallo RC, Margolis LB. Extracellular vesicles and viruses: are they close relatives? Proc Natl Acad Sci USA. 2016;. doi: 10.1073/pnas.1605146113.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):19–30; sup pp 1–13. doi: 10.1038/ncb2000.
  32. 32.
    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(1):216–23. doi: 10.1182/blood-2005-01-0220.CrossRefPubMedGoogle Scholar
  33. 33.
    Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004;104(10):3257–66. doi: 10.1182/blood-2004-03-0824.CrossRefPubMedGoogle Scholar
  34. 34.
    Zeelenberg IS, van Maren WW, Boissonnas A, Van Hout-Kuijer MA, Den Brok MH, Wagenaars JA, et al. Antigen localization controls T cell-mediated tumor immunity. J Immunol. 2011;187(3):1281–8. doi: 10.4049/jimmunol.1003905.CrossRefPubMedGoogle Scholar
  35. 35.
    Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001;7(3):297–303. doi: 10.1038/85438.CrossRefPubMedGoogle Scholar
  36. 36.
    Zech D, Rana S, Buchler MW, Zoller M. Tumor-exosomes and leukocyte activation: an ambivalent crosstalk. Cell Commun Signal. 2012;10(1):37. doi: 10.1186/1478-811X-10-37.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Muller L, Mitsuhashi M, Simms P, Gooding WE, Whiteside TL. Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets. Sci Rep. 2016;6:20254. doi: 10.1038/srep20254.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Whiteside TL. Exosomes and tumor-mediated immune suppression. J Clin Invest. 2016;126(4):1216–23. doi: 10.1172/JCI81136.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol. 2011;21(2):139–46. doi: 10.1016/j.semcancer.2011.01.002.CrossRefPubMedGoogle Scholar
  40. 40.
    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(6):883–91. doi: 10.1038/nm.2753.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35. doi: 10.1038/nature15756.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Rana S, Malinowska K, Zoller M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia. 2013;15(3):281–95.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Rana S, Yue S, Stadel D, Zoller M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol. 2012;44(9):1574–84. doi: 10.1016/j.biocel.2012.06.018.CrossRefPubMedGoogle Scholar
  44. 44.
    Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527(7576):100–4. doi: 10.1038/nature15376.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 2010;70(4):1668–78. doi: 10.1158/0008-5472.CAN-09-2470.CrossRefPubMedGoogle Scholar
  46. 46.
    Yoon YJ, Kim DK, Yoon CM, Park J, Kim YK, Roh TY, et al. Egr-1 activation by cancer-derived extracellular vesicles promotes endothelial cell migration via ERK1/2 and JNK signaling pathways. PLoS One. 2014;9(12):e115170. doi: 10.1371/journal.pone.0115170.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kim J, Morley S, Le M, Bedoret D, Umetsu DT, Di Vizio D, et al. Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells: potential effects on the tumor microenvironment. Cancer Biol Ther. 2014;15(4):409–18. doi: 10.4161/cbt.27627.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    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(5):619–24. doi: 10.1038/ncb1725.CrossRefPubMedGoogle Scholar
  49. 49.
    Luga V, Wrana JL. Tumor-stroma interaction: revealing fibroblast-secreted exosomes as potent regulators of Wnt-planar cell polarity signaling in cancer metastasis. Cancer Res. 2013;73(23):6843–7. doi: 10.1158/0008-5472.CAN-13-1791.CrossRefPubMedGoogle Scholar
  50. 50.
    Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, et al. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun. 2015;6:6716. doi: 10.1038/ncomms7716.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Hood JL, Pan H, Lanza GM, Wickline SA. Consortium for translational research in advanced I, nanomedicine. Paracrine induction of endothelium by tumor exosomes. Lab Investig. 2009;89(11):1317–28. doi: 10.1038/labinvest.2009.94.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25(4):501–15. doi: 10.1016/j.ccr.2014.03.007.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci USA. 2009;106(10):3794–9. doi: 10.1073/pnas.0804543106.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 2015;17(2):183–94. doi: 10.1038/ncb3094.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Cha DJ, Franklin JL, Dou Y, Liu Q, Higginbotham JN, Demory Beckler M, et al. KRAS-dependent sorting of miRNA to exosomes. eLife. 2015;4:e07197. doi: 10.7554/eLife.07197.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Wang Z, von Au A, Schnolzer M, Hackert T, Zoller M. CD44v6-competent tumor exosomes promote motility, invasion and cancer-initiating cell marker expression. Oncotarget. 2016;. doi: 10.18632/oncotarget.10580.Google Scholar
  57. 57.
    Lugini L, Valtieri M, Federici C, Cecchetti S, Meschini S, Condello M, et al. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells. Oncotarget. 2016;. doi: 10.18632/oncotarget.10574.PubMedGoogle Scholar
  58. 58.
    Zomer A, Maynard C, Verweij FJ, Kamermans A, Schafer R, Beerling E, et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015;161(5):1046–57. doi: 10.1016/j.cell.2015.04.042.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2016;. doi: 10.1038/onc.2016.353.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Leca J, Martinez S, Lac S, Nigri J, Secq V, Rubis M, et al. Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. J Clin Investig. 2016;. doi: 10.1172/JCI87734.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Javeed N, Sagar G, Dutta SK, Smyrk TC, Lau JS, Bhattacharya S, et al. Pancreatic cancer-derived exosomes cause paraneoplastic beta-cell dysfunction. Clin Cancer Res. 2015;21(7):1722–33. doi: 10.1158/1078-0432.CCR-14-2022.CrossRefPubMedGoogle Scholar
  62. 62.
    Sagar G, Sah RP, Javeed N, Dutta SK, Smyrk TC, Lau JS, et al. Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. Gut. 2016;65(7):1165–74. doi: 10.1136/gutjnl-2014-308350.CrossRefPubMedGoogle Scholar
  63. 63.
    Vader P, Breakefield XO, Wood MJ. Extracellular vesicles: emerging targets for cancer therapy. Trends Mol Med. 2014;20(7):385–93. doi: 10.1016/j.molmed.2014.03.002.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology. 2016;5(4):e1071008. doi: 10.1080/2162402X.2015.1071008.CrossRefPubMedGoogle Scholar
  65. 65.
    Ohno S, Kuroda M. Exosome-mediated targeted delivery of miRNAs. Methods Mol Biol. 2016;1448:261–70. doi: 10.1007/978-1-4939-3753-0_19.CrossRefPubMedGoogle Scholar
  66. 66.
    Erb U, Zoller M. Progress and potential of exosome analysis for early pancreatic cancer detection. Expert Rev Mol Diagn. 2016;16(7):757–67. doi: 10.1080/14737159.2016.1187563.CrossRefPubMedGoogle Scholar
  67. 67.
    Patel GK, Patton MC, Singh S, Khushman M, Singh AP. Pancreatic cancer exosomes: shedding off for a meaningful journey. Pancreat Disord Therapy. 2016;6(2):e148. doi: 10.4172/2165-7092.1000e148.CrossRefGoogle Scholar
  68. 68.
    Lu L, Risch HA. Exosomes: potential for early detection in pancreatic cancer. Future Oncol. 2016;12(8):1081–90. doi: 10.2217/fon-2015-0005.CrossRefPubMedGoogle Scholar
  69. 69.
    Babic A, Wolpin BM. Circulating exosomes in pancreatic cancer: will they succeed on the long, littered road to early detection marker? Clin Chem. 2016;62(2):307–9. doi: 10.1373/clinchem.2015.246538.CrossRefPubMedGoogle Scholar
  70. 70.
    Torrano V, Royo F, Peinado H, Loizaga-Iriarte A, Unda M, Falcon-Perez JM, et al. Vesicle-MaNiA: extracellular vesicles in liquid biopsy and cancer. Curr Opin Pharmacol. 2016;29:47–53. doi: 10.1016/j.coph.2016.06.003.CrossRefPubMedGoogle Scholar
  71. 71.
    Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523(7559):177–82. doi: 10.1038/nature14581.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Thery C. Cancer: diagnosis by extracellular vesicles. Nature. 2015;523(7559):161–2. doi: 10.1038/nature14626.CrossRefPubMedGoogle Scholar
  73. 73.
    Que R, Ding G, Chen J, Cao L. Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma. World J Surg Oncol. 2013;11:219. doi: 10.1186/1477-7819-11-219.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Taller D, Richards K, Slouka Z, Senapati S, Hill R, Go DB, et al. On-chip surface acoustic wave lysis and ion-exchange nanomembrane detection of exosomal RNA for pancreatic cancer study and diagnosis. Lab Chip. 2015;15(7):1656–66. doi: 10.1039/c5lc00036j.CrossRefPubMedGoogle Scholar
  75. 75.
    Joshi GK, Deitz-McElyea S, Liyanage T, Lawrence K, Mali S, Sardar R, et al. Label-free nanoplasmonic-based short noncoding RNA sensing at attomolar concentrations allows for quantitative and highly specific assay of MicroRNA-10b in biological fluids and circulating exosomes. ACS Nano. 2015;9(11):11075–89. doi: 10.1021/acsnano.5b04527.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    San Lucas FA, Allenson K, Bernard V, Castillo J, Kim DU, Ellis K, et al. Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes. Ann Oncol. 2016;27(4):635–41. doi: 10.1093/annonc/mdv604.CrossRefPubMedGoogle Scholar
  77. 77.
    Lau C, Kim Y, Chia D, Spielmann N, Eibl G, Elashoff D, et al. Role of pancreatic cancer-derived exosomes in salivary biomarker development. J Biol Chem. 2013;288(37):26888–97. doi: 10.1074/jbc.M113.452458.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, et al. CD90 + liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer. 2015;14:155. doi: 10.1186/s12943-015-0426-x.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Wunsch BH, Smith JT, Gifford SM, Wang C, Brink M, Bruce RL, et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nat Nanotechnol. 2016;11(11):936–40. doi: 10.1038/nnano.2016.134.CrossRefPubMedGoogle Scholar
  80. 80.
    Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, et al. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods. 2012;56(2):293–304. doi: 10.1016/j.ymeth.2012.01.002.CrossRefPubMedGoogle Scholar
  81. 81.
    Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protocols Cell Biol. 2006;Chapter 3:Unit 3 22. doi: 10.1002/0471143030.cb0322s30.
  82. 82.
    Van Deun J, Mestdagh P, Sormunen R, Cocquyt V, Vermaelen K, Vandesompele J, et al. The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J Extracell Vesicles. 2014;3. doi: 10.3402/jev.v3.24858.
  83. 83.
    Paolini L, Zendrini A, Di Noto G, Busatto S, Lottini E, Radeghieri A, et al. Residual matrix from different separation techniques impacts exosome biological activity. Sci Rep. 2016;6:23550. doi: 10.1038/srep23550.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Lobb RJ, Becker M, Wen SW, Wong CS, Wiegmans AP, Leimgruber A, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles. 2015;4:27031. doi: 10.3402/jev.v4.27031.CrossRefPubMedGoogle Scholar
  85. 85.
    Alvarez ML, Khosroheidari M, Kanchi Ravi R, DiStefano JK. Comparison of protein, microRNA, and mRNA yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers. Kidney Int. 2012;82(9):1024–32. doi: 10.1038/ki.2012.256.CrossRefPubMedGoogle Scholar
  86. 86.
    Weng Y, Sui Z, Shan Y, Hu Y, Chen Y, Zhang L, et al. Effective isolation of exosomes with polyethylene glycol from cell culture supernatant for in-depth proteome profiling. Analyst. 2016;. doi: 10.1039/c6an00892e.Google Scholar
  87. 87.
    Kalra H, Adda CG, Liem M, Ang CS, Mechler A, Simpson RJ, et al. Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma. Proteomics. 2013;13(22):3354–64. doi: 10.1002/pmic.201300282.CrossRefPubMedGoogle Scholar
  88. 88.
    Kanwar SS, Dunlay CJ, Simeone DM, Nagrath S. Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes. Lab Chip. 2014;14(11):1891–900. doi: 10.1039/c4lc00136b.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Chen C, Skog J, Hsu CH, Lessard RT, Balaj L, Wurdinger T, et al. Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip. 2010;10(4):505–11. doi: 10.1039/b916199f.CrossRefPubMedGoogle Scholar
  90. 90.
    He M, Crow J, Roth M, Zeng Y, Godwin AK. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab Chip. 2014;14(19):3773–80. doi: 10.1039/c4lc00662c.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Boing AN, van der Pol E, Grootemaat AE, Coumans FA, Sturk A, Nieuwland R. Single-step isolation of extracellular vesicles by size-exclusion chromatography. J Extracell Vesicles. 2014;3. doi: 10.3402/jev.v3.23430.
  92. 92.
    Ding G, Zhou L, Qian Y, Fu M, Chen J, Chen J, et al. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget. 2015;6(30):29877–88. doi: 10.18632/oncotarget.4924.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L. Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol. 2014;292(1–2):65–9. doi: 10.1016/j.cellimm.2014.09.004.CrossRefPubMedGoogle Scholar
  94. 94.
    Que RS, Lin C, Ding GP, Wu ZR, Cao LP. Increasing the immune activity of exosomes: the effect of miRNA-depleted exosome proteins on activating dendritic cell/cytokine-induced killer cells against pancreatic cancer. J Zhejiang Univ Sci B. 2016;17(5):352–60. doi: 10.1631/jzus.B1500305.PubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2017

Authors and Affiliations

  1. 1.Shengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Pancreatic and Thyroidal SurgeryShengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China

Personalised recommendations