Publikationsserver der Universitätsbibliothek Marburg

Titel:Charakterisierung der Interaktion zwischen Makrophagen und Pankreaskarzinomzellen
Autor:Sattler, Peter Benjamin
Weitere Beteiligte: Buchholz, Malte (Prof. Dr.)
Veröffentlicht:2018
URI:https://archiv.ub.uni-marburg.de/diss/z2018/0200
DOI: https://doi.org/10.17192/z2018.0200
URN: urn:nbn:de:hebis:04-z2018-02006
DDC: Medizin
Titel (trans.):Characterization of the interaction between macrophages and pancreatic cancer cells
Publikationsdatum:2018-05-03
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
miRNA, cancer, Pankreaskarzinom, Makrophagen, macrophages, pancreatic, Exosomen

Zusammenfassung:
Die Erstdiagnose eines Pankreaskarzinoms geht zumeist mit einer infausten Prognose einher. Ursächlich hierfür ist das Fehlen von Frühsymptomen, was zu einem unbemerkten Wachstum mit früher Metastasierung führt. Jedoch fehlen selbst bei früher Diagnosestellung noch effektive Therapieverfahren, die gezielt zur Bekämpfung des Karzinoms eingesetzt werden können. Hier könnte die Entdeckung von Exosomen und micro-RNAs in naher Zukunft eine wichtige Rolle spielen. In dieser Arbeit wurde der Fokus auf die Interaktion von Pankreaskarzinomzellen mit tumor-assoziierten Makrophagen gelegt. Es ist bekannt, dass es diverse Wechselwirkungen zwischen diesen Zellarten gibt, die sich auf die Invasivität, Metastasierung und somit auch auf die Prognose des Pankreaskarzinoms auswirken. Es wird vermutet, dass diese Wechselwirkung u.a. auf der Übertragung von Molekülen via Mikrovesikeln basiert, unter diesen auch die sog. Exosomen. Besonders interessierte uns dabei, ob es auch zur Übertragung von micro-RNAs von Karzinomzellen auf Makrophagen kommt und ob dies Auswirkungen auf deren Polarisation und somit Funktionalität hat. Zunächst wurde ein Protokoll entwickelt, mit welchem sich die schwierige Kultivierung und Polarisation von primären Monozyten und Makrophagen reproduzieren ließ. Mit den so gewonnenen Makrophagen wurde gezeigt, dass Subtypen von Makrophagen gewonnen werden können, die sich durch die Expression definierter Marker auf mRNA-Ebene charakterisieren lassen. Durch Hinzugabe von konzentrierten Überständen von Pankreaskarzinomzellen auf Monozyten wurde eine Polarisation in Richtung des M2-Subtyps ausgelöst. Mittels Färbung von Membranbestandteilen in Panc-1-Zellen und Co-Kultur mit Makrophagen konnte nachgewiesen werden, dass es zu einem Transfer von membranhaltigem Material von Pankreaskarzinomzellen auf Makrophagen kommt. Ebenfalls wurde gezeigt, dass die Polarisation in M1 und M2 kein fester Zustand ist, sondern durch äußere Einflüsse wieder geändert werden kann. So hielt eine Co-Kultur von Makrophagen mit Pankreaskarzinomzellen eine vorbestehende M2-Polarisation aufrecht und eine M1-Polarisation wurde wieder rückgängig gemacht. Zuletzt kam es zur Ausbildung einer Hybridpopulation mit Charakteristika beider Makrophagen-Subtypen, wenn Pankreaskarzinomzellen mit zwei verschiedenen micro-RNAs transfiziert wurden und anschließend mit Makrophagen co-kultiviert wurden.

Bibliographie / References

  1. Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 2010;70(14):5649-5669.
  2. Safaei R, Larson BJ, Cheng TC, et al. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther. 2005;4(10):1595-1604.
  3. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309-322.
  4. Heijnen HF, 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.
  5. Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14(10):1036-1045.
  6. Qian B, Deng Y, Im JH, et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One. 2009;4(8):e6562.
  7. Herreros-Villanueva M, Hijona E, Cosme A, Bujanda L. Adjuvant and neoadjuvant treatment in pancreatic cancer. World J Gastroenterol. 2012;18(14):1565-1572.
  8. Neoptolemos JP. Adjuvant treatment of pancreatic cancer. Eur J Cancer. 2011;47 Suppl 3:S378-380.
  9. Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7(3):163-172.
  10. Grant R, Ansa-Addo E, Stratton D, et al. A filtration-based protocol to isolate human plasma membrane-derived vesicles and exosomes from blood plasma. J Immunol Methods. 2011;371(1-2):143-151.
  11. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23-35.
  12. Zdanov A, Wlodawer A. A new look at cytokine signaling. Cell. 2008;132(2): 179-181.
  13. Oskarsson T, Acharyya S, Zhang XH, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 2011;17(7):867-874.
  14. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor- Promoting Inflammation in an NF-kappaB-Dependent Manner. Cancer Cell. 2010;17(2):135-147.
  15. Semenza GL. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene. 2013;32(35):4057-4063.
  16. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10(10):704-714.
  17. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 011;331(6024):1612-1616.
  18. Lotvall J, Valadi H. Cell to cell signalling via exosomes through esRNA. Cell Adh Migr. 2007;1(3):156-158.
  19. Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513-10518.
  20. Yachida S, White CM, Naito Y, et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res. 2012;18(22):6339-6347.
  21. Schmid MC, Avraamides CJ, Foubert P, et al. Combined blockade of integrin- alpha4beta1 plus cytokines SDF-1alpha or IL-1beta potently inhibits tumor inflammation and growth. Cancer Res. 2011;71(22):6965-6975.
  22. Tauro BJ, Greening DW, Mathias RA, 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.
  23. Matthaei H, Schulick RD, Hruban RH, Maitra A. Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2011;8(3):141-150.
  24. Calon A, Espinet E, Palomo-Ponce S, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22(5):571-584.
  25. Kleeff J, Kusama T, Rossi DL, et al. Detection and localization of Mip- 3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int J Cancer. 1999;81(4):650-657.
  26. Ying JE, Zhu LM, Liu BX. Developments in metastatic pancreatic cancer: is gemcitabine still the standard? World J Gastroenterol. 2012;18(8):736-745.
  27. Ruffell B, Affara NI, Coussens LM. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 2012;33(3):119-126.
  28. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114-1117.
  29. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):1806-1813.
  30. Dai JL, Turnacioglu KK, Schutte M, Sugar AY, Kern SE. Dpc4 transcriptional activation and dysfunction in cancer cells. Cancer Res. 1998;58(20):4592-4597.
  31. Mayer A, Lee S, Lendlein A, Jung F, Hiebl B. Efficacy of CD14(+) blood monocytes/macrophages isolation: positive versus negative MACS protocol.
  32. Greither T, Grochola LF, Udelnow A, Lautenschlager C, Wurl P, Taubert H. Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer. 2010;126(1):73-80.
  33. Pilzer D, Gasser O, Moskovich O, Schifferli JA, Fishelson Z. Emission of membrane vesicles: roles in complement resistance, immunity and cancer.
  34. Epidemiologische Daten aus der Internetrecherche
  35. Huffaker TB, Hu R, Runtsch MC, et al. Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep. 2012;2(6):1697- 1709.
  36. de Carvalho CM, Bonnefont-Rebeix C, Picandet S, et al. Evaluation of elutriation and magnetic microbead purification of canine monocytes. Vet Immunol Immunopathol. 2004;101(3-4):171-178.
  37. Aung T, Chapuy B, Vogel D, et al. Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proc Natl Acad Sci U S A. 2011;108(37):15336-15341.
  38. Rana S, Malinowska K, Zoller M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia. 2013;15(3):281-295.
  39. Koga Y, Yasunaga M, Moriya Y, et al. Exosome can prevent RNase from degrading microRNA in feces. J Gastrointest Oncol. 2011;2(4):215-222.
  40. Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000;113 Pt 19:3365-3374.
  41. 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):654-659.
  42. Exosome/microvesicle-mediated epigenetic reprogramming of cells. Am J Cancer Res. 2011;1(1):98-110.
  43. Kooijmans SA, Vader P, van Dommelen SM, van Solinge WW, Schiffelers RM. Exosome mimetics: a novel class of drug delivery systems. Int J Nanomedicine. 2012;7:1525-1541.
  44. Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet. 2012;21(R1):R125-134.
  45. Corrado C, Raimondo S, Chiesi A, Ciccia F, De Leo G, Alessandro R. Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci. 2013;14(3):5338-5366.
  46. van den Boorn JG, Dassler J, Coch C, Schlee M, Hartmann G. Exosomes as nucleic acid nanocarriers. Adv Drug Deliv Rev. 2013;65(3):331-335.
  47. Fevrier B, Raposo G. Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr Opin Cell Biol. 2004;16(4):415-421.
  48. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73(10):1907-1920.
  49. Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunol Lett. 2006;107(2):102-108.
  50. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013;32(3- 4):623-642.
  51. Harding CV, Heuser JE, Stahl PD. Exosomes: looking back three decades and into the future. J Cell Biol. 2013;200(4):367-371.
  52. Simpson RJ, Lim JW, Moritz RL, Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009;6(3):267-283.
  53. Bhatnagar S, Schorey JS. Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. J Biol Chem. 2007;282(35):25779-25789.
  54. Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21(4):575-581.
  55. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958-969.
  56. Lewis JS, Landers RJ, Underwood JC, Harris AL, Lewis CE. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol. 2000;192(2):150-158.
  57. Khan S, Aspe JR, Asumen MG, et al. Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential. Br J Cancer. 2009;100(7):1073-1086.
  58. S ELA, Mager I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12(5):347-357.
  59. Lund PK, Westvik AB, Joo GB, Ovstebo R, Haug KB, Kierulf P. Flow cytometric evaluation of apoptosis, necrosis and recovery when culturing monocytes. J Immunol Methods. 2001;252(1-2):45-55.
  60. Li H, Yang BB. Friend or foe: the role of microRNA in chemotherapy resistance. Acta Pharmacol Sin. 2013;34(7):870-879.
  61. Stoorvogel W. Functional transfer of microRNA by exosomes. Blood. 2012;119(3):646-648.
  62. Tugues S, Honjo S, Konig C, et al. Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization. Cancer Res. 2012;72(8):1953-1963.
  63. Nguyen DX, Massague J. Genetic determinants of cancer metastasis. Nat Rev Genet. 2007;8(5):341-352.
  64. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
  65. Giovannetti E, van der Velde A, Funel N, et al. High-throughput microRNA (miRNAs) arrays unravel the prognostic role of MiR-211 in pancreatic cancer.
  66. Park JE, Tan HS, Datta A, et al. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics. 2010;9(6):1085-1099.
  67. Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118(3):285-296.
  68. Olson P, Chu GC, Perry SR, Nolan-Stevaux O, Hanahan D. Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma. Proc Natl Acad Sci U S A. 2011;108(49):E1275-1284.
  69. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267-296.
  70. Yoshikawa K, Mitsunaga S, Kinoshita T, et al. Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci. 2012;103(11):2012-2020.
  71. Burris HA, 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413.
  72. Wang P, Hou J, Lin L, et al. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol. 2010;185(10):6226-6233.
  73. Kimura YN, Watari K, Fotovati A, et al. Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Sci. 2007;98(12):2009-2018.
  74. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457-1461.
  75. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163-189.
  76. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.
  77. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:Unit 3.22.
  78. Lasser C, Eldh M, Lotvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp. 2012(59):e3037.
  79. Wahl LM, Wahl SM, Smythies LE, Smith PD. Isolation of human monocyte populations. Curr Protoc Immunol. 2006;Chapter 7:Unit 7.6A.
  80. Schwanke U, Nabereit A, Moog R. Isolation of monocytes from whole blood- derived buffy coats by continuous counter-flow elutriation. J Clin Apher. 2006;21(3):153-157.
  81. Li J, Gong J, Li P, Li M, Liu Y, Liang S. Knockdown of microRNA-155 in Kupffer cells results in immunosuppressive effects and prolongs survival of mouse liver allografts. Transplantation. 2014;97(6):626-635.
  82. Kurahara H, Takao S, Maemura K, et al. M2-polarized tumor-associated macrophage infiltration of regional lymph nodes is associated with nodal lymphangiogenesis and occult nodal involvement in pN0 pancreatic cancer. Pancreas. 2013;42(1):155-159.
  83. Campbell AS, Albo D, Kimsey TF, White SL, Wang TN. Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion. J Surg Res. 2005;123(1):96-101.
  84. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11(10):889-896.
  85. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787-795.
  86. Antonios JK, Yao Z, Li C, Rao AJ, Goodman SB. Macrophage polarization in response to wear particles in vitro. Cell Mol Immunol. 2013;10(6):471-482.
  87. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol. 1994;55(3):410-422.
  88. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010;22(2):231-237.
  89. Lin EY, Li JF, Gnatovskiy L, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006;66(23):11238-11246.
  90. Stout RD, Jiang C, Matta B, Tietzel I, Watkins SK, Suttles J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol. 2005;175(1):342-349.
  91. Seton-Rogers S. Microenvironment: Making connections. Nat Rev Cancer. 2013;13(4):222-223.
  92. Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the human IL10 gene and further characterization of the 5' flanking sequence. Immunogenetics. 1997;46(2):120-128.
  93. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ- specific colonization. Nat Rev Cancer. 2009;9(4):274-284.
  94. Cho JA, Lee YS, Kim SH, Ko JK, Kim CW. MHC independent anti-tumor immune responses induced by Hsp70-enriched exosomes generate tumor regression in murine models. Cancer Lett. 2009;275(2):256-265.
  95. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239-252.
  96. O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA- 155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104(5):1604-1609.
  97. Nazari-Jahantigh M, Wei Y, Noels H, et al. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J Clin Invest. 2012;122(11):4190-4202.
  98. Ikenaga N, Ohuchida K, Mizumoto K, et al. MicroRNA-203 expression as a new prognostic marker of pancreatic adenocarcinoma. Ann Surg Oncol. 2010;17(12):3120-3128.
  99. Bian K, Fan J, Zhang X, et al. MicroRNA-203 leads to G1 phase cell cycle arrest in laryngeal carcinoma cells by directly targeting survivin. FEBS Lett. 2012;586(6):804-809.
  100. Giovannetti E, Funel N, Peters GJ, et al. MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Res. 2010;70(11):4528-4538.
  101. Sun B, Pu B, Chu D, Chu X, Li W, Wei D. MicroRNA-650 expression in glioma is associated with prognosis of patients. J Neurooncol. 2013;115(3):375-380.
  102. Szafranska AE, Davison TS, John J, et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007;26(30):4442-4452.
  103. Henry JC, Bassi C, Giovinazzo F, Bloomston M. MicroRNA from pancreatic duct aspirate differentiates cystic lesions of the pancreas. Ann Surg Oncol. 2013;20 Suppl 3:S661-666.
  104. Squadrito ML, Etzrodt M, De Palma M, Pittet MJ. MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol. 2013;34(7):350-359.
  105. O'Connell RM, Rao DS, Baltimore D. microRNA regulation of inflammatory responses. Annu Rev Immunol. 2012;30:295-312.
  106. Lindsay MA. microRNAs and the immune response. Trends Immunol. 2008;29(7):343-351.
  107. Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13(4):271-282.
  108. Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302(1):1-12.
  109. Fabbri M, Paone A, Calore F, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109(31):E2110-2116.
  110. Mitra AK, Zillhardt M, Hua Y, et al. MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov. 2012;2(12):1100-1108.
  111. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215-233.
  112. Aucher A, Rudnicka D, Davis DM. MicroRNAs transfer from human macrophages to hepato-carcinoma cells and inhibit proliferation. J Immunol. 2013;191(12):6250-6260.
  113. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing.
  114. Liu Y, Zhao L, Li D, et al. Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development. Protein Cell. 2013;4(12):932-941.
  115. Grange C, Tapparo M, Collino F, et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 2011;71(15):5346-5356.
  116. Yang M, Chen J, Su F, et al. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer. 2011;10:117.
  117. Pareek S, Roy S, Kumari B, Jain P, Banerjee A, Vrati S. miR-155 induction in microglial cells suppresses Japanese encephalitis virus replication and negatively modulates innate immune responses. J Neuroinflammation. 2014;11(1):97.
  118. Tili E, Croce CM, Michaille JJ. miR-155: on the crosstalk between inflammation and cancer. Int Rev Immunol. 2009;28(5):264-284.
  119. Takeshita N, Mori M, Kano M, et al. miR-203 inhibits the migration and invasion of esophageal squamous cell carcinoma by regulating LASP1. Int J Oncol. 2012;41(5):1653-1661.
  120. Squadrito ML, Pucci F, Magri L, et al. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Rep. 2012;1(2):141-154.
  121. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity.
  122. Wei J, Huang X, Zhang Z, et al. MyD88 as a target of microRNA-203 in regulation of lipopolysaccharide or Bacille Calmette-Guerin induced inflammatory response of macrophage RAW264.7 cells. Mol Immunol. 2013;55(3-4):303-309.
  123. Hasegawa H, Thomas HJ, Schooley K, Born TL. Native IL-32 is released from intestinal epithelial cells via a non-classical secretory pathway as a membrane- associated protein. Cytokine. 2011;53(1):74-83.
  124. Sheldon H, Heikamp E, Turley H, et al. New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood. 2010;116(13):2385-2394.
  125. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749-759.
  126. Ziegler-Heitbrock L, Ancuta P, Crowe S, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74-80.
  127. Kumar S, Keerthana R, Pazhanimuthu A, Perumal P. Overexpression of circulating miRNA-21 and miRNA-146a in plasma samples of breast cancer patients. Indian J Biochem Biophys. 2013;50(3):210-214.
  128. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607-620.
  129. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605-1617.
  130. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363(9414):1049-1057.
  131. Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157-188.
  132. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001;25(5):579-586.
  133. Hood JL, Pan H, Lanza GM, Wickline SA. Paracrine induction of endothelium by tumor exosomes. Lab Invest. 2009;89(11):1317-1328.
  134. Moffatt CE, Lamont RJ. Porphyromonas gingivalis induction of microRNA-203 expression controls suppressor of cytokine signaling 3 in gingival epithelial cells. Infect Immun. 2011;79(7):2632-2637.
  135. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6(8):2969-2972.
  136. Ostrowski M, Carmo NB, Krumeich S, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):19- 30; sup pp 11-13.
  137. Bobrie A, Krumeich S, Reyal F, et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 2012;72(19):4920-4930.
  138. Hsu C, Morohashi Y, Yoshimura S, et al. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol. 2010;189(2):223-232.
  139. Cai X, Yin Y, Li N, et al. Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J Mol Cell Biol. Vol 4. United States2012:341-343.
  140. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas- 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4(6):567-579.
  141. Lim JW, Mathias RA, Kapp EA, et al. Restoration of full-length APC protein in SW480 colon cancer cells induces exosome-mediated secretion of DKK-4.
  142. Geminard C, de Gassart A, Vidal M. Reticulocyte maturation: mitoptosis and exosome release. Biocell. 2002;26(2):205-215.
  143. Quah B, O'Neill HC. Review: the application of dendritic cell-derived exosomes in tumour immunotherapy. Cancer Biother Radiopharm. 2000;15(2):185-194.
  144. Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer.
  145. Iguchi H, Kosaka N, Ochiya T. Secretory microRNAs as a versatile communication tool. Commun Integr Biol. 2010;3(5):478-481.
  146. Blackford A, Serrano OK, Wolfgang CL, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15(14):4674-4679.
  147. Poliakov A, Spilman M, Dokland T, Amling CL, Mobley JA. Structural heterogeneity and protein composition of exosome-like vesicles (prostasomes) in human semen. Prostate. 2009;69(2):159-167.
  148. Winter JM, Brennan MF, Tang LH, et al. Survival after resection of pancreatic adenocarcinoma: results from a single institution over three decades. Ann Surg Oncol. 2012;19(1):169-175.
  149. Gogolak P, Rethi B, Hajas G, Rajnavolgyi E. Targeting dendritic cells for priming cellular immune responses. J Mol Recognit. 2003;16(5):299-317.
  150. Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73(3):1128-1141.
  151. Jones PM, George AM. The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci. 2004;61(6):682-699.
  152. Bao B, Azmi AS, Ali S, et al. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochim Biophys Acta. 2012;1826(2):272-296.
  153. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677-686.
  154. Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704-715.
  155. Jin J, Deng J, Wang F, et al. The expression and function of microRNA-203 in lung cancer. Tumour Biol. 2013;34(1):349-357.
  156. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455(7209):64-71.
  157. Martinez-Nunez RT, Louafi F, Sanchez-Elsner T. The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1 (IL13Ralpha1). J Biol Chem. 2011;286(3):1786-1794.
  158. Gallo A, Tandon M, Alevizos I, Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. 2012;7(3):e30679.
  159. Yachida S, Iacobuzio-Donahue CA. The pathology and genetics of metastatic pancreatic cancer. Arch Pathol Lab Med. 2009;133(3):413-422.
  160. Yu X, Harris SL, Levine AJ. The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006;66(9):4795-4801.
  161. Erkan M, Hausmann S, Michalski CW, et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2012;9(8):454-467.
  162. Shain KH, Landowski TH, Dalton WS. The tumor microenvironment as a determinant of cancer cell survival: a possible mechanism for de novo drug resistance. Curr Opin Oncol. 2000;12(6):557-563.
  163. Putz U, Howitt J, Doan A, et al. The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Sci Signal. 2012;5(243):ra70.
  164. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177(10):7303-7311.
  165. Warsame R, Grothey A. Treatment options for advanced pancreatic cancer: a review. Expert Rev Anticancer Ther. 2012;12(10):1327-1336.
  166. Jinushi M, Chiba S, Yoshiyama H, et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A. 2011;108(30):12425-12430.
  167. Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42(6):717-727.
  168. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71-78.
  169. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells.
  170. Bala S, Marcos M, Kodys K, et al. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem. 2011;286(2):1436-1444.
  171. Schoppmann SF, Fenzl A, Nagy K, et al. VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery. 2006;139(6):839-846.


* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten