[Frontiers In Bioscience, Landmark, 22, 1682-1696, June 1, 2017]

Exosomes-based biomarker discovery for diagnosis and prognosis of prostate cancer

Gati Krushna Panigrahi1, Gagan Deep1,2

1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, 2Wake Forest Baptist Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, North Carolina

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Exosomes: A brief history and mechanism of their biogenesis
4. Mechanism of exosome biogenesis
5. Exosomes uptake and intercellular communication
6. Exosomes in tumor diagnosis and prognosis
7. Exosomes as a therapeutic target
8. PCa-related health disparities
9. Exosome-based novel biomarkers in African American men with PCa
10. Conclusion and future direction.
11. Acknowledgement
12. References

1. ABSTRACT

African American men in the United States have higher incidence and mortality rates due to prostate cancer (PCa) compared to other races. In 2016 alone, nearly 30,000 cases of PCa in African American men were diagnosed and 4,450 men died from PCa. The underlying reasons for this health disparity in PCa are complex and include social, economic, and biologic determinants. To reduce or eliminate this health disparity, we must better understand the biology of the disease in African Americans and then develop novel diagnostic and prognostic biomarkers useful for timely and effective treatment decisions. Recently, there has been remarkable progress in understanding the role of exosomes (vesicles of 30-150 nm diameter) in cancer development and progression. Exosomes are loaded with unique cargo, including proteins, nucleic acids, lipids, and metabolites, that could predict the cells of their origin. Therefore, circulating exosomes in cancer patients are being used as a type of biopsy to identify novel biomarkers for early diagnosis, prognosis, and therapeutics. In this review, we discuss the promising use of exosomes to (a) identify race-related unique biological features of PCa, and (b) discover novel biomarkers for better diagnosis and prognosis of PCa, with the goal of reducing cancer health disparities.

12. REFERENCES

1. C. E. DeSantis, R. L. Siegel, A. G. Sauer, K. D. Miller, S. A. Fedewa, K. I. Alcaraz and A. Jemal: Cancer statistics for African Americans, 2016: Progress and opportunities in reducing racial disparities. CA Cancer J Clin, 66(4), 290-308 (2016)
DOI:10.3322/caac.21340

2. F. Khani, J. M. Mosquera, K. Park, M. Blattner, C. O'Reilly, T. Y. MacDonald, Z. Chen, A. Srivastava, A. K. Tewari, C. E. Barbieri, M. A. Rubin and B. D. Robinson: Evidence for molecular differences in prostate cancer between African American and Caucasian men. Clin Cancer Res, 20(18), 4925-34 (2014)
DOI:10.1158/1078-0432.CCR-13-2265

3. G. Chornokur, K. Dalton, M. E. Borysova and N. B. Kumar: Disparities at presentation, diagnosis, treatment, and survival in African American men, affected by prostate cancer. Prostate, 71(9), 985-97 (2011)
DOI:10.1002/pros.21314

4. B. Kwabi-Addo, S. Wang, W. Chung, J. Jelinek, S. R. Patierno, B. D. Wang, R. Andrawis, N. H. Lee, V. Apprey, J. P. Issa and M. Ittmann: Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian men. Clin Cancer Res, 16(14), 3539-47 (2010)
DOI:10.1158/1078-0432.CCR-09-3342

5. S. C. Theodore, J. S. Rhim, T. Turner and C. Yates: MiRNA 26a expression in a novel panel of African American prostate cancer cell lines. Ethn Dis, 20(1 Suppl 1), S1-96-100 (2010)

6. S. Koochekpour, T. Marlowe, K. K. Singh, K. Attwood and D. Chandra: Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer in African American men. PLoS One, 8(9), e74688 (2013)
DOI:10.1371/journal.pone.0074688

7. S. Koochekpour, E. Buckles, M. Shourideh, S. Hu, D. Chandra, J. Zabaleta and K. Attwood: Androgen receptor mutations and polymorphisms in African American prostate cancer. Int J Biol Sci, 10(6), 643-51 (2014)
DOI:10.7150/ijbs.8974

8. A. V. Sarma, R. L. Dunn, L. A. Lange, A. Ray, Y. Wang, E. M. Lange and K. A. Cooney: Genetic polymorphisms in CYP17, CYP3A4, CYP19A1, SRD5A2, IGF-1, and IGFBP-3 and prostate cancer risk in African-American men: the Flint Men's Health Study. Prostate, 68(3), 296-305 (2008)
DOI:10.1002/pros.20696

9. G. G. Schwartz, E. M. John, G. Rowland and S. A. Ingles: Prostate cancer in African-American men and polymorphism in the calcium-sensing receptor. Cancer Biol Ther, 9(12), 994-9 (2010)
DOI:10.4161/cbt.9.12.11689

10. K. E. Gaston, D. Kim, S. Singh, O. H. Ford, 3rd and J. L. Mohler: Racial differences in androgen receptor protein expression in men with clinically localized prostate cancer. J Urol, 170(3), 990-3 (2003)
DOI:10.1097/01.ju.0000079761.56154.e5

11. E. M. Lange, A. V. Sarma, A. Ray, Y. Wang, L. A. Ho, S. A. Anderson, J. M. Cunningham and K. A. Cooney: The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer susceptibility in African-American men: results from the Flint Men's Health Study. J Hum Genet, 53(3), 220-6 (2008)
DOI:10.1007/s10038-007-0240-4

12. M. L. Freedman, C. A. Haiman, N. Patterson, G. J. McDonald, A. Tandon, A. Waliszewska, K. Penney, R. G. Steen, K. Ardlie, E. M. John, I. Oakley-Girvan, A. S. Whittemore, K. A. Cooney, S. A. Ingles, D. Altshuler, B. E. Henderson and D. Reich: Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A, 103(38), 14068-73 (2006)
DOI:10.1073/pnas.0605832103

13. K. A. Moses, T. T. Abd, M. Goodman, W. Hsiao, J. A. Hall, F. F. Marshall, J. A. Petros and M. M. Issa: Increased low density lipoprotein and increased likelihood of positive prostate biopsy in black americans. J Urol, 182(5), 2219-25 (2009)
DOI:10.1016/j.juro.2009.07.039

14. B. D. Wang, K. Ceniccola, Q. Yang, R. Andrawis, V. Patel, Y. Ji, J. Rhim, J. Olender, A. Popratiloff, P. Latham, Y. Lai, S. R. Patierno and N. H. Lee: Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities. Clin Cancer Res, 21(21), 4970-84 (2015)
DOI:10.1158/1078-0432.CCR-14-1566

15. B. Shuch, M. Mikhail, J. Satagopan, P. Lee, H. Yee, C. Chang, C. Cordon-Cardo, S. S. Taneja and I. Osman: Racial disparity of epidermal growth factor receptor expression in prostate cancer. J Clin Oncol, 22(23), 4725-9 (2004)
DOI:10.1200/JCO.2004.06.134

16. E. van der Pol, A. N. Boing, P. Harrison, A. Sturk and R. Nieuwland: Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev, 64(3), 676-705 (2012)
DOI:10.1124/pr.112.005983

17. R. Kalluri: The biology and function of exosomes in cancer. J Clin Invest, 126(4), 1208-15 (2016)
DOI:10.1172/JCI81135

18. E. Cocucci, G. Racchetti and J. Meldolesi: Shedding microvesicles: artefacts no more. Trends Cell Biol, 19(2), 43-51 (2009)
DOI:10.1016/j.tcb.2008.11.003

19. M. Simons and G. Raposo: Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol, 21(4), 575-81 (2009)
DOI:10.1016/j.ceb.2009.03.007

20. S. Mathivanan, H. Ji and R. J. Simpson: Exosomes: extracellular organelles important in intercellular communication. J Proteomics, 73(10), 1907-20 (2010)
DOI:10.1016/j.jprot.2010.06.006

21. M. Record, C. Subra, S. Silvente-Poirot and M. Poirot: Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol, 81(10), 1171-82 (2011)
DOI:10.1016/j.bcp.2011.02.011

22. P. Wolf: Nature and Significance of Platelet Products in Human Plasma. British Journal of Haematology, 13(3), 269-& (1967)

23. A. J. Dalton: Microvesicles and Vesicles of Multivesicular Bodies Versus Virus-Like Particles. Journal of the National Cancer Institute, 54(5), 1137-1148 (1975)

24. H. F. Dvorak, S. C. Quay, N. S. Orenstein, A. M. Dvorak, P. Hahn, A. M. Bitzer and A. C. Carvalho: Tumor Shedding and Coagulation. Science, 212(4497), 923-924 (1981)
DOI:10.1126/science.7195067

25. R. M. Johnstone, M. Adam, J. R. Hammond, L. Orr and C. Turbide: Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem, 262(19), 9412-20 (1987)

26. B. T. Pan and R. M. Johnstone: Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell, 33(3), 967-78 (1983)
DOI:10.1016/0092-8674(83)90040-5

27. G. Raposo, H. W. Nijman, W. Stoorvogel, R. Liejendekker, C. V. Harding, C. J. Melief and H. J. Geuze: B lymphocytes secrete antigen-presenting vesicles. J Exp Med, 183(3), 1161-72 (1996)
DOI:10.1084/jem.183.3.1161

28. L. Zitvogel, A. Regnault, A. Lozier, J. Wolfers, C. Flament, D. Tenza, P. Ricciardi-Castagnoli, G. Raposo and S. Amigorena: Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med, 4(5), 594-600 (1998)
DOI:10.1038/nm0598-594

29. I. J. McGough and J. P. Vincent: Exosomes in developmental signalling. Development, 143(14), 2482-93 (2016)
DOI:10.1242/dev.126516

30. K. Junker, J. Heinzelmann, C. Beckham, T. Ochiya and G. Jenster: Extracellular Vesicles and Their Role in Urologic Malignancies. Eur Urol, 70(2), 323-31 (2016)
DOI:10.1016/j.eururo.2016.02.046

31. S. Cai, X. Cheng, X. Pan and J. Li: Emerging role of exosomes in liver physiology and pathology. Hepatol Res (2016)
DOI:10.1111/hepr.12794

32. A. Safdar, A. Saleem and M. A. Tarnopolsky: The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol, 12(9), 504-17 (2016)
DOI:10.1038/nrendo.2016.76

33. M. R. Anderson, F. Kashanchi and S. Jacobson: Exosomes in Viral Disease. Neurotherapeutics, 13(3), 535-46 (2016)
DOI:10.1007/s13311-016-0450-6

34. P. G. Deep G: Hypoxia-induced signaling promotes prostate cancer progression: Exosomes role as messenger of hypoxic response in tumor microenvironment. Critical Reviews in Oncogenesis, 20(5-6), 419-434 (2015)
DOI:10.1615/CritRevOncog.v20.i5-6.130

35. C. Thery, M. Boussac, P. Veron, P. Ricciardi-Castagnoli, G. Raposo, J. Garin and S. Amigorena: Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol, 166(12), 7309-18 (2001)
DOI:10.4049/jimmunol.166.12.7309

36. L. N. Ventimiglia and M. A. Alonso: Biogenesis and Function of T Cell-Derived Exosomes. Front Cell Dev Biol, 4, 84 (2016)
DOI:10.3389/fcell.2016.00084

37. M. Colombo, C. Moita, G. van Niel, J. Kowal, J. Vigneron, P. Benaroch, N. Manel, L. F. Moita, C. Thery and G. Raposo: Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. Journal of Cell Science, 126(24), 5553-5565 (2013)
DOI:10.1242/jcs.128868

38. A. C. Theos, S. T. Truschel, D. Tenza, I. Hurbain, D. C. Harper, J. F. Berson, P. C. Thomas, G. Raposo and M. S. Marks: A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev Cell, 10(3), 343-54 (2006)
DOI:10.1016/j.devcel.2006.01.012

39. K. Trajkovic, C. Hsu, S. Chiantia, L. Rajendran, D. Wenzel, F. Wieland, P. Schwille, B. Brugger and M. Simons: Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science, 319(5867), 1244-7 (2008)
DOI:10.1126/science.1153124

40. M. Ostrowski, N. B. Carmo, S. Krumeich, I. Fanget, G. Raposo, A. Savina, C. F. Moita, K. Schauer, A. N. Hume, R. P. Freitas, B. Goud, P. Benaroch, N. Hacohen, M. Fukuda, C. Desnos, M. C. Seabra, F. Darchen, S. Amigorena, L. F. Moita and C. Thery: Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol, 12(1), 19-30; sup pp 1-13 (2010)

41. S. I. Buschow, E. N. Nolte-'t Hoen, G. van Niel, M. S. Pols, T. ten Broeke, M. Lauwen, F. Ossendorp, C. J. Melief, G. Raposo, R. Wubbolts, M. H. Wauben and W. Stoorvogel: MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic, 10(10), 1528-42 (2009)
DOI:10.1111/j.1600-0854.2009.00963.x

42. G. van Niel, S. Charrin, S. Simoes, M. Romao, L. Rochin, P. Saftig, M. S. Marks, E. Rubinstein and G. Raposo: The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev Cell, 21(4), 708-21 (2011)
DOI:10.1016/j.devcel.2011.08.019

43. D. Mazurov, L. Barbashova and A. Filatov: Tetraspanin protein CD9 interacts with metalloprotease CD10 and enhances its release via exosomes. FEBS J, 280(5), 1200-13 (2013)
DOI:10.1111/febs.12110

44. S. Sinha, D. Hoshino, N. H. Hong, K. C. Kirkbride, N. E. Grega-Larson, M. Seiki, M. J. Tyska and A. M. Weaver: Cortactin promotes exosome secretion by controlling branched actin dynamics. J Cell Biol, 214(2), 197-213 (2016)
DOI:10.1083/jcb.201601025

45. M. Record, K. Carayon, M. Poirot and S. Silvente-Poirot: Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta, 1841(1), 108-20 (2014)
DOI:10.1016/j.bbalip.2013.10.004

46. I. R. Schlaepfer, D. K. Nambiar, A. Ramteke, R. Kumar, D. Dhar, C. Agarwal, B. Bergman, M. Graner, P. Maroni, R. P. Singh, R. Agarwal and G. Deep: Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation. Oncotarget, 6(26), 22836-56 (2015)
DOI:10.18632/oncotarget.4479

47. L. A. Mulcahy, R. C. Pink and D. R. Carter: Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles, 3 (2014)
DOI:10.3402/jev.v3.24641

48. D. Zech, S. Rana, M. W. Buchler and M. Zoller: Tumor-exosomes and leukocyte activation: an ambivalent crosstalk. Cell Commun Signal, 10(1), 37 (2012)
DOI:10.1186/1478-811X-10-37

49. S. Rana, S. Yue, D. Stadel and M. Zoller: Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol, 44(9), 1574-84 (2012)
DOI:10.1016/j.biocel.2012.06.018

50. T. I. Naslund, D. Paquin-Proulx, P. T. Paredes, H. Vallhov, J. K. Sandberg and S. Gabrielsson: Exosomes from breast milk inhibit HIV-1 infection of dendritic cells and subsequent viral transfer to CD4+ T cells. AIDS, 28(2), 171-80 (2014)
DOI:10.1097/QAD.0000000000000159

51. K. J. Svensson, H. C. Christianson, A. Wittrup, E. Bourseau-Guilmain, E. Lindqvist, L. M. Svensson, M. Morgelin and M. Belting: Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J Biol Chem, 288(24), 17713-24 (2013)
DOI:10.1074/jbc.M112.445403

52. M. Colombo, G. Raposo and C. Thery: Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol, 30, 255-89 (2014)
DOI:10.1146/annurev-cellbio-101512-122326

53. J. Skog, T. Wurdinger, S. van Rijn, D. H. Meijer, L. Gainche, M. Sena-Esteves, W. T. Curry, B. S. Carter, A. M. Krichevsky and X. O. Breakefield: Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biology, 10(12), 1470-U209 (2008)
DOI:10.1038/ncb1800

54. A. Ramteke, H. Ting, C. Agarwal, S. Mateen, R. Somasagara, A. Hussain, M. Graner, B. Frederick, R. Agarwal and G. Deep: Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog, 54(7), 554-65 (2015)
DOI:10.1002/mc.22124

55. G. Deep and I. R. Schlaepfer: Aberrant Lipid Metabolism Promotes Prostate Cancer: Role in Cell Survival under Hypoxia and Extracellular Vesicles Biogenesis. Int J Mol Sci, 17(7) (2016)
DOI:10.3390/ijms17071061

56. D. G. Meckes, Jr.: Exosomal communication goes viral. J Virol, 89(10), 5200-3 (2015)
DOI:10.1128/JVI.02470-14

57. M. Tkach and C. Thery: Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell, 164(6), 1226-1232 (2016)
DOI:10.1016/j.cell.2016.01.043

58. A. Clayton, J. P. Mitchell, J. Court, S. Linnane, M. D. Mason and Z. Tabi: Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol, 180(11), 7249-58 (2008)
DOI:10.4049/jimmunol.180.11.7249

59. A. Clayton, J. P. Mitchell, J. Court, M. D. Mason and Z. Tabi: Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res, 67(15), 7458-66 (2007)
DOI:10.1158/0008-5472.CAN-06-3456

60. T. Katsuda and T. Ochiya: Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair. Stem Cell Res Ther, 6, 212 (2015)
DOI:10.1186/s13287-015-0214-y

61. S. Kalimuthu, P. Gangadaran, X. J. Li, J. M. Oh, H. W. Lee, S. Y. Jeong, S. W. Lee, J. Lee and B. C. Ahn: In vivo therapeutic potential of mesenchymal stem cell-derived extracellular vesicles with optical imaging reporter in tumor mice model. Sci Rep, 6, 30418 (2016)
DOI:10.1038/srep30418

62. J. K. Lee, S. R. Park, B. K. Jung, Y. K. Jeon, Y. S. Lee, M. K. Kim, Y. G. Kim, J. Y. Jang and C. W. Kim: Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One, 8(12), e84256 (2013)
DOI:10.1371/journal.pone.0084256

63. H. Gu, R. Ji, X. Zhang, M. Wang, W. Zhu, H. Qian, Y. Chen, P. Jiang and W. Xu: Exosomes derived from human mesenchymal stem cells promote gastric cancer cell growth and migration via the activation of the Akt pathway. Mol Med Rep, 14(4), 3452-8 (2016)
DOI:10.3892/mmr.2016.5625

64. S. Shi, Q. Zhang, Y. Xia, B. You, Y. Shan, L. Bao, L. Li, Y. You and Z. Gu: Mesenchymal stem cell-derived exosomes facilitate nasopharyngeal carcinoma progression. Am J Cancer Res, 6(2), 459-72 (2016)

65. R. Ji, B. Zhang, X. Zhang, J. Xue, X. Yuan, Y. Yan, M. Wang, W. Zhu, H. Qian and W. Xu: Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer. Cell Cycle, 14(15), 2473-83 (2015)
DOI:10.1080/15384101.2015.1005530

66. H. W. King, M. Z. Michael and J. M. Gleadle: Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer, 12, 421 (2012)
DOI:10.1186/1471-2407-12-421

67. W. K. Ranasinghe, L. Xiao, S. Kovac, M. Chang, C. Michiels, D. Bolton, A. Shulkes, G. S. Baldwin and O. PaTel: The role of hypoxia-inducible factor 1alpha in determining the properties of castrate-resistant prostate cancers. PLoS One, 8(1), e54251 (2013)
DOI:10.1371/journal.pone.0054251

68. H. B. Ragnum, L. Vlatkovic, A. K. Lie, K. Axcrona, C. H. Julin, K. M. Frikstad, K. H. Hole, T. Seierstad and H. Lyng: The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. Br J Cancer, 112(2), 382-90 (2015)
DOI:10.1038/bjc.2014.604

69. M. Milosevic, P. Warde, C. Menard, P. Chung, A. Toi, A. Ishkanian, M. McLean, M. Pintilie, J. Sykes, M. Gospodarowicz, C. Catton, R. P. Hill and R. Bristow: Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res, 18(7), 2108-14 (2012)
DOI:10.1158/1078-0432.CCR-11-2711

70. R. Vergis, C. M. Corbishley, A. R. Norman, J. Bartlett, S. Jhavar, M. Borre, S. Heeboll, A. Horwich, R. Huddart, V. Khoo, R. Eeles, C. Cooper, M. Sydes, D. Dearnaley and C. Parker: Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol, 9(4), 342-51 (2008)
DOI:10.1016/S1470-2045(08)70076-7

71. L. Li, C. Li, S. Wang, Z. Wang, J. Jiang, W. Wang, X. Li, J. Chen, K. Liu, C. Li and G. Zhu: Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype. Cancer Res, 76(7), 1770-80 (2016)
DOI:10.1158/0008-5472.CAN-15-1625

72. M. F. Ribeiro, H. Zhu, R. W. Millard and G. C. Fan: Exosomes Function in Pro- and Anti-Angiogenesis. Curr Angiogenes, 2(1), 54-59 (2013)

73. T. Umezu, K. Ohyashiki, M. Kuroda and J. H. Ohyashiki: Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene, 32(22), 2747-55 (2013)
DOI:10.1038/onc.2012.295

74. M. T. Le, P. Hamar, C. Guo, E. Basar, R. Perdigao-Henriques, L. Balaj and J. Lieberman: miR-200-containing extracellular vesicles promote breast cancer cell metastasis. J Clin Invest, 124(12), 5109-28 (2014)
DOI:10.1172/JCI75695

75. B. Costa-Silva, N. M. Aiello, A. J. Ocean, S. Singh, H. Y. Zhang, B. K. Thakur, A. Becker, A. Hoshino, M. T. Mark, H. Molina, J. Xiang, T. Zhang, T. M. Theilen, G. Garcia-Santos, C. Williams, Y. Ararso, Y. J. Huang, G. Rodrigues, T. L. Shen, K. J. Labori, I. M. B. Lothe, E. H. Kure, J. Hernandez, A. Doussot, S. H. Ebbesen, P. M. Grandgenett, M. A. Hollingsworth, M. Jain, K. Mallya, S. K. Batra, W. R. Jarnagin, R. E. Schwartz, I. Matei, H. Peinado, B. Z. Stanger, J. Bromberg and D. Lyden: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biology, 17(6), 816-+ (2015)

76. A. Hoshino, B. Costa-Silva, T. L. Shen, G. Rodrigues, A. Hashimoto, M. T. Mark, H. Molina, S. Kohsaka, A. Di Giannatale, S. Ceder, S. Singh, C. Williams, N. Soplop, K. Uryu, L. Pharmer, T. King, L. Bojmar, A. E. Davies, Y. Ararso, T. Zhang, H. Zhang, J. Hernandez, J. M. Weiss, V. D. Dumont-Cole, K. Kramer, L. H. Wexler, A. Narendran, G. K. Schwartz, J. H. Healey, P. Sandstrom, K. J. Labori, E. H. Kure, P. M. Grandgenett, M. A. Hollingsworth, M. de Sousa, S. Kaur, M. Jain, K. Mallya, S. K. Batra, W. R. Jarnagin, M. S. Brady, O. Fodstad, V. Muller, K. Pantel, A. J. Minn, M. J. Bissell, B. A. Garcia, Y. Kang, V. K. Rajasekhar, C. M. Ghajar, I. Matei, H. Peinado, J. Bromberg and D. Lyden: Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578), 329-+ (2015)

77. H. Peinado, M. Aleckovic, S. Lavotshkin, I. Matei, B. Costa-Silva, G. Moreno-Bueno, M. Hergueta-Redondo, C. Williams, G. Garcia-Santos, C. M. Ghajar, A. Nitadori-Hoshino, C. Hoffman, K. Badal, B. A. Garcia, M. K. Callahan, J. D. Yuan, V. R. Martins, J. Skog, R. N. Kaplan, M. S. Brady, J. D. Wolchok, P. B. Chapman, Y. B. Kang, J. Bromberg and D. Lyden: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine, 18(6), 883-+ (2012)

78. S. Keller, J. Ridinger, A. K. Rupp, J. W. Janssen and P. Altevogt: Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med, 9, 86 (2011)
DOI:10.1186/1479-5876-9-86

79. C. Lasser: Identification and analysis of circulating exosomal microRNA in human body fluids. Methods Mol Biol, 1024, 109-28 (2013)
DOI:10.1007/978-1-62703-453-1_9

80. J. De Toro, L. Herschlik, C. Waldner and C. Mongini: Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol, 6, 203 (2015)
DOI:10.3389/fimmu.2015.00203

81. G. Raposo and W. Stoorvogel: Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol, 200(4), 373-83 (2013)
DOI:10.1083/jcb.201211138

82. S. A. Melo, L. B. Luecke, C. Kahlert, A. F. Fernandez, S. T. Gammon, J. Kaye, V. S. LeBleu, E. A. Mittendorf, J. Weitz, N. Rahbari, C. Reissfelder, C. Pilarsky, M. F. Fraga, D. Piwnica-Worms and R. Kalluri: Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature, 523(7559), 177-U82 (2015)
DOI:10.1038/nature14581

83. C. Corcoran, A. M. Friel, M. J. Duffy, J. Crown and L. O'Driscoll: Intracellular and extracellular microRNAs in breast cancer. Clin Chem, 57(1), 18-32 (2011)
DOI:10.1373/clinchem.2010.150730

84. J. Li, C. A. Sherman-Baust, M. Tsai-Turton, R. E. Bristow, R. B. Roden and P. J. Morin: Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer. BMC Cancer, 9, 244 (2009)
DOI:10.1186/1471-2407-9-244

85. M. Logozzi, A. De Milito, L. Lugini, M. Borghi, L. Calabro, M. Spada, M. Perdicchio, M. L. Marino, C. Federici, E. Iessi, D. Brambilla, G. Venturi, F. Lozupone, M. Santinami, V. Huber, M. Maio, L. Rivoltini and S. Fais: High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One, 4(4), e5219 (2009)
DOI:10.1371/journal.pone.0005219

86. J. Nilsson, J. Skog, A. Nordstrand, V. Baranov, L. Mincheva-Nilsson, X. O. Breakefield and A. Widmark: Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer, 100(10), 1603-7 (2009)
DOI:10.1038/sj.bjc.6605058

87. D. Turay, S. Khan, C. J. Diaz Osterman, M. P. Curtis, B. Khaira, J. W. Neidigh, S. Mirshahidi, C. A. Casiano and N. R. Wall: Proteomic Profiling of Serum-Derived Exosomes from Ethnically Diverse Prostate Cancer Patients. Cancer Invest, 34(1), 1-11 (2016)
DOI:10.3109/07357907.2015.1081921

88. S. Khan, J. M. Jutzy, M. M. Valenzuela, D. Turay, J. R. Aspe, A. Ashok, S. Mirshahidi, D. Mercola, M. B. Lilly and N. R. Wall: Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. PLoS One, 7(10), e46737 (2012)
DOI:10.1371/journal.pone.0046737

89. D. D. Taylor and C. Gercel-Taylor: MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol, 110(1), 13-21 (2008)
DOI:10.1016/j.ygyno.2008.04.033

90. A. B. S. Ahmed A. Moustafa, Koji Tsumagari, Mohamed Hassan, Emad Kandil, Asim B. Abdel-Mageed and Zakaria Y. Abd Elmageed: Differential expression of exosomes-associated onco-microRNAs in African Americans with prostate cancer. In: AACR 107th Annual Meeting 2016. AACR Publication, New Orleans, LA (2016)

91. G. Rabinowits, C. Gercel-Taylor, J. M. Day, D. D. Taylor and G. H. Kloecker: Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer, 10(1), 42-6 (2009)
DOI:10.3816/CLC.2009.n.006

92. Y. Tanaka, H. Kamohara, K. Kinoshita, J. Kurashige, T. Ishimoto, M. Iwatsuki, M. Watanabe and H. Baba: Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer, 119(6), 1159-67 (2013)
DOI:10.1002/cncr.27895

93. J. D. Long, T. B. Sullivan, J. Humphrey, T. Logvinenko, K. A. Summerhayes, S. Kozinn, N. Harty, I. C. Summerhayes, J. A. Libertino, A. H. Holway and K. M. Rieger-Christ: A non-invasive miRNA based assay to detect bladder cancer in cell-free urine. Am J Transl Res, 7(11), 2500-9 (2015)

94. Z. Li, Y. Y. Ma, J. Wang, X. F. Zeng, R. Li, W. Kang and X. K. Hao: Exosomal microRNA-141 is upregulated in the serum of prostate cancer patients. Onco Targets Ther, 9, 139-48 (2016)

95. S. R. Pfeffer, K. F. Grossmann, P. B. Cassidy, C. H. Yang, M. Fan, L. Kopelovich, S. A. Leachman and L. M. Pfeffer: Detection of Exosomal miRNAs in the Plasma of Melanoma Patients. J Clin Med, 4(12), 2012-27 (2015)
DOI:10.3390/jcm4121957

96. C. Kahlert, S. A. Melo, A. Protopopov, J. Tang, S. Seth, M. Koch, J. Zhang, J. Weitz, L. Chin, A. Futreal and R. Kalluri: Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem, 289(7), 3869-75 (2014)
DOI:10.1074/jbc.C113.532267

97. B. K. Thakur, H. Zhang, A. Becker, I. Matei, Y. Huang, B. Costa-Silva, Y. Zheng, A. Hoshino, H. Brazier, J. Xiang, C. Williams, R. Rodriguez-Barrueco, J. M. Silva, W. Zhang, S. Hearn, O. Elemento, N. Paknejad, K. Manova-Todorova, K. Welte, J. Bromberg, H. Peinado and D. Lyden: Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res, 24(6), 766-9 (2014)
DOI:10.1038/cr.2014.44

98. J. McKiernan, M. J. Donovan, V. O'Neill, S. Bentink, M. Noerholm, S. Belzer, J. Skog, M. W. Kattan, A. Partin, G. Andriole, G. Brown, J. T. Wei, I. M. Thompson, Jr. and P. Carroll: A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy. JAMA Oncol, 2(7), 882-9 (2016)
DOI:10.1001/jamaoncol.2016.0097

99. N. Kosaka, H. Iguchi, K. Hagiwara, Y. Yoshioka, F. Takeshita and T. Ochiya: Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem, 288(15), 10849-59 (2013)
DOI:10.1074/jbc.M112.446831

100. W. X. Chen, X. M. Liu, M. M. Lv, L. Chen, J. H. Zhao, S. L. Zhong, M. H. Ji, Q. Hu, Z. Luo, J. Z. Wu and J. H. Tang: Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One, 9(4), e95240 (2014)
DOI:10.1371/journal.pone.0095240

101. Y. Hu, C. Yan, L. Mu, K. Huang, X. Li, D. Tao, Y. Wu and J. Qin: Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer. PLoS One, 10(5), e0125625 (2015)
DOI:10.1371/journal.pone.0125625

102. M. C. Boelens, T. J. Wu, B. Y. Nabet, B. Xu, Y. Qiu, T. Yoon, D. J. Azzam, C. Twyman-Saint Victor, B. Z. Wiemann, H. Ishwaran, P. J. Ter Brugge, J. Jonkers, J. Slingerland and A. J. Minn: Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell, 159(3), 499-513 (2014)
DOI:10.1016/j.cell.2014.09.051

103. J. Yin, X. Yan, X. Yao, Y. Zhang, Y. Shan, N. Mao, Y. Yang and L. Pan: Secretion of annexin A3 from ovarian cancer cells and its association with platinum resistance in ovarian cancer patients. J Cell Mol Med, 16(2), 337-48 (2012)
DOI:10.1111/j.1582-4934.2011.01316.x

104. C. Federici, F. Petrucci, S. Caimi, A. Cesolini, M. Logozzi, M. Borghi, S. D'Ilio, L. Lugini, N. Violante, T. Azzarito, C. Majorani, D. Brambilla and S. Fais: Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLoS One, 9(2), e88193 (2014)
DOI:10.1371/journal.pone.0088193

105. V. Ciravolo, V. Huber, G. C. Ghedini, E. Venturelli, F. Bianchi, M. Campiglio, D. Morelli, A. Villa, P. Della Mina, S. Menard, P. Filipazzi, L. Rivoltini, E. Tagliabue and S. M. Pupa: Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol, 227(2), 658-67 (2012)
DOI:10.1002/jcp.22773

106. A. M. Marleau, C. S. Chen, J. A. Joyce and R. H. Tullis: Exosome removal as a therapeutic adjuvant in cancer. J Transl Med, 10, 134 (2012)
DOI:10.1186/1479-5876-10-134

107. T. E. Ichim, Z. Zhong, S. Kaushal, X. Zheng, X. Ren, X. Hao, J. A. Joyce, H. H. Hanley, N. H. Riordan, J. Koropatnick, V. Bogin, B. R. Minev, W. P. Min and R. H. Tullis: Exosomes as a tumor immune escape mechanism: possible therapeutic implications. J Transl Med, 6, 37 (2008)
DOI:10.1186/1479-5876-6-37

108. S. Koochekpour, S. S. Willard, M. Shourideh, S. Ali, C. Liu, G. Azabdaftari, M. Saleem and K. Attwood: Establishment and characterization of a highly tumorigenic African American prostate cancer cell line, E006AA-hT. Int J Biol Sci, 10(8), 834-45 (2014)
DOI:10.7150/ijbs.9406

109. S. Koochekpour, G. A. Maresh, A. Katner, K. Parker-Johnson, T. J. Lee, F. E. Hebert, Y. S. Kao, J. Skinner and W. Rayford: Establishment and characterization of a primary androgen-responsive African-American prostate cancer cell line, E006AA. Prostate, 60(2), 141-52 (2004)
DOI:10.1002/pros.20053

110. C. DeSantis, D. Naishadham and A. Jemal: Cancer statistics for African Americans, 2013. CA Cancer J Clin, 63(3), 151-66 (2013)
DOI:10.3322/caac.21173

111. B. Wei, Y. Zhang, B. Xi, J. Chang, J. Bai and J. Su: CYP17 T27C polymorphism and prostate cancer risk: a meta-analysis based on 31 studies. J Biomed Res, 24(3), 233-41 (2010)
DOI:10.1016/S1674-8301(10)60033-4

112. T. E. Mason, L. Ricks-Santi, W. Chen, V. Apprey, J. Joykutty, C. Ahaghotu, R. Kittles, G. Bonney and G. M. Dunston: Association of CD14 variant with prostate cancer in African American men. Prostate, 70(3), 262-9 (2010)

113. I. J. Powell, C. H. Bock, J. J. Ruterbusch and W. Sakr: Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men, and influences racial progression and mortality disparity. J Urol, 183(5), 1792-6 (2010)
DOI:10.1016/j.juro.2010.01.015

114. G. G. Schwartz: Vitamin D and the epidemiology of prostate cancer. Semin Dial, 18(4), 276-89 (2005)
DOI:10.1111/j.1525-139X.2005.18403.x

115. M. Tseng, V. Giri, D. W. Bruner and E. Giovannucci: Prevalence and correlates of vitamin D status in African American men. BMC Public Health, 9, 191 (2009)
DOI:10.1186/1471-2458-9-191

116. J. M. Weiss, W. Y. Huang, S. Rinaldi, T. R. Fears, N. Chatterjee, D. Chia, E. D. Crawford, R. Kaaks and R. B. Hayes: IGF-1 and IGFBP-3: Risk of prostate cancer among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer, 121(10), 2267-73 (2007)
DOI:10.1002/ijc.22921

117. D. L. Winter, A. L. Hanlon, S. L. Raysor, D. Watkins-Bruner, W. H. Pinover, G. E. Hanks and J. V. Tricoli: Plasma levels of IGF-1, IGF-2, and IGFBP-3 in white and African-American men at increased risk of prostate cancer. Urology, 58(4), 614-8 (2001)
DOI:10.1016/S0090-4295(01)01273-0

118. T. M. Vogt, S. T. Mayne, B. I. Graubard, C. A. Swanson, A. L. Sowell, J. B. Schoenberg, G. M. Swanson, R. S. Greenberg, R. N. Hoover, R. B. Hayes and R. G. Ziegler: Serum lycopene, other serum carotenoids, and risk of prostate cancer in US Blacks and Whites. Am J Epidemiol, 155(11), 1023-32 (2002)
DOI:10.1093/aje/155.11.1023

119. B. A. Rybicki, A. Rundle, O. N. Kryvenko, N. Mitrache, K. C. Do, M. Jankowski, D. A. Chitale, S. Trudeau, S. A. Belinsky and D. Tang: Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer. Int J Cancer, 138(12), 2884-93 (2016)
DOI:10.1002/ijc.30038

120. Y. Yang, D. Jia, H. Kim, Z. Y. Abd Elmageed, A. Datta, R. Davis, S. Srivastav, K. Moroz, B. E. Crawford, K. Moparty, R. Thomas, R. S. Hudson, S. Ambs and A. B. Abdel-Mageed: Dysregulation of miR-212 Promotes Castration Resistance through hnRNPH1-Mediated Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer. Clin Cancer Res, 22(7), 1744-56 (2016)
DOI:10.1158/1078-0432.CCR-15-1606

121. K. J. Lindquist, P. L. Paris, T. J. Hoffmann, N. J. Cardin, R. Kazma, J. A. Mefford, J. P. Simko, V. Ngo, Y. Chen, A. M. Levin, D. Chitale, B. T. Helfand, W. J. Catalona, B. A. Rybicki and J. S. Witte: Mutational Landscape of Aggressive Prostate Tumors in African American Men. Cancer Res, 76(7), 1860-8 (2016)
DOI:10.1158/0008-5472.CAN-15-1787

122. C. H. Stuart, R. Singh, T. L. Smith, R. D'Agostino, Jr., D. Caudell, K. C. Balaji and W. H. Gmeiner: Prostate-specific membrane antigen-targeted liposomes specifically deliver the Zn(2+) chelator TPEN inducing oxidative stress in prostate cancer cells. Nanomedicine (Lond), 11(10), 1207-22 (2016)
DOI:10.2217/nnm-2015-0017

123. I. Rishi, H. Baidouri, J. A. Abbasi, R. Bullard-Dillard, A. Kajdacsy-Balla, J. P. Pestaner, M. Skacel, R. Tubbs and O. Bagasra: Prostate cancer in African American men is associated with downregulation of zinc transporters. Appl Immunohistochem Mol Morphol, 11(3), 253-60 (2003)
DOI:10.1097/00129039-200309000-00009

124. O. N. Kryvenko, R. Balise, N. Soodana Prakash and J. I. Epstein: African-American Men with Gleason Score 3+3=6 Prostate Cancer Produce Less Prostate Specific Antigen than Caucasian Men: A Potential Impact on Active Surveillance. J Urol, 195(2), 301-6 (2016)
DOI:10.1016/j.juro.2015.08.089

125. H. Kalra, C. G. Adda, M. Liem, C. S. Ang, A. Mechler, R. J. Simpson, M. D. Hulett and S. Mathivanan: Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma. Proteomics, 13(22), 3354-64 (2013)
DOI:10.1002/pmic.201300282

126. M. Yanez-Mo, P. R. Siljander, Z. Andreu, A. B. Zavec, F. E. Borras, E. I. Buzas, K. Buzas, E. Casal, F. Cappello, J. Carvalho, E. Colas, A. Cordeiro-da Silva, S. Fais, J. M. Falcon-Perez, I. M. Ghobrial, B. Giebel, M. Gimona, M. Graner, I. Gursel, M. Gursel, N. H. Heegaard, A. Hendrix, P. Kierulf, K. Kokubun, M. Kosanovic, V. Kralj-Iglic, E. M. Kramer-Albers, S. Laitinen, C. Lasser, T. Lener, E. Ligeti, A. Line, G. Lipps, A. Llorente, J. Lotvall, M. Mancek-Keber, A. Marcilla, M. Mittelbrunn, I. Nazarenko, E. N. Nolte-'t Hoen, T. A. Nyman, L. O'Driscoll, M. Olivan, C. Oliveira, E. Pallinger, H. A. Del Portillo, J. Reventos, M. Rigau, E. Rohde, M. Sammar, F. Sanchez-Madrid, N. Santarem, K. Schallmoser, M. S. Ostenfeld, W. Stoorvogel, R. Stukelj, S. G. Van der Grein, M. H. Vasconcelos, M. H. Wauben and O. De Wever: Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles, 4, 27066 (2015)
DOI:10.3402/jev.v4.27066

127. S. Boukouris and S. Mathivanan: Exosomes in bodily fluids are a highly stable resource of disease biomarkers. Proteomics Clin Appl, 9(3-4), 358-67 (2015)
DOI:10.1002/prca.201400114

128. S. Tao, Z. Wang, J. Feng, F. C. Hsu, G. Jin, S. T. Kim, Z. Zhang, H. Gronberg, L. S. Zheng, W. B. Isaacs, J. Xu and J. Sun: A genome-wide search for loci interacting with known prostate cancer risk-associated genetic variants. Carcinogenesis, 33(3), 598-603 (2012)
DOI:10.1093/carcin/bgr316

Key Words: Prostate cancer, Exosomes, Health disparity, Biomarkers, Review

Send correspondence to: Gagan Deep, Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, Tel: 336-716-9363, Fax: 336-716-4480, E-mail: gdeep@wakehealth.edu