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Immunotherapy of prostate cancer: should we be targeting stem cells and EMT?

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Abstract

Cancer stem cells have been implicated in a number of solid malignancies including prostate cancer. In the case of localised prostate cancer, patients are often treated with surgery (radical prostatectomy) and/or radiotherapy. However, disease recurrence is an issue in about 30% of patients, who will then go on to receive hormone ablation therapy. Hormone ablation therapy is often palliative in a vast proportion of individuals, and for hormone-refractory patients, there are several immunotherapies targeting a number of prostate tumour antigens which are currently in development. However, clinical responses in this setting are inconsistent, and it is believed that the failure to achieve full and permanent tumour eradication is due to a small, resistant population of cells known as ‘cancer stem cells’ (CSCs). The stochastic and clonal evolution models are among several models used to describe cancer development. The general consensus is that cancer may arise in any cell as a result of genetic mutations in oncogenes and tumour suppressor genes, which consequently result in uncontrolled cell growth. The cancer stem cell theory, however, challenges previous opinion and proposes that like normal tissues, tumours are hierarchical and only the rare subpopulation of cells at the top of the hierarchy possess the biological properties required to initiate tumourigenesis. Furthermore, where most cancer models infer that every cell within a tumour is equally malignant, i.e. equally capable of reconstituting new tumours, the cancer stem cell theory suggests that only the rare cancer stem cell component possess tumour-initiating capabilities. Hence, according to this model, cancer stem cells are implicated in both tumour initiation and progression. In recent years, the role of epithelial–mesenchymal transition (EMT) in the advancement of prostate cancer has become apparent. Therefore, CSCs and EMT are both likely to play critical roles in prostate cancer tumourigenesis. This review summarises the current immunotherapeutic strategies targeting prostate tumour antigens taking into account the need to consider treatments that target cancer stem cells and cells involved in epithelial–mesenchymal transition.

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References

  1. Drewa T, Styczynski J, Szczepanek J (2008) Is the cancer stem cell population “a player” in multi-drug resistance? Acta Pol Pharm 65(4):493–500

    PubMed  CAS  Google Scholar 

  2. Gronberg H (2003) Prostate cancer epidemiology. Lancet 361(9360):859–864

    PubMed  Google Scholar 

  3. Stavridi F, Karapanagiotou EM, Syrigos KN (2010) Targeted therapeutic approaches for hormone-refractory prostate cancer. Cancer Treat Rev 36(2):122–130

    PubMed  CAS  Google Scholar 

  4. Hadaschik BA, Gleave ME (2007) Therapeutic options for hormone-refractory prostate cancer in 2007. Urol Oncol 25(5):413–419

    PubMed  CAS  Google Scholar 

  5. Boon T, Coulie PG, Van den Eynde B (1997) Tumor antigens recognized by T cells. Immunol Today 18(6):267–268

    PubMed  CAS  Google Scholar 

  6. Rosenberg SA (1999) A new era of cancer immunotherapy: converting theory to performance. CA Cancer J Clin 49(2):70–73

    PubMed  CAS  Google Scholar 

  7. Pejawar-Gaddy S, Finn OJ (2008) Cancer vaccines: accomplishments and challenges. Crit Rev Oncol Hematol 67(2):93–102

    PubMed  Google Scholar 

  8. Jager E, Jager D, Knuth A (2002) Clinical cancer vaccine trials. Curr Opin Immunol 14(2):178–182

    PubMed  CAS  Google Scholar 

  9. Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5(4):263–274

    PubMed  CAS  Google Scholar 

  10. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307

    PubMed  CAS  Google Scholar 

  11. Weeratna RD, Makinen SR, McCluskie MJ, Davis HL (2005) TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848). Vaccine 23(45):5263–5270

    PubMed  CAS  Google Scholar 

  12. Berry LJ, Moeller M, Darcy PK (2009) Adoptive immunotherapy for cancer: the next generation of gene-engineered immune cells. Tissue Antigens 74(4):277–289

    PubMed  CAS  Google Scholar 

  13. Eshhar Z (2010) Adoptive cancer immunotherapy using genetically engineered designer T-cells: first steps into the clinic. Curr Opin Mol Ther 12(1):55–63

    PubMed  CAS  Google Scholar 

  14. Zhang T, Herlyn D (2009) Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer. Cancer Immunol Immunother 58(4):475–492

    PubMed  CAS  Google Scholar 

  15. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73

    PubMed  CAS  Google Scholar 

  16. Jahnisch H, Fussel S, Kiessling A, Wehner R, Zastrow S, Bachmann M, Rieber EP, Wirth MP, Schmitz M (2010) Dendritic cell-based immunotherapy for prostate cancer. Clin Dev Immunol:517493

  17. Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI (2010) Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest 120(4):1111–1124

    PubMed  CAS  Google Scholar 

  18. Ochsenbein AF, Klenerman P, Karrer U, Ludewig B, Pericin M, Hengartner H, Zinkernagel RM (1999) Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci USA 96(5):2233–2238

    PubMed  CAS  Google Scholar 

  19. Prehn RT, Main JM (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18(6):769–778

    PubMed  CAS  Google Scholar 

  20. Speiser DE, Miranda R, Zakarian A, Bachmann MF, McKall-Faienza K, Odermatt B, Hanahan D, Zinkernagel RM, Ohashi PS (1997) Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: implications for immunotherapy. J Exp Med 186(5):645–653

    PubMed  CAS  Google Scholar 

  21. Nabhan C, Parsons B, Touloukian EZ, Stadler WM (2011) Novel approaches and future directions in castration-resistant prostate cancer. Ann Oncol doi:10.1093/annonc/mdq639

  22. Abelev GI (1971) Alpha-fetoprotein in ontogenesis and its association with malignant tumors. Adv Cancer Res 14:295–358

    PubMed  CAS  Google Scholar 

  23. Gold P, Krupey J, Ansari H (1970) Position of the carcinoembryonic antigen of the human digestive system in ultrastructure of tumor cell surface. J Natl Cancer Inst 45(2):219–225

    PubMed  CAS  Google Scholar 

  24. Brichard V, Van Pel A, Wolfel T, Wolfel C, De Plaen E, Lethe B, Coulie P, Boon T (1993) The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 178(2):489–495

    PubMed  CAS  Google Scholar 

  25. Chen D, Shou C (2001) Molecular cloning of a tumor-associated antigen recognized by monoclonal antibody 3H11. Biochem Biophys Res Commun 280(1):99–103

    PubMed  CAS  Google Scholar 

  26. Line A, Slucka Z, Stengrevics A, Li G, Rees RC (2002) Altered splicing pattern of TACC1 mRNA in gastric cancer. Cancer Genet Cytogenet 139(1):78–83

    PubMed  CAS  Google Scholar 

  27. Tureci O, Schmitt H, Fadle N, Pfreundschuh M, Sahin U (1997) Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin’s disease. J Biol Chem 272(10):6416–6422

    PubMed  CAS  Google Scholar 

  28. Skipper JC, Hendrickson RC, Gulden PH, Brichard V, Van Pel A, Chen Y, Shabanowitz J, Wolfel T, Slingluff CL Jr, Boon T, Hunt DF, Engelhard VH (1996) An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins. J Exp Med 183(2):527–534

    PubMed  CAS  Google Scholar 

  29. Demichelis F, Rubin MA (2007) TMPRSS2-ETS fusion prostate cancer: biological and clinical implications. J Clin Pathol 60(11):1185–1186

    PubMed  Google Scholar 

  30. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254(5038):1643–1647

    PubMed  Google Scholar 

  31. Burch PA, Croghan GA, Gastineau DA, Jones LA, Kaur JS, Kylstra JW, Richardson RL, Valone FH, Vuk-Pavlovic S (2004) Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a Phase 2 trial. Prostate 60(3):197–204

    PubMed  CAS  Google Scholar 

  32. Fong L, Brockstedt D, Benike C, Breen JK, Strang G, Ruegg CL, Engleman EG (2001) Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy. J Immunol 167(12):7150–7156

    PubMed  CAS  Google Scholar 

  33. Lodge PA, Jones LA, Bader RA, Murphy GP, Salgaller ML (2000) Dendritic cell-based immunotherapy of prostate cancer: immune monitoring of a phase II clinical trial. Cancer Res 60(4):829–833

    PubMed  CAS  Google Scholar 

  34. Tjoa BA, Lodge PA, Salgaller ML, Boynton AL, Murphy GP (1999) Dendritic cell-based immunotherapy for prostate cancer. CA Cancer J Clin 49(2):117–128

    PubMed  CAS  Google Scholar 

  35. Tjoa BA, Simmons SJ, Elgamal A, Rogers M, Ragde H, Kenny GM, Troychak MJ, Boynton AL, Murphy GP (1999) Follow-up evaluation of a phase II prostate cancer vaccine trial. Prostate 40(2):125–129

    PubMed  CAS  Google Scholar 

  36. Heiser A, Coleman D, Dannull J, Yancey D, Maurice MA, Lallas CD, Dahm P, Niedzwiecki D, Gilboa E, Vieweg J (2002) Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 109(3):409–417

    PubMed  CAS  Google Scholar 

  37. Ragde H, Cavanagh WA, Tjoa BA (2004) Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer. J Urol 172(6 Pt 2):2532–2538

    PubMed  Google Scholar 

  38. Waeckerle-Men Y, Uetz-von Allmen E, Fopp M, von Moos R, Bohme C, Schmid HP, Ackermann D, Cerny T, Ludewig B, Groettrup M, Gillessen S (2006) Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma. Cancer Immunol Immunother 55(12):1524–1533

    PubMed  Google Scholar 

  39. Bot A (2010) The landmark approval of Provenge, what it means to immunology and “in this issue”: the complex relation between vaccines and autoimmunity. Int Rev Immunol 29(3):235–238

    PubMed  CAS  Google Scholar 

  40. Krupa M, Canamero M, Gomez CE, Najera JL, Gil J, Esteban M (2011) Immunization with recombinant DNA and modified vaccinia virus Ankara (MVA) vectors delivering PSCA and STEAP1 antigens inhibits prostate cancer progression. Vaccine 29(7):1504–1513

    PubMed  CAS  Google Scholar 

  41. Challita-Eid PM, Morrison K, Etessami S, An Z, Morrison KJ, Perez-Villar JJ, Raitano AB, Jia XC, Gudas JM, Kanner SB, Jakobovits A (2007) Monoclonal antibodies to six-transmembrane epithelial antigen of the prostate-1 inhibit intercellular communication in vitro and growth of human tumor xenografts in vivo. Cancer Res 67(12):5798–5805

    PubMed  CAS  Google Scholar 

  42. Shukeir N, Arakelian A, Kadhim S, Garde S, Rabbani SA (2003) Prostate secretory protein PSP-94 decreases tumor growth and hypercalcemia of malignancy in a syngenic in vivo model of prostate cancer. Cancer Res 63(9):2072–2078

    PubMed  CAS  Google Scholar 

  43. Shukeir N, Garde S, Wu JJ, Panchal C, Rabbani SA (2005) Prostate secretory protein of 94 amino acids (PSP-94) and its peptide (PCK3145) as potential therapeutic modalities for prostate cancer. Anticancer Drugs 16(10):1045–1051

    PubMed  CAS  Google Scholar 

  44. Rubin MA, Zhou M, Dhanasekaran SM, Varambally S, Barrette TR, Sanda MG, Pienta KJ, Ghosh D, Chinnaiyan AM (2002) alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer. Jama 287(13):1662–1670

    PubMed  CAS  Google Scholar 

  45. Luo J, Zha S, Gage WR, Dunn TA, Hicks JL, Bennett CJ, Ewing CM, Platz EA, Ferdinandusse S, Wanders RJ, Trent JM, Isaacs WB, De Marzo AM (2002) Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer. Cancer Res 62(8):2220–2226

    PubMed  CAS  Google Scholar 

  46. Tao ZH, Mao XL, Wang CH, Chen XD, Yu KY, Weng ZL, Hu YP, Zhang XH, Xie H, Wang OC, Song QT, Li CD, Chen ZG (2007) Quantitative detection of DD3 mRNA in prostate cancer tissues by real-time fluorescent quantitative reverse transcription polymerase chain reaction. Zhonghua Nan Ke Xue 13(2):130–133

    PubMed  CAS  Google Scholar 

  47. Gonzalgo ML, Pavlovich CP, Lee SM, Nelson WG (2003) Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens. Clin Cancer Res 9(7):2673–2677

    PubMed  CAS  Google Scholar 

  48. Foster CS, Falconer A, Dodson AR, Norman AR, Dennis N, Fletcher A, Southgate C, Dowe A, Dearnaley D, Jhavar S, Eeles R, Feber A, Cooper CS (2004) Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome. Oncogene 23(35):5871–5879

    PubMed  CAS  Google Scholar 

  49. Rhodes DR, Sanda MG, Otte AP, Chinnaiyan AM, Rubin MA (2003) Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer. J Natl Cancer Inst 95(9):661–668

    PubMed  CAS  Google Scholar 

  50. Becker C, Piironen T, Pettersson K, Bjork T, Wojno KJ, Oesterling JE, Lilja H (2000) Discrimination of men with prostate cancer from those with benign disease by measurements of human glandular kallikrein 2 (HK2) in serum. J Urol 163(1):311–316

    PubMed  CAS  Google Scholar 

  51. Leman ES, Cannon GW, Trock BJ, Sokoll LJ, Chan DW, Mangold L, Partin AW, Getzenberg RH (2007) EPCA-2: a highly specific serum marker for prostate cancer. Urology 69(4):714–720

    PubMed  Google Scholar 

  52. Miles AK, Rogers A, Li G, Seth R, Powe D, McArdle SE, McCulloch TA, Bishop MC, Rees RC (2007) Identification of a novel prostate cancer-associated tumor antigen. Prostate 67(3):274–287

    PubMed  Google Scholar 

  53. Kasper S (2008) Exploring the origins of the normal prostate and prostate cancer stem cell. Stem Cell Rev 4(3):193–201

    PubMed  CAS  Google Scholar 

  54. Maitland NJ, Bryce SD, Stower MJ, Collins AT (2006) Prostate cancer stem cells: a target for new therapies. Ernst Schering Found Symp Proc 5:155–179

    PubMed  Google Scholar 

  55. Miki J, Furusato B, Li H, Gu Y, Takahashi H, Egawa S, Sesterhenn IA, McLeod DG, Srivastava S, Rhim JS (2007) Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens. Cancer Res 67(7):3153–3161

    PubMed  CAS  Google Scholar 

  56. Miki J, Rhim JS (2008) Prostate cell cultures as in vitro models for the study of normal stem cells and cancer stem cells. Prostate Cancer Prostatic Dis 11(1):32–39

    PubMed  CAS  Google Scholar 

  57. Lawson DA, Witte ON (2007) Stem cells in prostate cancer initiation and progression. J Clin Invest 117(8):2044–2050

    PubMed  CAS  Google Scholar 

  58. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951

    PubMed  CAS  Google Scholar 

  59. Signoretti S, Loda M (2007) Prostate stem cells: from development to cancer. Semin Cancer Biol 17(3):219–224

    PubMed  CAS  Google Scholar 

  60. Maitland NJ, Collins AT (2008) Prostate cancer stem cells: a new target for therapy. J Clin Oncol 26(17):2862–2870

    PubMed  Google Scholar 

  61. Peacock CD, Watkins DN (2008) Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 26(17):2883–2889

    PubMed  CAS  Google Scholar 

  62. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15(3):504–514

    PubMed  CAS  Google Scholar 

  63. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037

    PubMed  CAS  Google Scholar 

  64. O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    PubMed  Google Scholar 

  65. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115

    PubMed  CAS  Google Scholar 

  66. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH (2008) Identification of cells initiating human melanomas. Nature 451(7176):345–349

    PubMed  CAS  Google Scholar 

  67. Sell S, Leffert HL (2008) Liver cancer stem cells. J Clin Oncol 26(17):2800–2805

    PubMed  Google Scholar 

  68. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401

    PubMed  CAS  Google Scholar 

  69. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK (2006) Ovarian cancer side population defines cells with stem cell-like characteristics and mullerian inhibiting substance responsiveness. Proc Natl Acad Sci USA 103(30):11154–11159

    PubMed  CAS  Google Scholar 

  70. Boman BM, Huang E (2008) Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol 26(17):2828–2838

    PubMed  Google Scholar 

  71. Takaishi S, Okumura T, Wang TC (2008) Gastric cancer stem cells. J Clin Oncol 26(17):2876–2882

    PubMed  Google Scholar 

  72. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323

    PubMed  CAS  Google Scholar 

  73. Huff CA, Matsui W (2008) Multiple myeloma cancer stem cells. J Clin Oncol 26(17):2895–2900

    PubMed  Google Scholar 

  74. Moltzahn FR, Volkmer JP, Rottke D, Ackermann R (2008) “Cancer stem cells”-lessons from Hercules to fight the Hydra. Urol Oncol 26(6):581–589

    PubMed  Google Scholar 

  75. Wang Z, Li Y, Ahmad A, Azmi AS, Kong D, Banerjee S, Sarkar FH (2010) Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resist Updat 13(4–5):109–118

    PubMed  CAS  Google Scholar 

  76. Koch U, Krause M, Baumann M (2010) Cancer stem cells at the crossroads of current cancer therapy failures–radiation oncology perspective. Semin Cancer Biol 20(2):116–124

    PubMed  Google Scholar 

  77. Baumann M, Krause M, Hill R (2008) Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8(7):545–554

    PubMed  CAS  Google Scholar 

  78. Baumann M, Krause M, Thames H, Trott K, Zips D (2009) Cancer stem cells and radiotherapy. Int J Radiat Biol 85(5):391–402

    PubMed  CAS  Google Scholar 

  79. Fulda S, Pervaiz S (2010) Apoptosis signaling in cancer stem cells. Int J Biochem Cell Biol 42(1):31–38

    PubMed  CAS  Google Scholar 

  80. Iannolo G, Conticello C, Memeo L, De Maria R (2008) Apoptosis in normal and cancer stem cells. Crit Rev Oncol Hematol 66(1):42–51

    PubMed  Google Scholar 

  81. Testa U, Riccioni R (2007) Deregulation of apoptosis in acute myeloid leukemia. Haematologica 92(1):81–94

    PubMed  CAS  Google Scholar 

  82. Johannessen TC, Bjerkvig R, Tysnes BB (2008) DNA repair and cancer stem-like cells–potential partners in glioma drug resistance? Cancer Treat Rev 34(6):558–567

    PubMed  CAS  Google Scholar 

  83. Zhang Q, Shi S, Yen Y, Brown J, Ta JQ, Le AD (2010) A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett 289(2):151–160

    PubMed  CAS  Google Scholar 

  84. Neuzil J, Stantic M, Zobalova R, Chladova J, Wang X, Prochazka L, Dong L, Andera L, Ralph SJ (2007) Tumour-initiating cells versus cancer ‘stem’ cells and CD133: what’s in the name? Biochem Biophys Res Commun 355(4):855–859

    PubMed  CAS  Google Scholar 

  85. Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL (2008) CD44+ CD24(−) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br J Cancer 98(4):756–765

    PubMed  CAS  Google Scholar 

  86. Zhao RC, Zhu YS, Shi Y (2008) New hope for cancer treatment: exploring the distinction between normal adult stem cells and cancer stem cells. Pharmacol Ther 119(1):74–82

    PubMed  CAS  Google Scholar 

  87. Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT (2004) CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117(Pt 16):3539–3545

    PubMed  CAS  Google Scholar 

  88. Dick JE, Bhatia M, Gan O, Kapp U, Wang JC (1997) Assay of human stem cells by repopulation of NOD/SCID mice. Stem Cells 15(Suppl 1):199–203 discussion 204–197

    PubMed  Google Scholar 

  89. Shackleton M, Quintana E, Fearon ER, Morrison SJ (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5):822–829

    PubMed  CAS  Google Scholar 

  90. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111

    PubMed  CAS  Google Scholar 

  91. Sell S (2004) Stem Cells Handbook. Humana Press Inc, New Jersey

    Google Scholar 

  92. Miller SJ, Lavker RM, Sun TT (2005) Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implications. Biochim Biophys Acta 1756(1):25–52

    PubMed  CAS  Google Scholar 

  93. Mackenzie IC (2006) Stem cell properties and epithelial malignancies. Eur J Cancer 42(9):1204–1212

    PubMed  CAS  Google Scholar 

  94. Gao JX (2008) Cancer stem cells: the lessons from pre-cancerous stem cells. J Cell Mol Med 12(1):67–96

    PubMed  CAS  Google Scholar 

  95. Huang EH, Heidt DG, Li CW, Simeone DM (2007) Cancer stem cells: a new paradigm for understanding tumor progression and therapeutic resistance. Surgery 141(4):415–419

    PubMed  Google Scholar 

  96. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    PubMed  CAS  Google Scholar 

  97. Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1(1):39–49

    PubMed  CAS  Google Scholar 

  98. Chen YW, Chen KH, Huang PI, Chen YC, Chiou GY, Lo WL, Tseng LM, Hsu HS, Chang KW, Chiou SH (2010) Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma–derived CD44(+)ALDH1(+) cells. Mol Cancer Ther 9(11):2879–2892

    PubMed  CAS  Google Scholar 

  99. Du L, Wang H, He L, Zhang J, Ni B, Wang X, Jin H, Cahuzac N, Mehrpour M, Lu Y, Chen Q (2008) CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res 14(21):6751–6760

    PubMed  CAS  Google Scholar 

  100. Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R Jr, Badve S, Nakshatri H (2006) CD44+ /CD24− breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8(5):R59

    PubMed  Google Scholar 

  101. Kim CF, Dirks PB (2008) Cancer and stem cell biology: how tightly intertwined? Cell Stem Cell 3(2):147–150

    PubMed  CAS  Google Scholar 

  102. Tirino V, Camerlingo R, Franco R, Malanga D, La Rocca A, Viglietto G, Rocco G, Pirozzi G (2009) The role of CD133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer. Eur J Cardiothorac Surg 36(3):446–453

    PubMed  Google Scholar 

  103. Okada H, Danoff TM, Kalluri R, Neilson EG (1997) Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273(4 Pt 2):F563–F574

    PubMed  CAS  Google Scholar 

  104. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428

    PubMed  CAS  Google Scholar 

  105. Wallerand H, Robert G, Pasticier G, Ravaud A, Ballanger P, Reiter RE, Ferriere JM (2010) The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers. Urol Oncol 28(5):473–479

    PubMed  CAS  Google Scholar 

  106. Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H, Mori M (2010) Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101(2):293–299

    PubMed  CAS  Google Scholar 

  107. Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ (1999) Twist is a potential oncogene that inhibits apoptosis. Genes Dev 13(17):2207–2217

    PubMed  CAS  Google Scholar 

  108. Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA (2004) Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 18(10):1131–1143

    PubMed  CAS  Google Scholar 

  109. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939

    PubMed  CAS  Google Scholar 

  110. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer 5(9):744–749

    PubMed  CAS  Google Scholar 

  111. Kwok WK, Ling MT, Lee TW, Lau TC, Zhou C, Zhang X, Chua CW, Chan KW, Chan FL, Glackin C, Wong YC, Wang X (2005) Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res 65(12):5153–5162

    PubMed  CAS  Google Scholar 

  112. Wang X, Ling MT, Guan XY, Tsao SW, Cheung HW, Lee DT, Wong YC (2004) Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells. Oncogene 23(2):474–482

    PubMed  Google Scholar 

  113. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415–428

    PubMed  CAS  Google Scholar 

  114. Fuchs IB, Lichtenegger W, Buehler H, Henrich W, Stein H, Kleine-Tebbe A, Schaller G (2002) The prognostic significance of epithelial-mesenchymal transition in breast cancer. Anticancer Res 22(6A):3415–3419

    PubMed  Google Scholar 

  115. Tanaka H, Kono E, Tran CP, Miyazaki H, Yamashiro J, Shimomura T, Fazli L, Wada R, Huang J, Vessella RL, An J, Horvath S, Gleave M, Rettig MB, Wainberg ZA, Reiter RE (2010) Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 16(12):1414–1420

    PubMed  CAS  Google Scholar 

  116. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    PubMed  CAS  Google Scholar 

  117. Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46

    PubMed  Google Scholar 

  118. Kyprianou N (2010) ASK-ing EMT not to spread cancer. Proc Natl Acad Sci USA 107(7):2731–2732

    PubMed  CAS  Google Scholar 

  119. Zhau HE, Odero-Marah V, Lue HW, Nomura T, Wang R, Chu G, Liu ZR, Zhou BP, Huang WC, Chung LW (2008) Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model. Clin Exp Metastasis 25(6):601–610

    PubMed  CAS  Google Scholar 

  120. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512

    PubMed  CAS  Google Scholar 

  121. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351(15):1513–1520

    PubMed  CAS  Google Scholar 

  122. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3(12):895–902

    PubMed  CAS  Google Scholar 

  123. Stephenson WT, Poirier SM, Rubin L, Einhorn LH (1995) Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. J Clin Oncol 13(9):2278–2280

    PubMed  CAS  Google Scholar 

  124. Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ, Jordan CT (2002) Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci USA 99(25):16220–16225

    PubMed  CAS  Google Scholar 

  125. Tasso R, Pennesi G (2009) When stem cells meet immunoregulation. Int Immunopharmacol 9(5):596–598

    PubMed  CAS  Google Scholar 

  126. Drukker M, Katz G, Urbach A, Schuldiner M, Markel G, Itskovitz-Eldor J, Reubinoff B, Mandelboim O, Benvenisty N (2002) Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci USA 99(15):9864–9869

    PubMed  CAS  Google Scholar 

  127. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F (2008) Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+ CD25highFOXP3+ regulatory T cells. Stem Cells 26(1):212–222

    PubMed  CAS  Google Scholar 

  128. Wu A, Wiesner S, Xiao J, Ericson K, Chen W, Hall WA, Low WC, Ohlfest JR (2007) Expression of MHC I and NK ligands on human CD133+ glioma cells: possible targets of immunotherapy. J Neurooncol 83(2):121–131

    PubMed  CAS  Google Scholar 

  129. Gedye C, Quirk J, Browning J, Svobodova S, John T, Sluka P, Dunbar PR, Corbeil D, Cebon J, Davis ID (2009) Cancer/testis antigens can be immunological targets in clonogenic CD133+ melanoma cells. Cancer Immunol Immunother 58(10):1635–1646

    PubMed  CAS  Google Scholar 

  130. Yawata T, Nakai E, Park KC, Chihara T, Kumazawa A, Toyonaga S, Masahira T, Nakabayashi H, Kaji T, Shimizu K (2010) Enhanced expression of cancer testis antigen genes in glioma stem cells. Mol Carcinog 49(6):532–544

    PubMed  CAS  Google Scholar 

  131. Taylor RA, Toivanen R, Risbridger GP (2010) Stem cells in prostate cancer: treating the root of the problem. Endocr Relat Cancer 17(4):R273–R285

    PubMed  CAS  Google Scholar 

  132. Charafe-Jauffret E, Ginestier C, Birnbaum D (2009) Breast cancer stem cells: tools and models to rely on. BMC Cancer 9:202

    PubMed  Google Scholar 

  133. Murphy G, Tjoa B, Ragde H, Kenny G, Boynton A (1996) Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-specific peptides from prostate-specific membrane antigen. Prostate 29(6):371–380

    PubMed  CAS  Google Scholar 

  134. Murphy GP, Tjoa BA, Simmons SJ, Ragde H, Rogers M, Elgamal A, Kenny GM, Troychak MJ, Salgaller ML, Boynton AL (1999) Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment. Prostate 39(1):54–59

    PubMed  CAS  Google Scholar 

  135. Madan RA, Arlen PM, Mohebtash M, Hodge JW, Gulley JL (2009) Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 18(7):1001–1011

    PubMed  CAS  Google Scholar 

  136. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, Dahut WL, Arlen PM, Gulley JL, Godfrey WR (2010) Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 28(7):1099–1105

    PubMed  CAS  Google Scholar 

  137. Setlur SR, Royce TE, Sboner A, Mosquera JM, Demichelis F, Hofer MD, Mertz KD, Gerstein M, Rubin MA (2007) Integrative microarray analysis of pathways dysregulated in metastatic prostate cancer. Cancer Res 67(21):10296–10303

    PubMed  CAS  Google Scholar 

  138. Nadiminty N, Dutt S, Tepper C, Gao AC (2010) Microarray analysis reveals potential target genes of NF-kappaB2/p52 in LNCaP prostate cancer cells. Prostate 70(3):276–287

    PubMed  CAS  Google Scholar 

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  1. The John van Geest Cancer Research Centre, Nottingham Trent University, School of Science and Technology, Clifton Campus, Nottingham, NG11 8NS, UK

    Naomi L. Dunning, Stéphanie A. Laversin, Amanda K. Miles & Robert C. Rees

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  1. Naomi L. Dunning
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  2. Stéphanie A. Laversin
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Correspondence to Robert C. Rees.

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Naomi L. Dunning, Stéphanie A. Laversin and Amanda K. Miles have contributed equally.

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Dunning, N.L., Laversin, S.A., Miles, A.K. et al. Immunotherapy of prostate cancer: should we be targeting stem cells and EMT?. Cancer Immunol Immunother 60, 1181–1193 (2011). https://doi.org/10.1007/s00262-011-1065-8

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