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Prostate cell cultures as in vitro models for the study of normal stem cells and cancer stem cells

Abstract

Current existing therapies for prostate cancer eradicate the majority of cells within a tumor. However, most patients with advanced cancer still progress to androgen-independent metastatic disease that remains essentially incurable by current treatment strategies. Recent evidence has shown that cancer stem cells (CSCs) are a subset of the tumor cells that are responsible for initiating and maintaining the disease. Understanding normal stem cells and CSCs may provide insight into the origin of and new therapeutics for prostate cancer. Normal stem cells and CSCs have been identified in prostate tissue by the use of several markers or techniques. Although research on stem cells has been limited by the lack of suitable in vitro systems, recent studies show that not only primary cells but also several established cell lines may exhibit stem cell properties. This review discusses various in vitro culture systems to propagate normal prostate stem cells and prostate CSCs together with molecular markers. These in vitro cell culture models should be useful for elucidating the differentiation of prostatic epithelium and the biological features of prostate cancer.

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References

  1. Gronberg H . Prostate cancer epidemiology. Lancet 2003; 361: 859–864.

    PubMed  Google Scholar 

  2. Uzgare AR, Isaacs JT . Prostate cancer: potential targets of anti-proliferative and apoptotic signaling pathways. Int J Biochem Cell Biol 2005; 37: 707–714.

    CAS  PubMed  Google Scholar 

  3. Liu AY, True LD, LaTray L, Nelson PS, Ellis WJ, Vessella RL et al. Cell-cell interaction in prostate gene regulation and cytodifferentiation. Proc Natl Acad Sci USA 1997; 94: 10705–10710.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L et al. p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000; 157: 1769–1775.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. English HF, Santen RJ, Isaacs JT . Response of glandular versus basal rat ventral prostatic epithelial cells to androgen withdrawal and replacement. Prostate 1987; 11: 229–242.

    CAS  PubMed  Google Scholar 

  6. Isaacs JT, Coffey DS . Etiology and disease process of benign prostatic hyperplasia. Prostate Suppl 1989; 2: 33–50.

    CAS  PubMed  Google Scholar 

  7. Bonkhoff H, Stein U, Remberger K . Endocrine–paracrine cell types in the prostate and prostatic adenocarcinoma are postmitotic cells. Hum Pathol 1995; 26: 167–170.

    CAS  PubMed  Google Scholar 

  8. di Sant'Agnese PA . Neuroendocrine cells of the prostate and neuroendocrine differentiation in prostatic carcinoma: a review of morphologic aspects. Urology 1998; 51: 121–124.

    CAS  PubMed  Google Scholar 

  9. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL et al. Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 2006; 66: 9339–9344.

    CAS  PubMed  Google Scholar 

  10. Tang DG, Patrawala L, Calhoun T, Bhatia B, Choy G, Schneider-Broussard R et al. Prostate cancer stem/progenitor cells: identification, characterization, and implications. Mol Carcinog 2007; 46: 1–14.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Miki J, Furusato B, Li H, Gu Y, Takahashi H, Egawa S et al. 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 2007; 67: 3153–3161.

    CAS  PubMed  Google Scholar 

  13. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

    CAS  PubMed  Google Scholar 

  14. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.

    CAS  PubMed  Google Scholar 

  15. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.

    Article  CAS  PubMed  Google Scholar 

  16. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Nelson WG, De Marzo AM, Isaacs WB . Prostate cancer. N Engl J Med 2003; 349: 366–381.

    CAS  PubMed  Google Scholar 

  18. Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 2004; 64: 9209–9216.

    CAS  PubMed  Google Scholar 

  19. Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S et al. Highly purified CD44(+) prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006; 25: 1696–1708.

    CAS  PubMed  Google Scholar 

  20. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG . Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res 2005; 65: 6207–6219.

    CAS  PubMed  Google Scholar 

  21. Xin L, Ide H, Kim Y, Dubey P, Witte ON . In vivo regeneration of murine prostate from dissociated cell populations of postnatal epithelia and urogenital sinus mesenchyme. Proc Natl Acad Sci USA 2003; 100 (Suppl 1): 11896–11903.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Xin L, Lawson DA, Witte ON . The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci USA 2005; 102: 6942–6947.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sutherland HJ, Eaves CJ, Eaves AC, Dragowska W, Lansdorp PM . Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro. Blood 1989; 74: 1563–1570.

    CAS  PubMed  Google Scholar 

  24. Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE . Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci USA 1997; 94: 5320–5325.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH . Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. J Immunol 1984; 133: 157–165.

    CAS  PubMed  Google Scholar 

  26. Weigmann A, Corbeil D, Hellwig A, Huttner WB . Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci USA 1997; 94: 12425–12430.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 1997; 90: 5002–5012.

    CAS  PubMed  Google Scholar 

  28. Vercauteren SM, Sutherland HJ . CD133 (AC133) expression on AML cells and progenitors. Cytotherapy 2001; 3: 449–459.

    CAS  PubMed  Google Scholar 

  29. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 2000; 97: 14720–14725.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bussolati B, Bruno S, Grange C, Buttiglieri S, Deregibus MC, Cantino D et al. Isolation of renal progenitor cells from adult human kidney. Am J Pathol 2005; 166: 545–555.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Florek M, Haase M, Marzesco AM, Freund D, Ehninger G, Huttner WB et al. Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer. Cell Tissue Res 2005; 319: 15–26.

    CAS  PubMed  Google Scholar 

  32. O'Brien CA, Pollett A, Gallinger S, Dick JE . A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106–110.

    CAS  PubMed  Google Scholar 

  33. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445: 111–115.

    CAS  PubMed  Google Scholar 

  34. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183: 1797–1806.

    CAS  PubMed  Google Scholar 

  35. Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 2001; 7: 1028–1034.

    CAS  PubMed  Google Scholar 

  36. Storms RW, Goodell MA, Fisher A, Mulligan RC, Smith C . Hoechst dye efflux reveals a novel CD7(+)CD34(-) lymphoid progenitor in human umbilical cord blood. Blood 2000; 96: 2125–2133.

    CAS  PubMed  Google Scholar 

  37. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001; 107: 1395–1402.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA . Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 2002; 245: 42–56.

    CAS  PubMed  Google Scholar 

  39. Summer R, Kotton DN, Sun X, Ma B, Fitzsimmons K, Fine A . Side population cells and Bcrp1 expression in lung. Am J Physiol Lung Cell Mol Physiol 2003; 285: L97–104.

    CAS  PubMed  Google Scholar 

  40. Murayama A, Matsuzaki Y, Kawaguchi A, Shimazaki T, Okano H . Flow cytometric analysis of neural stem cells in the developing and adult mouse brain. J Neurosci Res 2002; 69: 837–847.

    CAS  PubMed  Google Scholar 

  41. Shimano K, Satake M, Okaya A, Kitanaka J, Kitanaka N, Takemura M et al. Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1. Am J Pathol 2003; 163: 3–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bhatt RI, Brown MD, Hart CA, Gilmore P, Ramani VA, George NJ et al. Novel method for the isolation and characterisation of the putative prostatic stem cell. Cytometry A 2003; 54: 89–99.

    PubMed  Google Scholar 

  43. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U et al. A distinct ‘side population’ of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 2004; 101: 14228–14233.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kondo T, Setoguchi T, Taga T . Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 2004; 101: 781–786.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Peehl DM . Are primary cultures realistic models of prostate cancer? J Cell Biochem 2004; 91: 185–195.

    CAS  PubMed  Google Scholar 

  46. Sandhu C, Peehl DM, Slingerland J . p16INK4A mediates cyclin dependent kinase 4 and 6 inhibition in senescent prostatic epithelial cells. Cancer Res 2000; 60: 2616–2622.

    CAS  PubMed  Google Scholar 

  47. Rhim JS . In vitro human cell culture models for the study of prostate cancer. Prostate Cancer Prostatic Dis 2000; 3: 229–235.

    CAS  PubMed  Google Scholar 

  48. Sobel RE, Sadar MD . Cell lines used in prostate cancer research: a compendium of old and new lines--part 1. J Urol 2005; 173: 342–359.

    CAS  PubMed  Google Scholar 

  49. Sobel RE, Sadar MD . Cell lines used in prostate cancer research: a compendium of old and new lines--part 2. J Urol 2005; 173: 360–372.

    CAS  PubMed  Google Scholar 

  50. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004; 64: 7011–7021.

    CAS  PubMed  Google Scholar 

  51. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 2003; 100: 15178–15183.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V et al. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67: 1030–1037.

    CAS  PubMed  Google Scholar 

  53. Gudjonsson T, Villadsen R, Ronnov-Jessen L, Petersen OW . Immortalization protocols used in cell culture models of human breast morphogenesis. Cell Mol Life Sci 2004; 61: 2523–2534.

    CAS  PubMed  Google Scholar 

  54. Petersen OW, Gudjonsson T, Villadsen R, Bissell MJ, Ronnov-Jessen L . Epithelial progenitor cell lines as models of normal breast morphogenesis and neoplasia. Cell Prolif 2003; 36 (Suppl 1): 33–44.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Setoguchi T, Taga T, Kondo T . Cancer stem cells persist in many cancer cell lines. Cell Cycle 2004; 3: 414–415.

    CAS  PubMed  Google Scholar 

  57. Zhou L, Wei X, Cheng L, Tian J, Jiang JJ . CD133, one of the markers of cancer stem cells in Hep-2 cell line. Laryngoscope 2007; 117: 455–460.

    CAS  PubMed  Google Scholar 

  58. Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H . Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 2006; 351: 820–824.

    CAS  PubMed  Google Scholar 

  59. Yin S, Li J, Hu C, Chen X, Yao M, Yan M et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 2007; 120: 1444–1450.

    CAS  PubMed  Google Scholar 

  60. Locke M, Heywood M, Fawell S, Mackenzie IC . Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res 2005; 65: 8944–8950.

    CAS  PubMed  Google Scholar 

  61. Gu G, Yuan J, Wills M, Kasper S . Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res 2007; 67: 4807–4815.

    CAS  PubMed  Google Scholar 

  62. Peehl DM . Primary cell cultures as models of prostate cancer development. Endocr Relat Cancer 2005; 12: 19–47.

    CAS  PubMed  Google Scholar 

  63. Uzgare AR, Xu Y, Isaacs JT . In vitro culturing and characteristics of transit amplifying epithelial cells from human prostate tissue. J Cell Biochem 2004; 91: 196–205.

    CAS  PubMed  Google Scholar 

  64. Hudson DL, O'Hare M, Watt FM, Masters JR . Proliferative heterogeneity in the human prostate: evidence for epithelial stem cells. Lab Invest 2000; 80: 1243–1250.

    CAS  PubMed  Google Scholar 

  65. Collins AT, Habib FK, Maitland NJ, Neal DE . Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J Cell Sci 2001; 114: 3865–3872.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Litvinov IV, Vander Griend DJ, Xu Y, Antony L, Dalrymple SL, Isaacs JT . Low-calcium serum-free defined medium selects for growth of normal prostatic epithelial stem cells. Cancer Res 2006; 66: 8598–8607.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Bello D, Webber MM, Kleinman HK, Wartinger DD, Rhim JS . Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. Carcinogenesis 1997; 18: 1215–1223.

    CAS  PubMed  Google Scholar 

  69. Tokar EJ, Ancrile BB, Cunha GR, Webber MM . Stem/progenitor and intermediate cell types and the origin of human prostate cancer. Differentiation 2005; 73: 463–473.

    CAS  PubMed  Google Scholar 

  70. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279: 349–352.

    CAS  PubMed  Google Scholar 

  71. Kogan I, Goldfinger N, Milyavsky M, Cohen M, Shats I, Dobler G et al. hTERT-immortalized prostate epithelial and stromal-derived cells: an authentic in vitro model for differentiation and carcinogenesis. Cancer Res 2006; 66: 3531–3540.

    CAS  PubMed  Google Scholar 

  72. Gu Y, Li H, Miki J, Kim KH, Furusato B, Sesterhenn IA et al. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines. Exp Cell Res 2006; 312: 831–843.

    CAS  PubMed  Google Scholar 

  73. Liu AY . Differential expression of cell surface molecules in prostate cancer cells. Cancer Res 2000; 60: 3429–3434.

    CAS  PubMed  Google Scholar 

  74. Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 2006; 24: 506–513.

    CAS  PubMed  Google Scholar 

  75. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006; 44: 240–251.

    CAS  PubMed  Google Scholar 

  76. Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH . Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 2007; 67: 3716–3724.

    CAS  PubMed  Google Scholar 

  77. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282: 1145–1147.

    CAS  PubMed  Google Scholar 

  78. Reynolds BA, Weiss S . Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 1996; 175: 1–13.

    CAS  PubMed  Google Scholar 

  79. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003; 17: 1253–1270.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63: 5821–5828.

    CAS  PubMed  Google Scholar 

  81. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005; 65: 5506–5511.

    CAS  PubMed  Google Scholar 

  82. Lang SH, Sharrard RM, Stark M, Villette JM, Maitland NJ . Prostate epithelial cell lines form spheroids with evidence of glandular differentiation in three-dimensional Matrigel cultures. Br J Cancer 2001; 85: 590–599.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hill RP . Identifying cancer stem cells in solid tumors: case not proven. Cancer Res 2006; 66: 1891–1895; discussion 1890.

    CAS  PubMed  Google Scholar 

  84. Taipale J, Beachy PA . The Hedgehog and Wnt signalling pathways in cancer. Nature 2001; 411: 349–354.

    CAS  PubMed  Google Scholar 

  85. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Edith Wolff (NIH) for her critical reading and suggestions. This work was funded by the Center for Prostate Disease Research through and ongoing grant from the US Army Medical Research and Material Command. The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense or the US Government.

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Miki, J., Rhim, J. Prostate cell cultures as in vitro models for the study of normal stem cells and cancer stem cells. Prostate Cancer Prostatic Dis 11, 32–39 (2008). https://doi.org/10.1038/sj.pcan.4501018

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