Prostate Cancer Stem Cells

  • Elaine M. Hurt
  • George J. Klarmann
  • Brian T. Kawasaki
  • Nima Sharifi
  • William L. Farrar


Prostate cancer is the leading cancer diagnosed in males. Emerging data suggests that cancer arises from only certain cells, termed cancer stem cells, contained within the prostate. In this chapter we will discuss in depth the prostate cancer stem cell. We detail the properties of both normal prostate stem cells and cancer stem cells and discuss the identification and isolation of the prostate cancer stem cells, including the current knowledge of the surface markers used for identification. Furthermore, we discuss the signaling pathways that are important in stem cell maintenance and comment on what is known about these pathways in prostate cancer stem cells and how these pathways, and others, may be targeted to inhibit or kill the tumor-initiating cancer stem cells. In conclusion, we provide a short discussion on the future directions for study of prostate cancer stem cells.


Prostate Cancer Cancer Stem Cell Notch Signaling Androgen Deprivation Therapy Side Population 



This publication has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract No. N01-CO-12400. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute.


  1. Al-Hajj, M. and Clarke, M.F. 2004. Self-renewal and solid tumor stem cells. Oncogene 23:7274–7282.PubMedGoogle Scholar
  2. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., and Clarke, M.F. 2003. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100:3983–3988.PubMedGoogle Scholar
  3. American Cancer Society, Cancer Facts and Figures 2007. 2007. (Accessed at”).
  4. Anton Aparicio, L.M., Garcia, C.R., Cassinello, E.J., Valladares, A.M., Reboredo, L.M., Diaz, P.S., and Aparicio, G.G. 2007. Prostate cancer and Hedgehog signalling pathway. Clin. Transpl. Oncol. 9:420–428.Google Scholar
  5. Babaie, Y., Herwig, R., Greber, B., Brink, T.C., Wruck, W., Groth, D., Lehrach, H., Burdon, T., and Adjaye, J. 2007. Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells. Stem Cells 25:500–510.PubMedGoogle Scholar
  6. Bao, S., Wu, Q., McLendon, R.E., Hao, Y., Shi, Q., Hjelmeland, A.B., Dewhirst, M.W., Bigner, D.D., and Rich, J.N. 2006. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760.PubMedGoogle Scholar
  7. Barker, N. and Clevers, H. 2006. Mining the Wnt pathway for cancer therapeutics. Nat. Rev. Drug Discov. 5:997–1014.PubMedGoogle Scholar
  8. Barqawi, A.B. and Crawford, E.D. 2007. The current use and future trends of focal surgical therapy in the management of localized prostate cancer. Cancer J. 13:313–317.PubMedGoogle Scholar
  9. Barrandon, Y. and Green, H. 1987. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Natl Acad. Sci. USA 84:2302–2306.PubMedGoogle Scholar
  10. Bastian, P.J., Ellinger, J., Wellmann, A., Wernert, N., Heukamp, L.C., Muller, S.C., and von Ruecker, A. 2005. Diagnostic and prognostic information in prostate cancer with the help of a small set of hypermethylated gene loci. Clin. Cancer Res. 11:4097–4106.PubMedGoogle Scholar
  11. Berman, D.M., Desai, N., Wang, X., Karhadkar, S.S., Reynon, M., Abate-Shen, C., Beachy, P.A., and Shen, M.M. 2004. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev. Biol. 267:387–398.PubMedGoogle Scholar
  12. Bhatt, R.I., Brown, M.D., Hart, C.A., Gilmore, P., Ramani, V.A., George, N.J., and Clarke, N.W. 2003. Novel method for the isolation and characterisation of the putative prostatic stem cell. Cytometry A 54:89–99.PubMedGoogle Scholar
  13. Bonnet, D. and Dick, J.E. 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3:730–737.PubMedGoogle Scholar
  14. Boyer, L.A., Lee, T.I., Cole, M.F., Johnstone, S.E., Levine, S.S., Zucker, J.P., Guenther, M.G., Kumar, R.M., Murray, H.L., Jenner, R.G., Gifford, D.K., Melton, D.A., Jaenisch, R., and Young, R.A. 2005. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956.PubMedGoogle Scholar
  15. Bruce, W.R. and Van Der Gaag, H. 1963. A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199:79–80.PubMedGoogle Scholar
  16. Bruxvoort, K.J., Charbonneau, H.M., Giambernardi, T.A., Goolsby, J.C., Qian, C.N., Zylstra, C.R., Robinson, D.R., Roy-Burman, P., Shaw, A.K., Buckner-Berghuis, B.D., Sigler, R.E., Resau, J.H., Sullivan, R., Bushman, W., and Williams, B.O. 2007. Inactivation of Apc in the mouse prostate causes prostate carcinoma. Cancer Res. 67:2490–2496.PubMedGoogle Scholar
  17. Cadigan, K.M. and Nusse, R. 1997. Wnt signaling: a common theme in animal development. Genes Dev. 11:3286–3305.PubMedGoogle Scholar
  18. Calabrese, C., Poppleton, H., Kocak, M., Hogg, T.L., Fuller, C., Hamner, B., Oh, E.Y., Gaber, M.W., Finklestein, D., Allen, M., Frank, A., Bayazitov, I.T., Zakharenko, S.S., Gajjar, A., Davidoff, A., and Gilbertson, R.J. 2007. A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82.PubMedGoogle Scholar
  19. Casey, G., Neville, P.J., Plummer, S.J., Xiang, Y., Krumroy, L.M., Klein, E.A., Catalona, W.J., Nupponen, N., Carpten, J.D., Trent, J.M., Silverman, R.H., and Witte, J.S. 2002. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat. Genet. 32:581–583.PubMedGoogle Scholar
  20. Clarke, M.F. 2005. A self-renewal assay for cancer stem cells. Cancer Chemother. Pharmacol. 56 Suppl 1:64–68.Google Scholar
  21. Collins, A.T. and Maitland, N.J. 2006. Prostate cancer stem cells. Eur. J. Cancer 42:1213–1218.PubMedGoogle Scholar
  22. Collins, A.T., Habib, F.K., Maitland, N.J., and Neal, D.E. 2001. Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J. Cell Sci. 114:3865–3872.PubMedGoogle Scholar
  23. Collins, A.T., Berry, P.A., Hyde, C., Stower, M.J., and Maitland, N.J. 2005. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65:10946–10951.PubMedGoogle Scholar
  24. de Jonge-Peeters, S.D., Kuipers, F., de Vries, E.G., and Vellenga, E. 2007. ABC transporter expression in hematopoietic stem cells and the role in AML drug resistance. Crit. Rev. Oncol. Hematol. 62:214–226.PubMedGoogle Scholar
  25. Dean, M., Fojo, T., and Bates, S. 2005. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5:275–284.PubMedGoogle Scholar
  26. Dontu, G., Abdallah, W.M., Foley, J.M., Jackson, K.W., Clarke, M.F., Kawamura, M.J., and Wicha, M.S. 2003a. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17:1253–1270.PubMedGoogle Scholar
  27. Dontu, G., Al-Hajj, M., Abdallah, W.M., Clarke, M.F., and Wicha, M.S. 2003b. Stem cells in normal breast development and breast cancer. Cell Prolif. 36 Suppl 1:59–72.Google Scholar
  28. Dontu, G., Jackson, K.W., McNicholas, E., Kawamura, M.J., Abdallah, W.M., and Wicha, M.S. 2004. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 6:R605–R615.PubMedGoogle Scholar
  29. English, H.F., Santen, R.J., and Isaacs, J.T. 1987. Response of glandular versus basal rat ventral prostatic epithelial cells to androgen withdrawal and replacement. Prostate 11:229–242.PubMedGoogle Scholar
  30. Fodde, R. and Brabletz, T. 2007. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol. 19:150–158.PubMedGoogle Scholar
  31. Freestone, S.H., Marker, P., Grace, O.C., Tomlinson, D.C., Cunha, G.R., Harnden, P., and Thomson, A.A. 2003. Sonic hedgehog regulates prostatic growth and epithelial differentiation. Dev. Biol. 264:352–362.PubMedGoogle Scholar
  32. Gal, H., Amariglio, N., Trakhtenbrot, L., Jacob-Hirsh, J., Margalit, O., Avigdor, A., Nagler, A., Tavor, S., Ein-Dor, L., Lapidot, T., Domany, E., Rechavi, G., and Givol, D. 2006. Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia 20:2147–2154.PubMedGoogle Scholar
  33. Galmozzi, E., Facchetti, F., and La Porta, C.A. 2006. Cancer stem cells and therapeutic perspectives. Curr. Med. Chem. 13:603–607.PubMedGoogle Scholar
  34. Gleason DF. The Veteran's Administration Cooperative Urologic Research Group: histologic grading and clinical staging of prostatic carcinoma. In Tannenbaum M (ed.) Urologic Pathology: The Prostate. Lea and Febiger, Philadelphia, 1977; 171–198.Google Scholar
  35. Goodell, M.A., Brose, K., Paradis, G., Conner, A.S., and Mulligan, R.C. 1996. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183:1797–1806.PubMedGoogle Scholar
  36. Grinstein, E. and Wernet, P. 2007. Cellular signaling in normal and cancerous stem cells. Cell Signal. 19:2428–2433.PubMedGoogle Scholar
  37. Gu, G., Yuan, J., Wills, M., and Kasper, S. 2007. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 67:4807–4815.PubMedGoogle Scholar
  38. Hadnagy, A., Gaboury, L., Beaulieu, R., and Balicki, D. 2006. SP analysis may be used to identify cancer stem cell populations. Exp. Cell Res. 312:3701–3710.Google Scholar
  39. Hall, C.L. and Keller, E.T. 2006. The role of Wnts in bone metastases. Cancer Metastasis Rev. 25:551–558.PubMedGoogle Scholar
  40. Hamburger, A.W. and Salmon, S.E. 1977. Primary bioassay of human tumor stem cells. Science 197:461–463.PubMedGoogle Scholar
  41. Hope, K.J., Jin, L., and Dick, J.E. 2004. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat. Immunol. 5:738–743.PubMedGoogle Scholar
  42. Hughes, S., Yoshimoto, M., Beheshti, B., Houlston, R.S., Squire, J.A., and Evans, A. 2006. The use of whole genome amplification to study chromosomal changes in prostate cancer: insights into genome-wide signature of preneoplasia associated with cancer progression. BMC Genom. 7:65.Google Scholar
  43. Huntly, B.J. and Gilliland, D.G. 2005. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat. Rev. Cancer 5:311–321.PubMedGoogle Scholar
  44. Hurt, E.M., Kawasaki, B.T., Klarmann, G.J., Thomas, S.B., and Farrar, W.L. 2008. CD44(+)CD24(–) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br. J. Cancer 98:756–765.PubMedGoogle Scholar
  45. Isaacs, J.T. and Coffey, D.S. 1989. Etiology and disease process of benign prostatic hyperplasia. Prostate Suppl 2:33–50.PubMedGoogle Scholar
  46. Joshua, A.M., Evans, A., Van der Kwast, T., Zielenska, M., Meeker, A.K., Chinnaiyan, A., and Squire, J.A. 2008. Prostatic preneoplasia and beyond. Biochim. Biophys. Acta. 1785: 156–181.Google Scholar
  47. Karhadkar, S.S., Bova, G.S., Abdallah, N., Dhara, S., Gardner, D., Maitra, A., Isaacs, J.T., Berman, D.M., and Beachy, P.A. 2004. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431:707–712.PubMedGoogle Scholar
  48. Kawano, Y. and Kypta, R. 2003. Secreted antagonists of the Wnt signalling pathway. J. Cell Sci. 116:2627–2634.PubMedGoogle Scholar
  49. Kawano, Y., Kitaoka, M., Hamada, Y., Walker, M.M., Waxman, J., and Kypta, R.M. 2006. Regulation of prostate cell growth and morphogenesis by Dickkopf-3. Oncogene 25:6528–6537.PubMedGoogle Scholar
  50. Kim, M., Turnquist, H., Jackson, J., Sgagias, M., Yan, Y., Gong, M., Dean, M., Sharp, J.G., and Cowan, K. 2002. The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin. Cancer Res. 8:22–28.PubMedGoogle Scholar
  51. Kyprianou, N. and Isaacs, J.T. 1988. Activation of programmed cell death in the rat ventral prostate after castration. Endocrinology 122:552–562.PubMedGoogle Scholar
  52. Lamm, M.L., Catbagan, W.S., Laciak, R.J., Barnett, D.H., Hebner, C.M., Gaffield, W., Walterhouse, D., Iannaccone, P., and Bushman, W. 2002. Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev. Biol. 249:349–366.PubMedGoogle Scholar
  53. Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M.A., and Dick, J.E. 1994. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648.PubMedGoogle Scholar
  54. Lawson, D.A. and Witte, O.N. 2007. Stem cells in prostate cancer initiation and progression. J. Clin. Invest. 117:2044–2050.PubMedGoogle Scholar
  55. Li, H., Chen, X., Calhoun-Davis, T., Claypool, K., and Tang, D.G. 2008. PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res. 68:1820–1825.PubMedGoogle Scholar
  56. Liu, A.Y., True, L.D., LaTray, L., Nelson, P.S., Ellis, W.J., Vessella, R.L., Lange, P.H., Hood, L., and van den Engh, G. 1997. Cell–cell interaction in prostate gene regulation and cytodifferentiation. Proc. Natl Acad. Sci. USA 94:10705–10710.PubMedGoogle Scholar
  57. Liu, S., Dontu, G., and Wicha, M.S. 2005. Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 7:86–95.PubMedGoogle Scholar
  58. Liu, S., Dontu, G., Mantle, I.D., Patel, S., Ahn, N.S., Jackson, K.W., Suri, P., and Wicha, M.S. 2006. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66:6063–6071.PubMedGoogle Scholar
  59. Liu, R., Wang, X., Chen, G.Y., Dalerba, P., Gurney, A., Hoey, T., Sherlock, G., Lewicki, J., Shedden, K., and Clarke, M.F. 2007. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N. Engl. J. Med. 356:217–226.PubMedGoogle Scholar
  60. Lobo, N.A., Shimono, Y., Qian, D., and Clarke, M.F. 2007. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 23:675-699.PubMedGoogle Scholar
  61. McNeal, J.E., Redwine, E.A., Freiha, F.S., and Stamey, T.A. 1988. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am. J. Surg. Pathol. 12:897–906.PubMedGoogle Scholar
  62. Mimeault, M., Hauke, R., and Batra, S.K. 2007a. Recent advances on the molecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies. Clin. Pharmacol. Ther. 83:673–691.PubMedGoogle Scholar
  63. Mimeault, M., Hauke, R., Mehta, P.P., and Batra, S.K. 2007b. Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J. Cell Mol. Med. 11:981–1011.PubMedGoogle Scholar
  64. Mohinta, S., Wu, H., Chaurasia, P., and Watabe, K. 2007. Wnt pathway and breast cancer. Front Biosci. 12:4020–4033.PubMedGoogle Scholar
  65. Molofsky, A.V., Pardal, R., Iwashita, T., Park, I.K., Clarke, M.F., and Morrison, S.J. 2003. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967.PubMedGoogle Scholar
  66. Morrison, S.J. and Weissman, I.L. 1994. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1:661–673.PubMedGoogle Scholar
  67. Nagle, R.B., Ahmann, F.R., McDaniel, K.M., Paquin, M.L., Clark, V.A., and Celniker, A. 1987. Cytokeratin characterization of human prostatic carcinoma and its derived cell lines. Cancer Res. 47:281–286.PubMedGoogle Scholar
  68. Nelson, W.G., De Marzo, A.M., and Isaacs, W.B. 2003. Prostate cancer. N. Engl. J. Med. 349:366–381.PubMedGoogle Scholar
  69. Nupponen, N.N. and Visakorpi, T. 2000. Molecular cytogenetics of prostate cancer. Microsc. Res. Tech. 51:456–463.PubMedGoogle Scholar
  70. Nybakken, K. and Perrimon, N. 2002. Hedgehog signal transduction: recent findings. Curr. Opin. Genet. Dev. 12:503–511.PubMedGoogle Scholar
  71. Pan, G. and Thomson, J.A. 2007. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 17:42–49.PubMedGoogle Scholar
  72. Pardal, R., Clarke, M.F., and Morrison, S.J. 2003. Applying the principles of stem-cell biology to cancer. Nat. Rev. Cancer 3:895–902.PubMedGoogle Scholar
  73. Pasca di Magliano, M. and Hebrok, M. 2003. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 3:903–911.PubMedGoogle Scholar
  74. Patrawala, L., Calhoun, T., Schneider-Broussard, R., Zhou, J., Claypool, K., and Tang, D.G. 2005. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and A. Cancer Res. 65:6207–6219.PubMedGoogle Scholar
  75. Patrawala, L., Calhoun, T., Schneider-Broussard, R., Li, H., Bhatia, B., Tang, S., Reilly, J.G., Chandra, D., Zhou, J., Claypool, K., Coghlan, L., and Tang, D.G. 2006. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25:1696–1708.PubMedGoogle Scholar
  76. Pereira, L., Yi, F., and Merrill, B.J. 2006. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol. Cell Biol. 26:7479–7491.Google Scholar
  77. Perryman, S.V. and Sylvester, K.G. 2006. Repair and regeneration: opportunities for carcinogenesis from tissue stem cells. J. Cell Mol. Med. 10:292–308.PubMedGoogle Scholar
  78. Pesce, M. and Scholer, H.R. 2001. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19:271–278.PubMedGoogle Scholar
  79. Prins, G.S. and Birch, L. 1995. The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology 136:1303–1314.PubMedGoogle Scholar
  80. Ramirez-Castillejo, C., Sanchez-Sanchez, F., Andreu-Agullo, C., Ferron, S.R., Aroca-Aguilar, J.D., Sanchez, P., Mira, H., Escribano, J., and Farinas, I. 2006. Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat. Neurosci. 9:331–339.PubMedGoogle Scholar
  81. Reya, T., Duncan, A.W., Ailles, L., Domen, J., Scherer, D.C., Willert, K., Hintz, L., Nusse, R., and Weissman, I.L. 2003. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423:409–414.PubMedGoogle Scholar
  82. Reynolds, B.A. and Weiss, S. 1996. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev. Biol. 175:1–13.PubMedGoogle Scholar
  83. Richardson, G.D., Robson, C.N., Lang, S.H., Neal, D.E., Maitland, N.J., and Collins, A.T. 2004. CD133, a novel marker for human prostatic epithelial stem cells. J. Cell Sci. 117:3539–3545.PubMedGoogle Scholar
  84. Risbridger, G.P., Almahbobi, G.A., and Taylor, R.A. 2005. Early prostate development and its association with late-life prostate disease. Cell Tissue Res. 322:173–181.PubMedGoogle Scholar
  85. Rizzo, S., Attard, G., and Hudson, D.L. 2005. Prostate epithelial stem cells. Cell Prolif. 38:363–374.PubMedGoogle Scholar
  86. Robinson, E.J., Neal, D.E., and Collins, A.T. 1998. Basal cells are progenitors of luminal cells in primary cultures of differentiating human prostatic epithelium. Prostate 37:149–160.PubMedGoogle Scholar
  87. Rubin, L.L. and De Sauvage, F.J. 2006. Targeting the Hedgehog pathway in cancer. Nat. Rev. Drug Discov. 5:1026–1033.Google Scholar
  88. Salm, S.N., Burger, P.E., Coetzee, S., Goto, K., Moscatelli, D., and Wilson, E.L. 2005. TGF-{beta} maintains dormancy of prostatic stem cells in the proximal region of ducts. J. Cell Biol. 170:81–90.PubMedGoogle Scholar
  89. Sanchez, P., Hernandez, A.M., Stecca, B., Kahler, A.J., DeGueme, A.M., Barrett, A., Beyna, M., Datta, M.W., Datta, S., and Altaba, A. 2004. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc. Natl Acad. Sci. USA 101:12561–12566.PubMedGoogle Scholar
  90. Santagata, S., Demichelis, F., Riva, A., Varambally, S., Hofer, M.D., Kutok, J.L., Kim, R., Tang, J., Montie, J.E., Chinnaiyan, A.M., Rubin, M.A., and Aster, J.C. 2004. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 64:6854–6857.PubMedGoogle Scholar
  91. Sar, M., Lubahn, D.B., French, F.S., and Wilson, E.M. 1990. Immunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology 127:3180–3186.PubMedGoogle Scholar
  92. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., and Brivanlou, A.H. 2004. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med. 10:55–63.PubMedGoogle Scholar
  93. Scher, H.I. and Sawyers, C.L. 2005. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J. Clin. Oncol. 23:8253–8261.PubMedGoogle Scholar
  94. Sell, S. 2006. Cancer stem cells and differentiation therapy. Tumour Biol. 27:59–70.PubMedGoogle Scholar
  95. Sharifi, N., Gulley, J.L., and Dahut, W.L. 2005. Androgen deprivation therapy for prostate cancer. JAMA 294:238–244.PubMedGoogle Scholar
  96. Sharifi, N., Kawasaki, B.T., Hurt, E.M., and Farrar, W.L. 2006. Stem cells in prostate cancer: resolving the castrate-resistant conundrum and implications for hormonal therapy. Cancer Biol. Ther. 5:901–906.PubMedGoogle Scholar
  97. Shen, Q., Goderie, S.K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K., and Temple, S. 2004. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304:1338–1340.PubMedGoogle Scholar
  98. Shou, J., Ross, S., Koeppen, H., De Sauvage, F.J., and Gao, W.Q. 2001. Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res. 61:7291–7297.PubMedGoogle Scholar
  99. Shukla, S., Wu, C.P., and Ambudkar, S.V. 2008. Development of inhibitors of ATP-binding cassette drug transporters: present status and challenges. Expert Opin. Drug Metab. Toxicol. 4:205–223.PubMedGoogle Scholar
  100. Siemers, E.R., Dean, R.A., Friedrich, S., Ferguson-Sells, L., Gonzales, C., Farlow, M.R., and May, P.C. 2007. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin. Neuropharmacol. 30:317–325.PubMedGoogle Scholar
  101. Signoretti, S., Waltregny, D., Dilks, J., Isaac, B., Lin, D., Garraway, L., Yang, A., Montironi, R., McKeon, F., and Loda, M. 2000. p63 is a prostate basal cell marker and is required for prostate development. Am. J. Pathol. 157:1769–1775.PubMedGoogle Scholar
  102. Signoretti, S., Pires, M.M., Lindauer, M., Horner, J.W., Grisanzio, C., Dhar, S., Majumder, P., McKeon, F., Kantoff, P.W., Sellers, W.R., and Loda, M. 2005. p63 regulates commitment to the prostate cell lineage. Proc. Natl Acad. Sci. USA 102:11355–11360.PubMedGoogle Scholar
  103. Sims-Mourtada, J., Izzo, J.G., Ajani, J., and Chao, K.S. 2007. Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 26:5674–5679.PubMedGoogle Scholar
  104. Southam, C.M. and Brunschwig, A. 1961. Quantitative studies of autotransplantation of human cancer. Cancer 14:971–978.Google Scholar
  105. Stanbrough, M., Bubley, G.J., Ross, K., Golub, T.R., Rubin, M.A., Penning, T.M., Febbo, P.G., and Balk, S.P. 2006. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66:2815–2825.PubMedGoogle Scholar
  106. Stingl, J. and Caldas, C. 2007. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat. Rev. Cancer 7:791–799.PubMedGoogle Scholar
  107. Taipale, J. and Beachy, P.A. 2001. The Hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354.PubMedGoogle Scholar
  108. Tang, D.G., Patrawala, L., Calhoun, T., Bhatia, B., Choy, G., Schneider-Broussard, R., and Jeter, C. 2007. Prostate cancer stem/progenitor cells: identification, characterization, and implications. Mol. Carcinog. 46:1–14.PubMedGoogle Scholar
  109. Tavil, B., Cetin, M., and Tuncer, M. 2006. CD34/CD117 positivity in assessment of prognosis in children with myelodysplastic syndrome. Leuk. Res. 30:222–224.PubMedGoogle Scholar
  110. Terry, S., Yang, X., Chen, M.W., Vacherot, F., and Buttyan, R. 2006. Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer. J. Cell Biochem. 99:402–410.PubMedGoogle Scholar
  111. Thomson, A.A. and Marker, P.C. 2006. Branching morphogenesis in the prostate gland and seminal vesicles. Differentiation 74:382–392.PubMedGoogle Scholar
  112. Tomlins, S.A., Mehra, R., Rhodes, D.R., Cao, X., Wang, L., Dhanasekaran, S.M., Kalyana-Sundaram, S., Wei, J.T., Rubin, M.A., Pienta, K.J., Shah, R.B., and Chinnaiyan, A.M. 2007. Integrative molecular concept modeling of prostate cancer progression. Nat. Genet. 39:41–51.PubMedGoogle Scholar
  113. Tran, C.P., Lin, C., Yamashiro, J., and Reiter, R.E. 2002. Prostate stem cell antigen is a marker of late intermediate prostate epithelial cells. Mol. Cancer Res 1:113–121.PubMedGoogle Scholar
  114. Tsujimura, A., Koikawa, Y., Salm, S., Takao, T., Coetzee, S., Moscatelli, D., Shapiro, E., Lepor, H., Sun, T.T., and Wilson, E.L. 2002. Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J. Cell Biol. 157:1257–1265.PubMedGoogle Scholar
  115. van Leenders, G.J. and Schalken, J.A. 2001. Stem cell differentiation within the human prostate epithelium: implications for prostate carcinogenesis. BJU Int. 88 Suppl 2:35–42.PubMedGoogle Scholar
  116. Verhagen, A.P., Ramaekers, F.C., Aalders, T.W., Schaafsma, H.E., Debruyne, F.M., and Schalken, J.A. 1992. Colocalization of basal and luminal cell-type cytokeratins in human prostate cancer. Cancer Res 52:6182–6187.PubMedGoogle Scholar
  117. Walsh, P.C., DeWeese, T.L., and Eisenberger, M.A. 2007. Clinical practice. Localized prostate cancer. N. Engl. J. Med. 357:2696–2705.PubMedGoogle Scholar
  118. Wang, J.C. and Dick, J.E. 2005. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 15:494–501.PubMedGoogle Scholar
  119. Wang, X.D., Shou, J., Wong, P., French, D.M., and Gao, W.Q. 2004. Notch1-expressing cells are indispensable for prostatic branching morphogenesis during development and re-growth following castration and androgen replacement. J. Biol. Chem. 279:24733–24744.PubMedGoogle Scholar
  120. Wang, X.D., Leow, C.C., Zha, J., Tang, Z., Modrusan, Z., Radtke, F., Aguet, M., De Sauvage, F.J., and Gao, W.Q. 2006. Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation. Dev. Biol. 290:66–80.PubMedGoogle Scholar
  121. Wei, C., Guomin, W., Yujun, L., and Ruizhe, Q. 2007. Cancer stem-like cells in human prostate carcinoma cells DU145: the seeds of the cell line? Cancer Biol. Ther. 6:763–768.PubMedGoogle Scholar
  122. Weng, A.P. and Aster, J.C. 2004. Multiple niches for Notch in cancer: context is everything. Curr. Opin. Genet. Dev. 14:48–54.PubMedGoogle Scholar
  123. Whittemore, A.S., Kolonel, L.N., Wu, A.H., John, E.M., Gallagher, R.P., Howe, G.R., Burch, J.D., Hankin, J., Dreon, D.M., West, D.W., The C.Z., and Paffenbarger R.S., Jr. 1995. Prostate cancer in relation to diet, physical activity, and body size in blacks, whites, and Asians in the United States and Canada. J. Natl Cancer Inst. 87: 652–661.Google Scholar
  124. Wicha, M.S., Liu, S., and Dontu, G. 2006. Cancer stem cells: an old idea—a paradigm shift. Cancer Res. 66:1883–1890.PubMedGoogle Scholar
  125. Wissmann, C., Wild, P.J., Kaiser, S., Roepcke, S., Stoehr, R., Woenckhaus, M., Kristiansen, G., Hsieh, J.C., Hofstaedter, F., Hartmann, A., Knuechel, R., Rosenthal, A., and Pilarsky, C. 2003. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J. Pathol. 201:204–212.PubMedGoogle Scholar
  126. Xin, L., Lawson, D.A., and Witte, O.N. 2005. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc. Natl Acad. Sci. USA 102:6942–6947.PubMedGoogle Scholar
  127. Yang, F., Li, X., Sharma, M., Sasaki, C.Y., Longo, D.L., Lim, B., and Sun, Z. 2002. Linking beta-catenin to androgen-signaling pathway. J. Biol. Chem. 277:11336–11344.PubMedGoogle Scholar
  128. Zhang, Y., Wang, Z., Ahmed, F., Banerjee, S., Li, Y., and Sarkar, F.H. 2006. Down-regulation of Jagged-1 induces cell growth inhibition and S phase arrest in prostate cancer cells. Int. J. Cancer 119:2071–2077.PubMedGoogle Scholar
  129. Zheng, S.L., Sun, J., Wiklund, F., Smith, S., Stattin, P., Li, G., Adami, H.O., Hsu, F.C., Zhu, Y., Balter, K., Kader, A.K., Turner, A.R., Liu, W., Bleecker, E.R., Meyers, D.A., Duggan, D., Carpten, J.D., Chang, B.L., Isaacs, W.B., Xu, J., and Gronberg, H. 2008. Cumulative association of five genetic variants with prostate cancer. N. Engl. J. Med. 358:910–919.PubMedGoogle Scholar
  130. Zhou, S., Schuetz, J.D., Bunting, K.D., Colapietro, A.M., Sampath, J., Morris, J.J., Lagutina, I., Grosveld, G.C., Osawa, M., Nakauchi, H., and Sorrentino, B.P. 2001. 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. 7:1028–1034.PubMedGoogle Scholar
  131. Zhou, S., Morris, J.J., Barnes, Y., Lan, L., Schuetz, J.D., and Sorrentino, B.P. 2002. Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proc. Natl Acad. Sci. USA 99:12339–12344.PubMedGoogle Scholar
  132. Zhu, G., Zhau, H.E., He, H., Zhang, L., Shehata, B., Wang, X., Cerwinka, W.H., Elmore, J., and He, D. 2007. Sonic and desert hedgehog signaling in human fetal prostate development. Prostate 67:674–684.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Elaine M. Hurt
    • 1
  • George J. Klarmann
    • 2
  • Brian T. Kawasaki
    • 3
  • Nima Sharifi
    • 4
  • William L. Farrar
    • 5
  1. 1.Laboratory of Cancer PreventionNCI-FrederickFrederickUSA
  2. 2.Basic Research ProgramSAIC-Frederick, Inc., NCI-FrederickFrederickUSA
  3. 3.Cancer Stem Cell Section, Laboratory of Cancer PreventionCenter for Cancer Research, National Cancer Institute at Frederick, National Institutes of HealthFrederickUSA
  4. 4.Division of Hematology/OncologyUniversity of Texas Southwestern Medical CenterDallasUSA
  5. 5.Laboratory of Cancer PreventionNCI-FrederickFrederickUSA

Personalised recommendations