Prostate Cancer Stem Cells: A Brief Review

  • Xin Chen
  • Dean G. Tang


Human cancers have been shown to harbor stem cell-like cells called cancer stem cells (CSCs). These cells are thought to be endowed with indefinite self-renewal ability and believed to be involved in tumor initiation, promotion, progression, metastasis, and therapy resistance. Prostate cancers (PCa) have also been shown to contain CSCs. Here we briefly review the literature reports of CSCs in various tumor systems. We then summarize studies of prostate CSCs (PCSCs) in human cancers and mouse models and discuss their respective limitations. We further discuss the current controversies with respect to identifying the cell of origin for PCa. Elucidating the unique characteristics of PCSCs will enhance our understanding of the mechanisms underlying the emergence of castration-resistant disease and may provide new opportunities for developing therapeutics that target the recurrent PCa.


Cancer Stem Cell Side Population Luminal Cell Cancer Stem Cell Population Aldefluor Assay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Androgen-deprivation therapy


Aldehyde dehydrogenase


Acute myeloid leukemia


Androgen receptor


Cancer stem cells


Human prostate cancer




Prostate cancer


Prostate cancer stem cells


Stem cells


Side population


Tumor-initiating cells



The work in the authors’ lab was supported, in part, by grants from NIH (R21-CA150009 and R01-CA155693-01A1), Department of Defense (W81XWH-11-1-0331), CPRIT (RP120380), and the MDACC Center for Cancer Epigenetics (D.G.T) and by two Center Grants (CCSG-5 P30 CA166672). X. Chen was supported by the Cockrell Fund from the Department of Molecular Carcinogenesis.


  1. Abate-Shen C, Shen MM (2000) Molecular genetics of prostate cancer. Genes Dev 14(19): 2410–2434PubMedCrossRefGoogle Scholar
  2. Abou-Kheir WG, Hynes PG, Martin PL et al (2010) Characterizing the contribution of stem/progenitor cells to tumorigenesis in the Pten-/-TP53-/- prostate cancer model. Stem Cells 28(12):2129–2140PubMedCrossRefGoogle Scholar
  3. Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988PubMedCrossRefGoogle Scholar
  4. Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760PubMedCrossRefGoogle Scholar
  5. Bleau AM, Hambardzumyan D, Ozawa T et al (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4(3):226–235PubMedCrossRefGoogle Scholar
  6. Boiko AD, Razorenova OV, van de Rijn M et al (2010) Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466(7302):133–137PubMedCrossRefGoogle Scholar
  7. Bonkhoff H, Stein U, Remberger K (1994) The proliferative function of basal cells in the normal and hyperplastic human prostate. Prostate 24(3):114–118PubMedCrossRefGoogle Scholar
  8. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737PubMedCrossRefGoogle Scholar
  9. Bruce WR, Van Der Gaag H (1963) A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199:79–80PubMedCrossRefGoogle Scholar
  10. Cairo S, Armengol C, De Reyniès A et al (2008) Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell 14(6):471–484PubMedCrossRefGoogle Scholar
  11. Choi N, Zhang B, Zhang L et al (2012) Adult murine prostate basal and luminal cells are self-­sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 21(2):253–265PubMedCrossRefGoogle Scholar
  12. Clarke MF, Dick JE, Dirks PB et al (2006) Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66(19):9339–9344PubMedCrossRefGoogle Scholar
  13. Clarkson BD (1969) Review of recent studies of cellular proliferation in acute leukemia. Natl Cancer Inst Monogr 30:81–120PubMedGoogle Scholar
  14. Clarkson B, Fried J, Strife A et al (1970) Studies of cellular proliferation in human leukemia. 3. Behavior of leukemic cells in three adults with acute leukemia given continuous infusions of 3H-thymidine for 8 or 10 days. Cancer 25(6):1237–1260PubMedCrossRefGoogle Scholar
  15. Clevers H (2011) The cancer stem cell: premises, promises and challenges. Nat Med. 17 (3):313–339, ReviewGoogle Scholar
  16. Collins AT, Berry PA, Hyde C et al (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951PubMedCrossRefGoogle Scholar
  17. Curtis SJ, Sinkevicius KW, Li D et al (2010) Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell 7(1):127–133PubMedCrossRefGoogle Scholar
  18. Dalerba P, Dylla SJ, Park IK et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104(24):10158–10163PubMedCrossRefGoogle Scholar
  19. Dubrovska A, Kim S, Salamone RJ et al (2009) The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 106(1):268–273PubMedCrossRefGoogle Scholar
  20. Dubrovska A, Elliott J, Salamone RJ et al (2010) Combination therapy targeting both tumor-­initiating and differentiated cell populations in prostate carcinoma. Clin Cancer Res 16(23):5692–5702PubMedCrossRefGoogle Scholar
  21. Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1(1):34–45PubMedCrossRefGoogle Scholar
  22. Furth J, Kahn M (1937) The transmission of leukemia of mice with a single cell. Am J Cancer 31:276–282Google Scholar
  23. Germann M, Wetterwald A, Guzmán-Ramirez N et al (2012) Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. Stem Cells 30(6):1076–1086PubMedCrossRefGoogle Scholar
  24. Ginestier C, Hur MH, Charafe-Jauffret E et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567PubMedCrossRefGoogle Scholar
  25. Goldstein AS, Huang J, Guo C et al (2010) Identification of a cell of origin for human prostate cancer. Science 329(5991):568–571PubMedCrossRefGoogle Scholar
  26. Grange C, Tapparo M, Collino F et al (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71(15):5346–5356PubMedCrossRefGoogle Scholar
  27. Guzmán-Ramírez N, Völler M, Wetterwald A et al (2009) In vitro propagation and characterization of neoplastic stem/progenitor-like cells from human prostate cancer tissue. Prostate 69(15):1683–1693PubMedCrossRefGoogle Scholar
  28. Hirschmann-Jax C, Foster AE, Wulf GG et al (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101(39):14228–14233PubMedCrossRefGoogle Scholar
  29. Ho MM, Ng AV, Lam S et al (2007) Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 67(10):4827–4833PubMedCrossRefGoogle Scholar
  30. Huang EH, Hynes MJ, Zhang T et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69(8):3382–3389PubMedCrossRefGoogle Scholar
  31. Inoda S, Hirohashi Y, Torigoe T et al (2011) Cytotoxic T lymphocytes efficiently recognize human colon cancer stem-like cells. Am J Pathol 178(4):1805–1813PubMedCrossRefGoogle Scholar
  32. Jeter CR, Badeaux M, Choy G et al (2009) Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27(5):993–1005PubMedCrossRefGoogle Scholar
  33. Jeter CR, Liu B, Liu X et al (2011) NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30(36):3833–3845PubMedCrossRefGoogle Scholar
  34. Killmann SA, Cronkite EP, Robertson JS et al (1963) Estimation of phases of the life cycle of leukemic cells from labeling in human beings in vivo with tritiated thymidine. Lab Invest 12:671–684PubMedGoogle Scholar
  35. Korsten H, Ziel-van der Made A, Ma X et al (2009) Accumulating progenitor cells in the luminal epithelial cell layer are candidate tumor initiating cells in a Pten knockout mouse prostate cancer model. PLoS One 4(5):e5662PubMedCrossRefGoogle Scholar
  36. Lapidot T, Sirard C, Vormoor J et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367(6464):645–648PubMedCrossRefGoogle Scholar
  37. Lawson DA, Zong Y, Memarzadeh S et al (2010) Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc Natl Acad Sci USA 107(6):2610–2615PubMedCrossRefGoogle Scholar
  38. Li C, Heidt DG, Dalerba P et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037PubMedCrossRefGoogle Scholar
  39. Li H, Chen X, Calhoun-Davis T et al (2008) PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res 68(6):1820–1825PubMedCrossRefGoogle Scholar
  40. Li H, Jiang M, Honorio S et al (2009) Methodologies in assaying prostate cancer stem cells. Methods Mol Biol 568:85–138PubMedCrossRefGoogle Scholar
  41. Li T, Su Y, Mei Y et al (2010) ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients’ outcome. Lab Invest 90(2):234–244PubMedCrossRefGoogle Scholar
  42. Liu C, Kelnar K, Liu B et al (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17(2):211–215PubMedCrossRefGoogle Scholar
  43. Lonardo E, Hermann PC, Mueller MT et al (2011) Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 9(5):433–446PubMedCrossRefGoogle Scholar
  44. Lukacs RU, Memarzadeh S, Wu H et al (2010) Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell 7(6):682–693PubMedCrossRefGoogle Scholar
  45. Ma X, Ziel-van der Made AC, Autar B et al (2005) Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation but not by reduced apoptosis. Cancer Res 65(13):5730–5739PubMedCrossRefGoogle Scholar
  46. Matsumoto K, Arao T, Tanaka K et al (2009) mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. Cancer Res 69(18):7160–7164PubMedCrossRefGoogle Scholar
  47. Meirelles K, Benedict LA, Dombkowski D et al (2011) Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Proc Natl Acad Sci USA 109(7):2358–2363CrossRefGoogle Scholar
  48. Mulholland DJ, Xin L, Morim A et al (2009) Lin-Sca-1 + CD49fhigh stem/progenitors are tumor-­initiating cells in the Pten-null prostate cancer model. Cancer Res 69(22):8555–8562PubMedCrossRefGoogle Scholar
  49. Mulholland DJ, Kobayashi N, Ruscetti M et al (2012) Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res 72(7):1878–1889PubMedCrossRefGoogle Scholar
  50. Nishizawa S, Hirohashi Y, Torigoe T et al (2012) HSP DNAJB8 controls tumor-initiating ability in renal cancer stem-like cells. Cancer Res 72(11):2844–2854PubMedCrossRefGoogle Scholar
  51. O’Brien CA, Pollett A, Gallinger S et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110PubMedCrossRefGoogle Scholar
  52. Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-­formation as an assay for stem cells. Cell Stem Cell 8(5):486–498PubMedCrossRefGoogle Scholar
  53. Patrawala L, Calhoun T, Schneider-Broussard R et al (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res 65(14):6207–6219PubMedCrossRefGoogle Scholar
  54. Patrawala L, Calhoun T, Schneider-Broussard R et al (2006) Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25(12):1696–1708PubMedCrossRefGoogle Scholar
  55. Patrawala L, Calhoun-Davis T, Schneider-Broussard R et al (2007) Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44 + alpha2beta1+ cell population is enriched in tumor-initiating cells. Cancer Res 67(14):6796–6805PubMedCrossRefGoogle Scholar
  56. Pece S, Tosoni D, Confalonieri S et al (2010) Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140(1):62–73PubMedCrossRefGoogle Scholar
  57. Pienta KJ, Abate-Shen C, Agus DB et al (2008) The current state of preclinical prostate cancer animal models. Prostate 68(6):629–639PubMedCrossRefGoogle Scholar
  58. Pierce GB Jr, Dixon FJ Jr, Verney EL (1960) Teratocarcinogenic and tissue-forming potentials of the cell types comprising neoplastic embryoid bodies. Lab Invest 9:583–602PubMedGoogle Scholar
  59. Prince ME, Sivanandan R, Kaczorowski A et al (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104(3):973–978PubMedCrossRefGoogle Scholar
  60. Qin J, Liu X, Laffin B et al (2012) The PSA(-/lo) Prostate Cancer Cell Population Harbors Self-­Renewing Long-Term Tumor-Propagating Cells that Resist Castration. Cell Stem Cell 10(5):556–569PubMedCrossRefGoogle Scholar
  61. Quintana E, Shackleton M, Sabel MS et al (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593–598PubMedCrossRefGoogle Scholar
  62. Rajasekhar VK, Studer L, Gerald W et al (2011) Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling. Nat Commun 2:162PubMedCrossRefGoogle Scholar
  63. Ricci-Vitiani L, Lombardi DG, Pilozzi E et al (2007) Identification and expansion of human colon-­cancer-initiating cells. Nature 445(7123):111–115PubMedCrossRefGoogle Scholar
  64. Schatton T, Murphy GF, Frank NY et al (2008) Identification of cells initiating human melanomas. Nature 451(7176):345–349PubMedCrossRefGoogle Scholar
  65. Sharifi N, Kawasaki BT, Hurt EM et al (2006) Stem cells in prostate cancer: resolving the castrate-­resistant conundrum and implications for hormonal therapy. Cancer Biol Ther 5(8):901–906PubMedCrossRefGoogle Scholar
  66. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29PubMedCrossRefGoogle Scholar
  67. Silva IA, Bai S, McLean K et al (2011) Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 71(11):3991–4001PubMedCrossRefGoogle Scholar
  68. Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401PubMedCrossRefGoogle Scholar
  69. Tang DG (2012) Understanding cancer stem cell heterogeneity and plasticity. Cell Res 22(3):457–472PubMedCrossRefGoogle Scholar
  70. Taylor RA, Toivanen R, Frydenberg M et al (2012) Human epithelial basal cells are cells of origin of prostate cancer, independent of CD133 status. Stem Cells 30(6):1087–1096PubMedCrossRefGoogle Scholar
  71. Todaro M, Alea MP, Di Stefano AB et al (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1(4):389–402PubMedCrossRefGoogle Scholar
  72. van den Hoogen C, van der Horst G, Cheung H et al (2010) High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res 70(12):5163–5173PubMedCrossRefGoogle Scholar
  73. Vander Griend DJ, Karthaus WL, Dalrymple S et al (2008) The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res 68(23):9703–9711PubMedCrossRefGoogle Scholar
  74. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8(10):755–768PubMedCrossRefGoogle Scholar
  75. Wang S, Garcia AJ, Wu M et al (2006) Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci USA 103(5):1480–1485PubMedCrossRefGoogle Scholar
  76. Wang X, Kruithof-de Julio M, Economides KD et al (2009) A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461(7263):495–500PubMedCrossRefGoogle Scholar
  77. Xin L, Lawson DA, Witte ON (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(19):6942–6947PubMedCrossRefGoogle Scholar
  78. Yan H, Chen X, Zhang Q et al (2011) Drug-tolerant cancer cells show reduced tumor-initiating capacity: depletion of CD44 cells and evidence for epigenetic mechanisms. PLoS One 6(9):e24397PubMedCrossRefGoogle Scholar
  79. Yang ZF, Ho DW, Ng MN et al (2008a) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13(2):153–166PubMedCrossRefGoogle Scholar
  80. Yang ZJ, Ellis T, Markant SL et al (2008b) Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14(2):135–145PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Department of Molecular CarcinogenesisThe University of Texas M.D. Anderson Cancer Center, Science ParkSmithvilleUSA
  2. 2.Program in Molecular CarcinogenesisGraduate School of Biomedical Sciences (GSBS)HoustonUSA

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