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Hormone-refractory prostate cancer: a multi-step and multi-event process

Prostate Cancer and Prostatic Diseases volume 4, pages 204–212 (2001)Cite this article

Abstract

Since the pioneering studies of Huggins in 1941, it has been known that prostate cancer cells, like certain normal epithelial cells, can chronically depend on a critical level of androgenic stimulation for their continuous growth and survival. The entire issue of the development of resistance to androgen ablation therapy for metastatic prostate cancer is based on the fact that a portion of cells can survive without androgen stimulation. The cell mechanism of androgen independent status is unclear. For some authors, a portion of the cells present within a patient with a prostate cancer before therapy is naturally androgen independent (selection hypothesis). However, this hypothesis does not consider gene alteration during prostate cancer natural history and probably hormone-refractory prostate cancer (HRPC) is due to a multi-step and multi-event process. In this literature review, different cell pathways that lead to HRPC are described.

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References

  1. Boring CC, Squires TS, Tong T, Montgomery S Cancer statistics, 1994. CA Cancer J Clin 1994 44 7–26

    CAS  PubMed  Google Scholar 

  2. Mettlin CJ, Murphy GP, Ho R, Menck HR The National Cancer Data Base report on longitudinal observations on prostate cancer. Cancer 1996 77 2162–2166

    CAS  PubMed  Google Scholar 

  3. Krongrad A, Lai H, Lai S Survival after radical prostatectomy. JAMA 1997 278 44–46

    CAS  PubMed  Google Scholar 

  4. Huggins C, Hodges CV Studies on prostate cancer: effect of castration, estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941 4 293–297

    Google Scholar 

  5. Huggins C, Hodges CV Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin 1972 22 232–240

    CAS  PubMed  Google Scholar 

  6. Isaacs JT, Coffey DS Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. Cancer Res 1981 41 5070–5075

    CAS  PubMed  Google Scholar 

  7. Isaacs JT The biology of hormone refractory prostate cancer. Why does it develop? Urol Clin North Am 1999 26 263–273

    CAS  PubMed  Google Scholar 

  8. van der Kwast TH et al Androgen receptors in endocrine-therapy-resistant human prostate. Int J Cancer 1991 48 189–193

    CAS  PubMed  Google Scholar 

  9. Culig Z et al Synergistic activation of androgen receptor by androgen and luteinizing hormone-releasing hormone in prostatic carcinoma cells. Prostate 1997 32 106–114

    CAS  PubMed  Google Scholar 

  10. Gil-Diez de Medina S et al Modulation of cytokeratin subtype, EGF receptor, and androgen receptor expression during progression of prostate cancer. Hum Pathol 1998 29 1005–1012

    CAS  PubMed  Google Scholar 

  11. Hockenbery DM et al BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci USA 1991 88 6961–6965

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Colombel M et al Androgen suppressed apoptosis is modified in p53 deficient mice. Oncogene 1995 10 1269–1274

    CAS  PubMed  Google Scholar 

  13. Cardillo M et al Resistance to apoptosis and up regulation of Bcl-2 in benign prostatic hyperplasia after androgen deprivation. J Urol 1997 158 212–216

    CAS  PubMed  Google Scholar 

  14. Keshgegian AA, Johnston E, Cnaan A Bcl-2 oncoprotein positivity and high MIB-1 (Ki-67) proliferative rate are independent predictive markers for recurrence in prostate carcinoma. Am J Clin Pathol 1998 110 443–449

    CAS  PubMed  Google Scholar 

  15. Huang A et al p53 and bcl-2 immunohistochemical alterations in prostate cancer treated with radiation therapy. Urology 1998 51 346–351

    CAS  PubMed  Google Scholar 

  16. Beham AW et al Molecular correlates of bcl-2-enhanced growth following androgen-ablation in prostate carcinoma cells in vivo Int J Mol Med 1998 1 953–959

    CAS  PubMed  Google Scholar 

  17. Zhang X et al Abnormal prostate development in C3(1)-bcl-2 transgenic mice. Prostate 1997 32 16–26

    PubMed  Google Scholar 

  18. Bruckheimer EM et al Bcl-2 accelerates multistep prostate carcinogenesis in vivo Oncogene 2000 19 5251–5258

    CAS  PubMed  Google Scholar 

  19. Westin P, Brandstrom A, Damber JE, Bergh A Castration plus oestrogen treatment induces but castration alone suppresses epithelial cell apoptosis in an androgen-sensitive rat prostatic adenocarcinoma. Br J Cancer 1995 72 140–145

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rampino N et al Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997 275 967–969

    CAS  PubMed  Google Scholar 

  21. Levine AJ, Momand J, Finlay CA The p53 tumour suppressor gene. Nature 1991 351 453–456

    CAS  PubMed  Google Scholar 

  22. Gartel AL, Serfas MS, Tyner AL p21--negative regulator of the cell cycle. Proc Soc Exp Biol Med 1996 213 138–149

    CAS  PubMed  Google Scholar 

  23. Miyashita T et al Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo Oncogene 1994 9 1799–1805

    CAS  PubMed  Google Scholar 

  24. McCurrach ME et al bax-Deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Acad Sci USA 1997 94 2345–2349

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Girinsky T et al Attenuated response of p53 and p21 in primary cultures of human prostatic epithelial cells exposed to DNA-damaging agents. Cancer Res 1995 55 3726–3731

    CAS  PubMed  Google Scholar 

  26. Nigro JM et al Mutations in the p53 gene occur in diverse human tumour types. Nature 1989 342 705–708

    CAS  PubMed  Google Scholar 

  27. Heidenberg HB et al The role of the p53 tumor suppressor gene in prostate cancer: a possible biomarker? Urology 1996 48 971–979

    CAS  PubMed  Google Scholar 

  28. Stricker HJ et al Determining prognosis of clinically localized prostate cancer by immunohistochemical detection of mutant p53. Urology 1996 47 366–369

    CAS  PubMed  Google Scholar 

  29. Bauer JJ et al p53 Nuclear protein expression is an independent prognostic marker in clinically localized prostate cancer patients undergoing radical prostatectomy. Clin Cancer Res 1995 1 1295–1300

    CAS  PubMed  Google Scholar 

  30. Yang G et al Clustered p53 immunostaining: a novel pattern associated with prostate cancer progression. Clin Cancer Res 1996 2 399–401

    CAS  PubMed  Google Scholar 

  31. Harris CC, Hollstein M Clinical implications of the p53 tumor-suppressor gene. New Engl J Med 1993 329 1318–1827

    CAS  PubMed  Google Scholar 

  32. Berner A et al Hormone resistant prostatic adenocarcinoma. An evaluation of prognostic factors in pre- and post-treatment specimens. Br J Cancer 1993 68 380–384

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Thomas DJ et al p53 expression and clinical outcome in prostate cancer. Br J Urol 1993 72 778–781

    CAS  PubMed  Google Scholar 

  34. Montenarh M Biochemical properties of the growth suppressor/oncoprotein p53. Oncogene 1992 7 1673–1680

    CAS  PubMed  Google Scholar 

  35. Vogelstein B, Kinzler KW p53 Function and dysfunction. Cell 1992 70 523–526

    CAS  PubMed  Google Scholar 

  36. Hollstein M, Sidransky D, Vogelstein B, Harris CC p53 Mutations in human cancers. Science 1991 253 49–53

    CAS  PubMed  Google Scholar 

  37. Jost CA, Marin MC, Kaelin WG Jr p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature 1997 389 191–194

    CAS  PubMed  Google Scholar 

  38. Bentel JM, Tilley WD Androgen receptors in prostate cancer. J Endocrinol 1996 151 1–11

    CAS  PubMed  Google Scholar 

  39. Wilding G Endocrine control of prostate cancer. Cancer Surv 1995 23 43–62

    CAS  PubMed  Google Scholar 

  40. Magi-Galluzzi C et al Heterogeneity of androgen receptor content in advanced prostate cancer. Mod Pathol 1997 10 839–845

    CAS  PubMed  Google Scholar 

  41. Visakorpi T et al in vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genet 1995 9 401–406

    CAS  PubMed  Google Scholar 

  42. Culig Z et al Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 1994 54 5474–5478

    CAS  PubMed  Google Scholar 

  43. Taplin ME et al Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. New Engl J Med 1995 332 1393–1398

    CAS  PubMed  Google Scholar 

  44. Veldscholte J et al A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 1990 173 534–540

    CAS  PubMed  Google Scholar 

  45. Shen R et al Transdifferentiation of cultured human prostate cancer cells to a neuroendocrine cell phenotype in a hormone-depleted medium. Urol Oncol 1997 3 67–75

    CAS  PubMed  Google Scholar 

  46. Suzuki H et al Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome. Prostate 1996 29 153–158

    CAS  PubMed  Google Scholar 

  47. Fenton MA et al Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin Cancer Res 1997 3 1383–1388

    CAS  PubMed  Google Scholar 

  48. Kuil CW, Brinkmann AO Androgens, antiandrogens and androgen receptor abnormalities. Eur Urol 1996 29 (Suppl 2): 78–82

    Google Scholar 

  49. Tan J et al Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 1997 11 450–459

    CAS  PubMed  Google Scholar 

  50. Akakura K et al Effects of intermittent androgen suppression on androgen-dependent tumors. Apoptosis and serum prostate-specific antigen. Cancer 1993 71 2782–2790

    CAS  PubMed  Google Scholar 

  51. Yuan S et al Androgen-induced inhibition of cell proliferation in an androgen-insensitive prostate cancer cell line (PC-3) transfected with a human androgen receptor complementary DNA. Cancer Res 1993 53 1304–1311

    CAS  PubMed  Google Scholar 

  52. Zhau HY et al Androgen-repressed phenotype in human prostate cancer. Proc Natl Acad Sci USA 1996 93 15152–15157

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Umekita Y, Hiipakka RA, Kokontis JM, Liao S Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride. Proc Natl Acad Sci USA 1996 93 11802–11807

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Edwards A et al Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 1992 12 241–253

    CAS  PubMed  Google Scholar 

  55. Giovannucci E et al The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 1997 94 3320–3323

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Stanford JL et al Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 1997 57 1194–1198

    CAS  PubMed  Google Scholar 

  57. Takahashi H et al Prevalence of androgen receptor gene mutations in latent prostatic carcinomas from Japanese men. Cancer Res 1995 55 1621–1624

    CAS  PubMed  Google Scholar 

  58. Makridakis N et al A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Res 1997 57 1020–1022

    CAS  PubMed  Google Scholar 

  59. Krammer PH et al The role of APO-1-mediated apoptosis in the immune system. Immunol Rev 1994 142 175–191

    CAS  PubMed  Google Scholar 

  60. Chinnaiyan AM, Dixit VM Portrait of an executioner: the molecular mechanism of FAS/APO-1-induced apoptosis. Semin Immunol 1997 9 69–76

    CAS  PubMed  Google Scholar 

  61. Bookstein R et al Promoter deletion and loss of retinoblastoma gene expression in human prostate carcinoma. Proc Natl Acad Sci USA 1990 87 7762–7766

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Phillips SM et al Loss of the retinoblastoma susceptibility gene (RB1) is a frequent and early event in prostatic tumorigenesis. Br J Cancer 1994 70 1252–1257

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Brooks JD, Bova GS, Isaacs WB Allelic loss of the retinoblastoma gene in primary human prostatic adenocarcinomas. Prostate 1995 26 35–39

    CAS  PubMed  Google Scholar 

  64. Buttyan R et al Enhanced expression of the c-myc protooncogene in high-grade human prostate cancers. Prostate 1987 11 327–337

    CAS  PubMed  Google Scholar 

  65. Fleming WH et al Expression of the c-myc protooncogene in human prostatic carcinoma and benign prostatic hyperplasia. Cancer Res 1986 46 1535–1538

    CAS  PubMed  Google Scholar 

  66. Westin P, Stattin P, Damber JE, Bergh A Castration therapy rapidly induces apoptosis in a minority and decreases cell proliferation in a majority of human prostatic tumors. Am J Pathol 1995 146 1368–1375

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hsu B et al Evidence that c-myc mediated apoptosis does not require wild-type p53 during lymphomagenesis. Oncogene 1995 11 175–179

    CAS  PubMed  Google Scholar 

  68. Gao X et al Somatic mutations of the WAF1/CIP1 gene in primary prostate cancer. Oncogene 1995 11 1395–1398

    CAS  PubMed  Google Scholar 

  69. Byrne RL et al The expression of waf-1, p53 and bcl-2 in prostatic adenocarcinoma. Br J Urol 1997 79 190–195

    CAS  PubMed  Google Scholar 

  70. Park DJ et al Molecular analysis of the INK4 family of genes in prostate carcinomas. J Urol 1997 157 1995–1999

    CAS  PubMed  Google Scholar 

  71. Watanabe M et al International comparison on ras gene mutations in latent prostate carcinoma. Int J Cancer 1994 58 174–178

    CAS  PubMed  Google Scholar 

  72. Anwar K et al Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas. Cancer Res 1992 52 5991–5996

    CAS  PubMed  Google Scholar 

  73. Thompson TC, Southgate J, Kitchener G, Land H Multistage carcinogenesis induced by ras and myc oncogenes in a reconstituted organ. Cell 1989 56 917–930

    CAS  PubMed  Google Scholar 

  74. Thompson TC et al Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer. Oncogene 1995 10 869–879

    CAS  PubMed  Google Scholar 

  75. Bova GS, Isaacs WB Review of allelic loss and gain in prostate cancer. World J Urol 1996 14 338–346

    CAS  PubMed  Google Scholar 

  76. Carter BS et al Allelic loss of chromosomes 16q and 10q in human prostate cancer. Proc Natl Acad Sci USA 1990 87 8751–8755

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Massenkeil G et al P53 mutations and loss of heterozygosity on chromosomes 8p, 16q, 17p, and 18q are confined to advanced prostate cancer. Anticancer Res 1994 14 2785–2790

    CAS  PubMed  Google Scholar 

  78. Visakorpi T et al Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. Cancer Res 1995 55 342–347

    CAS  PubMed  Google Scholar 

  79. Trybus TM et al Distinct areas of allelic loss on chromosomal regions 10p and 10q in human prostate cancer. Cancer Res 1996 56 2263–2267

    CAS  PubMed  Google Scholar 

  80. Teng DH et al MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 1997 57 5221–5225

    CAS  PubMed  Google Scholar 

  81. Di Sant'Agnese PA Neuroendocrine differentiation in human prostatic carcinoma. Hum Pathol 1992 23 287–296

    CAS  PubMed  Google Scholar 

  82. Gkonos PJ, Krongrad A, Roos BA Neuroendocrine peptides in the prostate. Urol Res 1995 23 81–87

    CAS  PubMed  Google Scholar 

  83. Bonkhoff H et al Relation of endocrine-paracrine cells to cell proliferation in normal, hyperplastic, and neoplastic human prostate. Prostate 1991 19 91–98

    CAS  PubMed  Google Scholar 

  84. Abrahamsson PA Neuroendocrine differentiation in the human prostate gland. Curr Trends Exp Endocrinol 1994 2 21–40

    Google Scholar 

  85. Di Sant' Agnese PA, Cockett AT The prostatic endocrine-paracrine (neuroendocrine) regulatory system and neuroendocrine differentiation in prostatic carcinoma: a review and future directions in basic research. J Urol 1994 152 1927–1931

    CAS  Google Scholar 

  86. Krijnen JL et al The prognostic value of neuroendocrine differentiation in adenocarcinoma of the prostate in relation to progression of disease after endocrine therapy. J Urol 1997 158 171–174

    CAS  PubMed  Google Scholar 

  87. Guate JL et al Neuroendocrine cells in benign prostatic hyperplasia and prostatic carcinoma: effect of hormonal treatment. Urol Int 1997 59 149–153

    CAS  PubMed  Google Scholar 

  88. Weinstein MH, Partin AW, Veltri RW, Epstein JI Neuro-endocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy. Hum Pathol 1996 27 683–687

    CAS  PubMed  Google Scholar 

  89. Angelsen A et al Neuroendocrine differentiation in carcinomas of the prostate: do neuroendocrine serum markers reflect immunohistochemical findings? Prostate 1997 30 1–6

    CAS  PubMed  Google Scholar 

  90. Tarle M, Rados N Investigation on serum neurone-specific enolase in prostate cancer diagnosis and monitoring: comparative study of a multiple tumor marker assay. Prostate 1991 19 23–33

    CAS  PubMed  Google Scholar 

  91. Bang YJ et al Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. Proc Natl Acad Sci USA 1994 91 5330–5334

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Qiu Y, Robinson D, Pretlow TG, Kung HJ Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3′-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc Natl Acad Sci USA 1998 95 3644–3649

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Takayama H et al Fas gene mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens. Lab Invest 2001 81 283–288

    CAS  PubMed  Google Scholar 

  94. Diaz JI et al Cytometric analysis of Fas and Bcl-2 expression in normal prostatic epithelium and prostate cancer. Urol Oncol 2000 5 149–154

    CAS  PubMed  Google Scholar 

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  1. Department of Urology, Hopital Henri Mondor, Créteil, France

    A de la Taille, F Vacherot, L Salomon, C Druel, S Gil Diez de Medina, C Abbou & D Chopin

  2. Department of Urology, Columbia Presbyterian Medical Center, New York, USA

    A de la Taille & R Buttyan

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  1. A de la Taille
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  2. F Vacherot
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de la Taille, A., Vacherot, F., Salomon, L. et al. Hormone-refractory prostate cancer: a multi-step and multi-event process. Prostate Cancer Prostatic Dis 4, 204–212 (2001). https://doi.org/10.1038/sj.pcan.4500534

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