J Korean Med Assoc.  2010 Feb;53(2):98-106.

Pathogenesis of Prostate Cancer

Affiliations
  • 1Department of Urology, Seoul National University College of Medicine, Korea. yoonyong@snubh.org, ssbyun@snubh.org

Abstract

Prostate cancer is one of the most frequent cancers in Western countries and has been also one of the most rapidly increasing malignant diseases in Korean men. This disease shows diverse features in clinical course ranging from an indolent disease to a lethal one. Accordingly, underlying molecular mechanisms and genetic changes involved in the development and progression of various types of prostate cancer are very heterogeneous. Thus, investigation of pathogenesis of prostate cancer is very challenging, and, at this point of time, only a handful of molecular and genetic factors were identified as pathogenic factors for prostate cancer. Plenty of data support the strong relationship between age, race and family history and the development of prostate cancer. In addition, androgen related factors such as androgen metabolism and receptor signaling are highly correlated with tumor development and progression. Numerous genetic or epigenetic changes including gene mutation and methylation contribute to the development and progression of prostate cancer. In this article, we summarize the current understanding of the pathogenesis of prostate cancer, with a special focus on underlying genetic and epigenetic alterations.

Keyword

Prostate cancer; Pathogenesis; Gene; Epigenetics

MeSH Terms

Continental Population Groups
Epigenomics
Hand
Humans
Male
Methylation
Prostate
Prostatic Neoplasms

Reference

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008. 58:71–96.
Article
2. Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 2009. 73:Suppl 5. S4–S10.
Article
3. Platz EA, Rimm EB, Willett WC, Kantoff PW, Giovannucci E. Racial variation in prostate cancer incidence and in hormonal system markers among male health professionals. J Natl Cancer Inst. 2000. 92:2009–2017.
Article
4. Jones RA, Wenzel J. Prostate cancer among African-American males: understanding the current issues. J Natl Black Nurses Assoc. 2005. 16:55–62.
5. Muir CS, Nectoux J, Staszewski J. The epidemiology of prostatic cancer. Geographical distribution and time-trends. Acta Oncol. 1991. 30:133–140.
Article
6. Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM. Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer. 1991. 63:963–966.
Article
7. Rodriguez C, McCullough ML, Mondul AM, Jacobs EJ, Chao A, Patel AV, Thun MJ, Calle EE. Meat consumption among Black and White men and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev. 2006. 15:211–216.
Article
8. Drisaldi B, Coomaraswamy J, Mastrangelo P, Strome B, Yang J, Watts JC, Chishti MA, Marvi M, Windl O, Ahrens R, Major F, Sy MS, Kretzschmar H, Fraser PE, Mount HT, Westaway D. Genetic mapping of activity determinants within cellular prion proteins: N-terminal modules in PrPC offset pro-apoptotic activity of the Doppel helix B/B' region. J Biol Chem. 2004. 279:55443–55454.
Article
9. Steers WD. 5alpha-reductase activity in the prostate. Urology. 2001. 58:6 Suppl 1. 17–24. discussion.
10. Marks LS. 5alpha-reductase: history and clinical importance. Rev Urol. 2004. 6:Suppl 9. S11–S21.
11. Wilbert DM, Griffin JE, Wilson JD. Characterization of the cytosol androgen receptor of the human prostate. J Clin Endocrinol Metab. 1983. 56:113–120.
Article
12. Zhu YS, Sun GH. 5alpha-Reductase Isozymes in the prostate. J Med Sci. 2005. 25:1–12.
13. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest. 1993. 92:903–910.
Article
14. Andriole G, Bruchovsky N, Chung LW, Matsumoto AM, Rittmaster R, Roehrborn C, Russell D, Tindall D. Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol. 2004. 172(4 Pt 1):1399–1403.
Article
15. Bonkhoff H, Stein U, Aumuller G, Remberger K. Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas. Prostate. 1996. 29:261–267.
Article
16. Iehle C, Radvanyi F, Gil Diez de Medina S, Ouafik LH, Gerard H, Chopin D, Raynaud JP, Martin PM. Differences in steroid 5alpha-reductase iso-enzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol. 1999. 68:189–195.
17. Pelletier G, Luu-The V, Huang XF, Lapointe H, Labrie F. Localization by in situ hybridization of steroid 5alpha-reductase isozyme gene expression in the human prostate and preputial skin. J Urol. 1998. 160:577–582.
Article
18. Tindall DJ, Rittmaster RS. The rationale for inhibiting 5alpha-reductase isoenzymes in the prevention and treatment of prostate cancer. J Urol. 2008. 179:1235–1242.
Article
19. Imperato-McGinley J, Gautier T, Zirinsky K, Hom T, Palomo O, Stein E, Vaughan ED, Markisz JA, Ramirez de Arellano E, Kazam E. Prostate visualization studies in males homozygous and heterozygous for 5 alpha-reductase deficiency. J Clin Endocrinol Metab. 1992. 75:1022–1026.
Article
20. Wilson JD, Roehrborn C. Long-term consequences of castration in men: lessons from the Skoptzy and the eunuchs of the Chinese and Ottoman courts. J Clin Endocrinol Metab. 1999. 84:4324–4331.
Article
21. Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y, Nakagawa H. Novel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Sci. 2008. 99:81–86.
22. Wu AH, Whittemore AS, Kolonel LN, John EM, Gallagher RP, West DW, Hankin J, Teh CZ, Dreon DM, Paffenbarger RS Jr. Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. Cancer Epidemiol Biomarkers Prev. 1995. 4:735–741.
23. Rittmaster RS. 5alpha-reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction. Best Pract Res Clin Endocrinol Metab. 2008. 22:389–402.
Article
24. Litman HJ, Bhasin S, Link CL, Araujo AB, McKinlay JB. Serum androgen levels in black, Hispanic, and white men. J Clin Endocrinol Metab. 2006. 91:4326–4334.
Article
25. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003. 349:215–224.
Article
26. Andriole G, Bostwick D, Brawley O, Gomella L, Marberger M, Tindall D, Breed S, Somerville M, Rittmaster R. REDUCE Study Group. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol. 2004. 172(4 Pt 1):1314–1317.
Article
27. Cannon LA, Bishop DT, Skolnick MH. Segregation and linkage analysis of breast cancer in the Dutch and Utah families. Genet Epidemiol Suppl. 1986. 1:43–48.
Article
28. Woolf CM. An investigation of the familial aspects of carcinoma of the prostate. Cancer. 1960. 13:739–744.
Article
29. Eeles RA, Dearnaley DP, Ardern-Jones A, Shearer RJ, Easton DF, Ford D, Edwards S, Dowe A. Familial prostate cancer: the evidence and the Cancer Research Campaign/British Prostate Group (CRC/BPG) UK Familial Prostate Cancer Study. Br J Urol. 1997. 79:Suppl 1. 8–14.
Article
30. Ahlbom A, Lichtenstein P, Malmstrom H, Feychting M, Hemminki K, Pedersen NL. Cancer in twins: genetic and nongenetic familial risk factors. J Natl Cancer Inst. 1997. 89:287–293.
Article
31. Gronberg H, Isaacs SD, Smith JR, Carpten JD, Bova GS, Freije D, Xu J, Meyers DA, Collins FS, Trent JM, Walsh PC, Isaacs WB. Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA. 1997. 278:1251–1255.
Article
32. Carter BS, Bova GS, Beaty TH, Steinberg GD, Childs B, Isaacs WB, Walsh PC. Hereditary prostate cancer: epidemiologic and clinical features. J Urol. 1993. 150:97–802.
Article
33. Spitz MR, Currier RD, Fueger JJ, Babaian RJ, Newell GR. Familial patterns of prostate cancer: a case-control analysis. J Urol. 1991. 146:1305–1307.
Article
34. Bratt O. Hereditary prostate cancer: clinical aspects. J Urol. 2002. 168:906–913.
Article
35. Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P, Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Grönberg H, Meltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet. 2002. 30:181–184.
Article
36. Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M, Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH, Neuhausen S, Rommens J, Cannon-Albright LA. A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet. 2001. 27:172–180.
Article
37. Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu JJ, Sterling D, Lange EM, Hawkins GA, Turner A, Ewing CM, Faith DA, Johnson JR, Suzuki H, Bujnovszky P, Wiley KE, DeMarzo AM, Bova GS, Chang B, Hall MC, McCullough DL, Partin AW, Kassabian VS, Carpten JD, Bailey-Wilson JE, Trent JM, Ohar J, Bleecker ER, Walsh PC, Isaacs WB, Meyers DA. Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet. 2002. 32:321–325.
Article
38. Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, Qian C, Marks AF, Slager SL, Peterson BJ, Smith DI, Cheville JC, Blute ML, Jacobsen SJ, Schaid DJ, Tindall DJ, Thibodeau SN, Liu W. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003. 72:270–280.
Article
39. Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, Jackson R, Southgate C, Singh R, Falconer A, Dearnaley DP, Ardern-Jones A, Murkin A, Dowe A, Kelly J, Williams S, Oram R, Stevens M, Teare DM, Ponder BA, Gayther SA, Easton DF, Eeles RA. Cancer Research UK/Bristish Prostate Group UK Familial Prostate Cancer Study Collaborators. British Association of Urological Surgeons Section of Oncology. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003. 72:1–12.
Article
40. Marchesani M, Hakkarainen A, Tuomainen TP, Kaikkonen J, Pukkala E, Uimari P, Seppälä E, Matikainen M, Kallioniemi OP, Schleutker J, Lehtimäki T, Salonen JT. New paraoxonase 1 polymorphism I102V and the risk of prostate cancer in Finnish men. J Natl Cancer Inst. 2003. 95:812–818.
Article
41. Xu J, Zheng SL, Turner A, Isaacs SD, Wiley KE, Hawkins GA, Chang BL, Bleecker ER, Walsh PC, Meyers DA, Isaacs WB. Associations between hOGG1 sequence variants and prostate cancer susceptibility. Cancer Res. 2002. 62:2253–2257.
42. Lindmark F, Zheng SL, Wiklund F, Bensen J, Balter KA, Chang B, Hedelin M, Clark J, Stattin P, Meyers DA, Adami HO, Isaacs W, Grönberg H, Xu J. H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer. J Natl Cancer Inst. 2004. 96:1248–1254.
Article
43. Berthon P, Valeri A, Cohen-Akenine A, Drelon E, Paiss T, Wohr G, Latil A, Millasseau P, Mellah I, Cohen N, Blanché H, Bellané-Chantelot C, Demenais F, Teillac P, Le Duc A, de Petriconi R, Hautmann R, Chumakov I, Bachner L, Maitland NJ, Lidereau R, Vogel W, Fournier G, Mangin P, Cussenot O, et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet. 1998. 62:1416–1424.
Article
44. Gibbs M, Stanford JL, McIndoe RA, Jarvik GP, Kolb S, Goode EL, Chakrabarti L, Schuster EF, Buckley VA, Miller EL, Brandzel S, Li S, Hood L, Ostrander EA. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet. 1999. 64:776–787.
Article
45. Xu J, Meyers D, Freije D, Isaacs S, Wiley K, Nusskern D, Ewing C, Wilkens E, Bujnovszky P, Bova GS, Walsh P, Isaacs W, Schleutker J, Matikainen M, Tammela T, Visakorpi T, Kallioniemi OP, Berry R, Schaid D, French A, McDonnell S, Schroeder J, Blute M, Thibodeau S, Grönberg H, Emanuelsson M, Damber JE, Bergh A, Jonsson BA, Smith J, Bailey-Wilson J, Carpten J, Stephan D, Gillanders E, Amundson I, Kainu T, Freas-Lutz D, Baffoe-Bonnie A, Van Aucken A, Sood R, Collins F, Brownstein M, Trent J. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet. 1998. 20:175–179.
Article
46. Cher ML, Lewis PE, Banerjee M, Hurley PM, Sakr W, Grignon DJ, Powell IJ. A similar pattern of chromosomal alterations in prostate cancers from African-Americans and Caucasian Americans. Clin Cancer Res. 1998. 4:1273–1278.
47. Cher ML, Bova GS, Moore DH, Small EJ, Carroll PR, Pin SS, Epstein JI, Isaacs WB, Jensen RH. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res. 1996. 56:3091–3102.
48. Cher ML, MacGrogan D, Bookstein R, Brown JA, Jenkins RB, Jensen RH. Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer. Genes Chromosomes Cancer. 1994. 11:153–162.
Article
49. Bergerheim US, Kunimi K, Collins VP, Ekman P. Deletion mapping of chromosomes 8, 10, and 16 in human prostatic carcinoma. Genes Chromosomes Cancer. 1991. 3:215–220.
Article
50. Bergerheim US, Collins VP, Ekman P, Kunimi K. Recessive genetic mechanisms in the oncogenesis of prostatic car -cinoma. Scand J Urol Nephrol Suppl. 1991. 138:93–96.
51. He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall DJ, Gelmann EP, Abate-Shen C, Carter KC. A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics. 1997. 43:69–77.
Article
52. Prescott JL, Blok L, Tindall DJ. Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. Prostate. 1998. 04. 01. 35:71–80.
Article
53. Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, Gelmann EP. Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res. 2000. 60:6111–6115.
54. Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Young P, Norton CR, Gridley T, Cardiff RD, Cunha GR, Abate-Shen C, Shen MM. Roles for Nkx3.1 in prostate development and cancer. Genes Dev. 1999. 13:966–977.
Article
55. Tanaka M, Komuro I, Inagaki H, Jenkins NA, Copeland NG, Izumo S. Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Dev Dyn. 219:248–260.
Article
56. Gurumurthy S, Vasudevan KM, Rangnekar VM. Regulation of apoptosis in prostate cancer. Cancer Metastasis Rev. 2001. 20:225–243.
Article
57. Fossa A, Lilleby W, Fossa SD, Gaudernack G, Torlakovic G, Berner A. Independent prognostic significance of HER-2 oncoprotein expression in pN0 prostate cancer undergoing curative radiotherapy. Int J Cancer. 2002. 99:100–105.
Article
58. Qian J, Hirasawa K, Bostwick DG, Bergstralh EJ, Slezak JM, Anderl KL, Borell TJ, Lieber MM, Jenkins RB. Loss of p53 and c-myc overrepresentation in stage T(2-3)N(1-3)M(0) prostate cancer are potential markers for cancer progression. Mod Pathol. 2002. 15:35–44.
Article
59. McDonnell TJ, Navone NM, Troncoso P, Pisters LL, Conti C, von Eschenbach AC, Brisbay S, Logothetis CJ. Expression of bcl-2 oncoprotein and p53 protein accumulation in bone marrow metastases of androgen independent prostate cancer. J Urol. 1997. 157:569–574.
Article
60. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992. 52:6940–6944.
61. DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI. Pathological and molecular aspects of prostate cancer. Lancet. 2003. 361:955–964.
Article
62. Rubin MA, Gerstein A, Reid K, Bostwick DG, Cheng L, Parsons R, Papadopoulos N. 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2-3,N+) versus lymph node-negative (pT2-3,N0) prostate cancer. Hum Pathol. 2000. 31:504–508.
Article
63. Umbas R, Schalken JA, Aalders TW, Carter BS, Karthaus HF, Schaafsma HE, Debruyne FM, Isaacs WB. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res. 1992. 52:5104–5109.
64. Li LC, Zhao H, Nakajima K, Oh BR, Ribeiro Filho LA, Carroll P, Dahiya R. Methylation of the E-cadherin gene promoter correlates with progression of prostate cancer. J Urol. 2001. 166:705–709.
Article
65. Gonzalgo ML, Isaacs WB. Molecular pathways to prostate cancer. J Urol. 2003. 170(6 Pt 1):2444–2452.
Article
66. Isaacs NM. The surgical treatment of epilepsy. J Neurosurg Nurs. 1976. 8:155–168.
Article
67. Nakayama M, Gonzalgo ML, Yegnasubramanian S, Lin X, De Marzo AM, Nelson WG. GSTP1 CpG island hypermethylation as a molecular biomarker for prostate cancer. J Cell Biochem. 2004. 91:540–552.
Article
68. Bostwick DG, Burke HB, Djakiew D, Euling S, Ho SM, Landolph J, Morrison H, Sonawane B, Shifflett T, Waters DJ, Timms B. Human prostate cancer risk factors. Cancer. 2004. 101:Suppl 10. 2371–2490.
Article
69. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004. 10:33–39.
Article
70. Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, Bartsch G, Klocker H. 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.
71. Craft N, Shostak Y, Carey M, Sawyers CL. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999. 5:280–285.
Article
Full Text Links
  • JKMA
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr