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  • Review Article
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Inflammation in prostate carcinogenesis

Key Points

  • Prostate cancer is the most common form of non-skin cancer in men in developed countries. The cause(s) of prostate cancer have not yet been clarified. Although heritable factors are implicated, immigration studies indicate that environmental exposures are also important.

  • Chronic infection and inflammation cause cancer in several organs including the stomach, liver and large intestine. Data from histopathological, molecular histopathological, epidemiological and genetic epidemiological studies show that chronic inflammation might also be important in prostate carcinogenesis.

  • The source of intraprostatic inflammation is often unknown, but might be caused by infection (for example, with sexually transmitted agents), cell injury (owing to exposure to chemical and physical trauma from urine reflux and prostatic calculi formation), hormonal variations and/or exposures, or dietary factors such as charred meats. The resultant epithelial cellular injury might cause a loss of tolerance to normal prostatic antigens, resulting in a self-perpetuating autoimmune reaction.

  • Exposures to infectious agents and dietary carcinogens are postulated to directly injure the prostate epithelium, resulting in the histological lesions known as proliferative inflammatory atrophy (PIA), or proliferative atrophy. These lesions are postulated to be a manifestation of the 'field effect' caused by environmental exposures.

  • Despite a strong genetic component to prostate cancer risk, no highly penetrant hereditary prostate cancer genes have been uncovered to date. Although complex, genetic variation in inflammatory genes is associated with prostate cancer risk.

  • Several challenges remain regarding the inflammation hypothesis in prostate cancer, including the determination of the cause(s) of chronic inflammation in the prostate, an understanding of the cellular and molecular biology of the immune response in the prostate, whether inflammatory cells are truly causative in the process, and the determination of the target cell types within the proposed precursor lesions of prostate cancer.

  • The refinement and application of new epidemiological approaches, including high-throughput genetic epidemiology, improved rodent models of prostate inflammation and cancer, and advances in the application of molecular techniques to histopathological studies should provide insights into the cause of prostate inflammation and its relevance to prostate carcinogenesis.

Abstract

About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease.

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Figure 1: Zonal predisposition to prostate disease.
Figure 2: Possible causes of prostate inflammation.
Figure 3: Cellular and molecular model of early prostate neoplasia progression.

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References

  1. Jemal, A. et al. Cancer statistics, 2005. CA Cancer J. Clin. 55, 10–30 (2005).

    Article  PubMed  Google Scholar 

  2. Ames, B. N., Gold, L. S. & Willett, W. C. The causes and prevention of cancer. Proc. Natl Acad. Sci. USA 92, 5258–5265 (1995). This paper describes the main environmental causes of cancer and the molecular mechanisms by which they function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. ACS. Cancer Facts and FIGS 2005. American Cancer Society, 1–64 (2005).

  5. De Marzo, A. M. et al. Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment. J. Cell Biochem. 91, 459–477 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Nelson, W. G., De Marzo, A. M. & Isaacs, W. B. Prostate cancer. N. Engl. J. Med. 349, 366–381 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Platz, E. A. & De Marzo, A. M. Epidemiology of inflammation and prostate cancer. J. Urol. 171, S36–S40 (2004).

    Article  PubMed  Google Scholar 

  8. Gonzalgo, M. L. & Isaacs, W. B. Molecular pathways to prostate cancer. J. Urol. 170, 2444–2452 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Shand, R. L. & Gelmann, E. P. Molecular biology of prostate-cancer pathogenesis. Curr. Opin. Urol. 16, 123–131 (2006).

    Article  PubMed  Google Scholar 

  10. Pihan, G. A., Wallace, J., Zhou, Y. & Doxsey, S. J. Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res. 63, 1398–1404 (2003).

    CAS  PubMed  Google Scholar 

  11. Meeker, A. K. Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology. Urol. Oncol. 24, 122–130 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Bostwick, D. G. in Urologic Surgical Pathology (eds Bostwick, D. G. & Eble, J. N.) 423–456 (Mosby, St. Louis, 1997).

    Google Scholar 

  13. Hsing, A. W., Tsao, L. & Devesa, S. S. International trends and patterns of prostate cancer incidence and mortality. Int. J. Cancer 85, 60–67 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Peto, J. Cancer epidemiology in the last century and the next decade. Nature 411, 390–395 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. McNeal, J. E., Redwine, E. A., Freiha, F. S. & Stamey, T. A. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am. J. Surg. Pathol. 12, 897–906 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Franks, L. M. Atrophy and hyperplasia in the prostate proper. J. Pathol. Bacteriol. 68, 617–621 (1954).

    Article  CAS  PubMed  Google Scholar 

  17. McNeal, J. E. in Histology for Pathologists (ed. Sternberg, S. S.) 997–1017 (Lippincott-Raven, Philadelphia, 1997). This book chapter describes in detail the now well established zonal anatomy of the prostate.

    Google Scholar 

  18. De Marzo, A. M., Marchi, V. L., Epstein, J. I. & Nelson, W. G. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am. J. Pathol. 155, 1985–1992 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rich, A. R. On the frequency of occurrence of occult carcinoma of the prostate. J. Urol. 33, 215–223 (1934).

    Article  Google Scholar 

  20. McNeal, J. E. Normal histology of the prostate. Am. J. Surg. Pathol. 12, 619–633 (1988).

    Article  CAS  PubMed  Google Scholar 

  21. Feneley, M. R., Young, M. P., Chinyama, C., Kirby, R. S. & Parkinson, M. C. Ki-67 expression in early prostate cancer and associated pathological lesions. J. Clin. Pathol. 49, 741–748 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ruska, K. M., Sauvageot, J. & Epstein, J. I. Histology and cellular kinetics of prostatic atrophy. Am. J. Surg. Pathol. 22, 1073–1077 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. van Leenders, G. J. et al. Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy. Am. J. Pathol. 162, 1529–1537 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Montironi, R., Mazzucchelli, R. & Scarpelli, M. Precancerous lesions and conditions of the prostate: from morphological and biological characterization to chemoprevention. Ann. NY Acad. Sci. 963, 169–184 (2002).

    Article  PubMed  Google Scholar 

  25. Nakayama, M. et al. Hypermethylation of the human GSTP1 CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using Laser-Capture Microdissection. Am. J. Pathol. 163, 923–933 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Putzi, M. J. & De Marzo, A. M. Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia. Urology 56, 828–832 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Bethel, C. R. et al. Decreased NKX3. 1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia and adenocarcinoma: association with Gleason score and chromosome 8p deletion. Cancer Res. 66, 10683–10690 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Abate-Shen, C. & Shen, M. M. Mouse models of prostate carcinogenesis. Trends Genet. 18, S1–S5 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Pelouze, P. S. Gonorrhea in the male and female: a book for practitioners (W. B. Saunders Company, Philadelphia, 1935).

    Google Scholar 

  30. Poletti, F. et al. Isolation of Chlamydia trachomatis from the prostatic cells in patients affected by nonacute abacterial prostatitis. J. Urol. 134, 691–693 (1985).

    Article  CAS  PubMed  Google Scholar 

  31. Gardner, W. A. Jr, Culberson, D. E. & Bennett, B. D. Trichomonas vaginalis in the prostate gland. Arch. Pathol. Lab. Med. 110, 430–432 (1986).

    PubMed  Google Scholar 

  32. Thomson, L. Syphilis of the prostate. Am. J. Syphilis 4, 323–341 (1920).

    Google Scholar 

  33. Cohen, R. J., Shannon, B. A., McNeal, J. E., Shannon, T. & Garrett, K. L. Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: a possible link to cancer evolution? J. Urol. 173, 1969–1974 (2005).

    Article  PubMed  Google Scholar 

  34. Bushman, W. in Prostatic Diseases (ed. Lepor, H.) 550–557 (W. B. Saunders Company, Philadelphia, 2000).

    Google Scholar 

  35. Handsfield, H. H., Lipman, T. O., Harnisch, J. P., Tronca, E. & Holmes, K. K. Asymptomatic gonorrhea in men. Diagnosis, natural course, prevalence and significance. N. Engl. J. Med. 290, 117–123 (1974).

    Article  CAS  PubMed  Google Scholar 

  36. Strickler, H. D. & Goedert, J. J. Sexual behavior and evidence for an infectious cause of prostate cancer. Epidemiol Rev. 23, 144–151 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Zambrano, A., Kalantari, M., Simoneau, A., Jensen, J. L. & Villarreal, L. P. Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. Prostate 53, 263–276 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Samanta, M., Harkins, L., Klemm, K., Britt, W. J. & Cobbs, C. S. High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J. Urol. 170, 998–1002 (2003).

    Article  PubMed  Google Scholar 

  39. Riley, D. E., Berger, R. E., Miner, D. C. & Krieger, J. N. Diverse and related 16S rRNA-encoding DNA sequences in prostate tissues of men with chronic prostatitis. J. Clin. Microbiol. 36, 1646–1652 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Urisman, A. et al. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2, e25 (2006). This study used a new gene chip containing all known viral nucleic acids to identify a new virus in the prostate. Only men with inherited inactive RNASEL alleles were at a high risk of harbouring the virus.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Platz, E. A. et al. Nonsteroidal anti-inflammatory drugs and risk of prostate cancer in the Baltimore Longitudinal Study of Aging. Cancer Epidemiol. Biomarkers Prev. 14, 390–396 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Mahmud, S., Franco, E. & Aprikian, A. Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and meta-analysis. Br. J. Cancer 90, 93–99 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chan, J. M., Feraco, A., Shuman, M. & Hernandez-Diaz, S. The epidemiology of prostate cancer — with a focus on nonsteroidal anti-inflammatory drugs. Hematol. Oncol. Clin. North Am. 20, 797–809 (2006).

    Article  PubMed  Google Scholar 

  44. Jacobs, E. J. et al. A large cohort study of aspirin and other nonsteroidal anti-inflammatory drugs and prostate cancer incidence. J. Natl Cancer Inst. 97, 975–980 (2005).

    Article  PubMed  Google Scholar 

  45. Dennis, L. K., Lynch, C. F. & Torner, J. C. Epidemiologic association between prostatitis and prostate cancer. Urology 60, 78–83 (2002).

    Article  PubMed  Google Scholar 

  46. Sarma, A. V. et al. Sexual behavior, sexually transmitted diseases and prostatitis: the risk of prostate cancer in black men. J. Urol. 176, 1108–1113 (2006).

    Article  PubMed  Google Scholar 

  47. Sutcliffe, S. et al. Gonorrhea, syphilis, clinical prostatitis, and the risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 15, 2160–2166 (2006).

    Article  PubMed  Google Scholar 

  48. Nickel, J. C. et al. Consensus development of a histopathological classification system for chronic prostatic inflammation. BJU Int. 87, 797–805 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Feigl, P. et al. Design of the Prostate Cancer Prevention Trial (PCPT). Control Clin. Trials 16, 150–163 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Kirby, R. S., Lowe, D., Bultitude, M. I. & Shuttleworth, K. E. Intra-prostatic urinary reflux: an aetiological factor in abacterial prostatitis. Br. J. Urol. 54, 729–731 (1982).

    Article  CAS  PubMed  Google Scholar 

  51. Persson, B. E. & Ronquist, G. Evidence for a mechanistic association between nonbacterial prostatitis and levels of urate and creatinine in expressed prostatic secretion. J. Urol. 155, 958–960 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). This paper presented genetic evidence that uric acid crystals can activate the inflammasome, and therefore produce a potent inflammatory response.

    Article  CAS  PubMed  Google Scholar 

  53. Drachenberg, C. B. & Papadimitriou, J. C. Prostatic corpora amylacea and crystalloids: similarities and differences on ultrastructural and histochemical studies. J. Submicrosc. Cytol. Pathol. 28, 141–150 (1996).

    CAS  PubMed  Google Scholar 

  54. Gardner, W. A. & Bennett, B. D. in Pathology and pathobiology of the urinary bladder and prostate (eds Weinstein, R. S. & Garnder, W. A.) 129–148 (Williams and Wilkens, Baltimore, 1992).

    Google Scholar 

  55. Meares, E. M. Jr. Infection stones of prostate gland. Laboratory diagnosis and clinical management. Urology 4, 560–566 (1974).

    Article  PubMed  Google Scholar 

  56. Joachim, H. La lithiase prostatique peut-elle etre consideree comme un facteur cancerogene? Urologia (Treviso) 28, 1–11 (1961).

    Google Scholar 

  57. Cristol, D. S. & Emmett, J. L. Incidence of coincident prostatic calculi, prostatic hyperplasia and carcinoma of prostate gland. JAMA 124, 646–652 (1944).

    Article  Google Scholar 

  58. Sondergaard, G., Vetner, M. & Christensen, P. O. Prostatic calculi. Acta Pathol. Microbiol. Immunol. Scand. [A] 95, 141–145 (1987).

    CAS  Google Scholar 

  59. Isaacs, J. T. Prostatic structure and function in relation to the etiology of prostatic cancer. Prostate 4, 351–366 (1983).

    Article  CAS  PubMed  Google Scholar 

  60. Leitzmann, M. F., Platz, E. A., Stampfer, M. J., Willett, W. C. & Giovannucci, E. Ejaculation frequency and subsequent risk of prostate cancer. JAMA 291, 1578–1586 (2004). This paper presents evidence that high ejaculation frequency, especially in young men, is related to reduced prostate cancer incidence, and therefore suggests that the 'flushing' of the prostate of harmful chemicals or infectious agents might reduce prostate cancer risk.

    Article  CAS  PubMed  Google Scholar 

  61. Chen, X., Zhao, J., Salim, S. & Garcia, F. U. Intraprostatic spermatozoa: zonal distribution and association with atrophy. Hum. Pathol. 37, 345–351 (2006).

    Article  PubMed  Google Scholar 

  62. Giovannucci, E. et al. A prospective study of dietary fat and risk of prostate cancer. J. Natl Cancer Inst. 85, 1571–1579 (1993).

    Article  CAS  PubMed  Google Scholar 

  63. Norrish, A. E. et al. Heterocyclic amine content of cooked meat and risk of prostate cancer. J. Natl Cancer Inst. 91, 2038–2044 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Michaud, D. S. et al. A prospective study on intake of animal products and risk of prostate cancer. Cancer Causes Control 12, 557–567 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Sugimura, T., Wakabayashi, K., Nakagama, H. & Nagao, M. Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish. Cancer Sci. 95, 290–299 (2004). This paper reviews the intriguing discovery of highly mutagenic and carcinogenic compounds formed during the high-temperature cooking of meats.

    Article  CAS  PubMed  Google Scholar 

  66. Knize, M. G. & Felton, J. S. Formation and human risk of carcinogenic heterocyclic amines formed from natural precursors in meat. Nutr. Rev. 63, 158–165 (2005). This paper reviews the discovery and significance of PhIP as the most abundant of the heterocyclic amines produced by high-temperature cooking of meats.

    Article  PubMed  Google Scholar 

  67. Inaguma, S. et al. High susceptibility of the ACI and spontaneously hypertensive rat (SHR) strains to 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) prostate carcinogenesis. Cancer Sc.i 94, 974–979 (2003).

    Article  CAS  Google Scholar 

  68. Nakai, Y., Nelson, W. G. & De Marzo, A. M. The dietary charred meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4, 5b]pyridine (PhIP) acts as both an initiator and tumor promoter in the rat ventral prostate. Cancer Res. 67, 1378–1384 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Borowsky, A. D. et al. Inflammation and atrophy precede prostatic neoplasia in a PhIP-induced rat model. Neoplasia 8, 708–715 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Malaviya, R., Ikeda, T., Ross, E. & Abraham, S. N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 381, 77–80 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Choo-Kang, B. S. et al. TNF-blocking therapies: an alternative mode of action? Trends Immunol. 26, 518–522 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Araki, Y., Andoh, A., Fujiyama, Y. & Bamba, T. Development of dextran sulphate sodium-induced experimental colitis is suppressed in genetically mast cell-deficient Ws/Ws rats. Clin. Exp. Immunol. 119, 264–269 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Coffey, D. S. Similarities of prostate and breast cancer: Evolution, diet, and estrogens. Urology 57, 31–38 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Harkonen, P. L. & Makela, S. I. Role of estrogens in development of prostate cancer. J. Steroid Biochem. Mol. Biol. 92, 297–305 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Gilleran, J. P. et al. The role of prolactin in the prostatic inflammatory response to neonatal estrogen. Endocrinology 144, 2046–2054 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Huang, L., Pu, Y., Alam, S., Birch, L. & Prins, G. S. Estrogenic regulation of signaling pathways and homeobox genes during rat prostate development. J. Androl. 25, 330–337 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Naslund, M. J., Strandberg, J. D. & Coffey, D. S. The role of androgens and estrogens in the pathogenesis of experimental nonbacterial prostatitis. J. Urol. 140, 1049–1053 (1988).

    Article  CAS  PubMed  Google Scholar 

  78. Huang, L., Pu, Y., Alam, S., Birch, L. & Prins, G. S. The role of Fgf10 signaling in branching morphogenesis and gene expression of the rat prostate gland: lobe-specific suppression by neonatal estrogens. Dev. Biol. 278, 396–414 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Prins, G. S. et al. Estrogen imprinting of the developing prostate gland is mediated through stromal estrogen receptor a: studies with aERKO and bERKO mice. Cancer Res. 61, 6089–6097 (2001).

    CAS  PubMed  Google Scholar 

  80. Ponniah, S., Arah, I. & Alexander, R. B. PSA is a candidate self-antigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome. Prostate 44, 49–54 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Theyer, G. et al. Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. Lab. Invest. 66, 96–107 (1992).

    CAS  PubMed  Google Scholar 

  82. Bostwick, D. G., de la Roza, G., Dundore, P., Corica, F. A. & Iczkowski, K. A. Intraepithelial and stromal lymphocytes in the normal human prostate. Prostate 55, 187–193 (2003).

    Article  PubMed  Google Scholar 

  83. De Marzo, A. M. in Prostate Cancer: Biology, Genetics and the New Therapeutics (eds Chung, L. W. K., Isaacs, W. B. & Simons, J. W.) (Humana Press, Totawa, NJ, in the press).

  84. Steiner, G. E. et al. The picture of the prostatic lymphokine network is becoming increasingly complex. Rev. Urol. 4, 171–177 (2002).

    PubMed  PubMed Central  Google Scholar 

  85. Steiner, G. E. et al. Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate. Prostate 56, 171–182 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Steiner, G. E. et al. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab. Invest. 83, 1131–1146 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Erdman, S. E. et al. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am. J. Pathol. 162, 691–702 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Miller, A. M. et al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J. Immunol. 177, 7398–7405 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006). This paper reviews the discovery and characterization of a new class of T cells responsible for some forms of autoimmunity and perhaps cancer formation in a number of systems.

    Article  CAS  PubMed  Google Scholar 

  90. Langowski, J. L. et al. IL-23 promotes tumour incidence and growth. Nature 442, 461–465 (2006). This paper shows the requirement for IL23 in carcinogen-induced skin cancers in animals, and that it functions by inhibiting tumour immune surveillance.

    Article  CAS  PubMed  Google Scholar 

  91. Schaid, D. J. The complex genetic epidemiology of prostate cancer. Hum. Mol. Genet. 13 Spec No 1, R103–R121 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Smith, J. R. et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274, 1371–1374 (1996). This is the first report in which, using a genome-wide scanning approach, a major prostate cancer-susceptibility gene was identified.

    Article  CAS  PubMed  Google Scholar 

  93. Carpten, J. et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature Genet. 30, 181–184 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Silverman, R. H. Implications for RNase L in prostate cancer biology. Biochemistry 42, 1805–1812 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Hassel, B. A., Zhou, A., Sotomayor, C., Maran, A. & Silverman, R. H. A dominant negative mutant of 2–5A-dependent RNase suppresses antiproliferative and antiviral effects of interferon. EMBO J. 12, 3297–3304 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wiklund, F. et al. Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer. Clin. Cancer Res. 10, 7150–7156 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Maier, C. et al. Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene. Br. J. Cancer 92, 1159–1164 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rennert, H. et al. Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men. Cancer Epidemiol. Biomarkers Prev. 14, 949–957 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Kotar, K., Hamel, N., Thiffault, I. & Foulkes, W. D. The RNASEL 471delAAAG allele and prostate cancer in Ashkenazi Jewish men. J. Med. Genet. 40, e22 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Malathi, K. et al. A transcriptional signaling pathway in the IFN system mediated by 2'-5'-oligoadenylate activation of RNase L. Proc. Natl Acad. Sci. USA 102, 14533–14538 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Xu, J. et al. Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nature Genet. 32, 321–325 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Gough, P. J., Greaves, D. R. & Gordon, S. A naturally occurring isoform of the human macrophage scavenger receptor (SR-A) gene generated by alternative splicing blocks modified LDL uptake. J. Lipid. Res. 39, 531–543 (1998).

    Article  CAS  PubMed  Google Scholar 

  103. Peiser, L. et al. The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria meningitidis which is independent of lipopolysaccharide and not required for secretory responses. Infect. Immun. 70, 5346–5354 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ozeki, Y. et al. Macrophage scavenger receptor down-regulates mycobacterial cord factor-induced proinflammatory cytokine production by alveolar and hepatic macrophages. Microb. Pathog. 40, 171–176 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Cotena, A., Gordon, S. & Platt, N. The class A macrophage scavenger receptor attenuates CXC chemokine production and the early infiltration of neutrophils in sterile peritonitis. J. Immunol. 173, 6427–6432 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Xu, J. et al. Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Am. J. Hum. Genet. 72, 208–212 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Miller, D. C. et al. Germ-line mutations of the macrophage scavenger receptor 1 gene: association with prostate cancer risk in African-American men. Cancer Res. 63, 3486–3489 (2003).

    CAS  PubMed  Google Scholar 

  108. Wang, L. et al. No association of germline alteration of MSR1 with prostate cancer risk. Nature Genet. 35, 128–129 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Seppala, E. H. et al. Germ-line alterations in MSR1 gene and prostate cancer risk. Clin. Cancer Res. 9, 5252–5256 (2003).

    PubMed  Google Scholar 

  110. Hope, Q. et al. Macrophage scavenger receptor 1 999C>T (R293X) mutation and risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 14, 397–402 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Lindmark, F. et al. Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer. Prostate 59, 132–140 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Sun, J. et al. Meta-analysis of association of rare mutations and common sequence variants in the MSR1 gene and prostate cancer risk. Prostate 66, 728–737 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Janeway, C. A. Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Zheng, S. L. et al. Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res. 64, 2918–2922 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Sun, J. et al. Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J. Natl Cancer Inst. 97, 525–532 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  PubMed  Google Scholar 

  117. Ohashi, K., Burkart, V., Flohe, S. & Kolb, H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164, 558–561 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Chen, Y. C. et al. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res. 65, 11771–11778 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Chuang, T. & Ulevitch, R. J. Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim. Biophys. Acta 1518, 157–161 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Takeuchi, O. et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10–14 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Yamamoto, M., Takeda, K. & Akira, S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol. Immunol. 40, 861–868 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Takeuchi, O. et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933–940 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Hajjar, A. M. et al. Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. J. Immunol. 166, 15–19 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Lindmark, F. et al. H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer. J. Natl Cancer Inst. 96, 1248–1254 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Lindmark, F. et al. Interleukin-1 receptor antagonist haplotype associated with prostate cancer risk. Br. J. Cancer 93, 493–497 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. McCarron, S. L. et al. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res. 62, 3369–3372 (2002).

    CAS  PubMed  Google Scholar 

  127. Michaud, D. S. et al. Genetic polymorphisms of interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and risk of prostate cancer. Cancer Res. 66, 4525–4530 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Zheng, S. L. et al. A comprehensive association study for genes in inflammation pathway provides support for their roles in prostate cancer risk in the CAPS study. Prostate 66, 1556–1564 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Kasper, S. Survey of genetically engineered mouse models for prostate cancer: analyzing the molecular basis of prostate cancer development, progression, and metastasis. J. Cell Biochem. 94, 279–297 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Freedman, M. L. et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl Acad. Sci. USA 103, 14068–14073 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Amundadottir, L. T. et al. A common variant associated with prostate cancer in European and African populations. Nature Genet. 38, 652–658 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Groopman, J. D. & Kensler, T. W. Role of metabolism and viruses in aflatoxin-induced liver cancer. Toxicol. Appl. Pharmacol. 206, 131–137 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Lewis, C. E. & Pollard, J. W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605–612 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. de Visser, K. E., Eichten, A. & Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nature Rev. Cancer 6, 24–37 (2006).

    Article  CAS  Google Scholar 

  136. Chisari, F. V. Rous-Whipple Award Lecture. Viruses, immunity, and cancer: lessons from hepatitis B. Am. J. Pathol. 156, 1117–1132 (2000). This paper reviews the key discovery that liver cancer can be induced simply by the transfer of activated T cells that recognize virally encoded antigens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Neill, M. G. & Fleshner, N. E. An update on chemoprevention strategies in prostate cancer for 2006. Curr. Opin. Urol. 16, 132–137 (2006).

    Article  PubMed  Google Scholar 

  138. Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–90 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nature Rev. Cancer 4, 11–22 (2004).

    Article  CAS  Google Scholar 

  140. Tsujimoto, Y., Takayama, H., Nonomura, N., Okuyama, A. & Aozasa, K. Postatrophic hyperplasia of the prostate in Japan: histologic and immunohistochemical features and p53 gene mutation analysis. Prostate 52, 279–287 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Tsujimoto, Y. et al. In situ shortening of CAG repeat length within the androgen receptor gene in prostatic cancer and its possible precursors. Prostate 58, 283–290 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Shah, R., Mucci, N. R., Amin, A., Macoska, J. A. & Rubin, M. A. Postatrophic hyperplasia of the prostate gland: neoplastic precursor or innocent bystander? Am. J. Pathol. 158, 1767–1773 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yildiz-Sezer, S. et al. Assessment of aberrations on chromosome 8 in prostatic atrophy. BJU Int. 98, 184–188 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Macoska, J. A., Trybus, T. M. & Wojno, K. J. 8p22 loss concurrent with 8c gain is associated with poor outcome in prostate cancer. Urology 55, 776–782 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Guo, Y. P., Sklar, G. N., Borkowski, A. & Kyprianou, N. Loss of the cyclin-dependent kinase inhibitor P27(Kip1) protein in human prostate cancer correlates with tumor grade. Clin. Cancer Res. 3, 2269–2274 (1997).

    CAS  PubMed  Google Scholar 

  146. De Marzo, A. M., Meeker, A. K., Epstein, J. I. & Coffey, D. S. Prostate stem cell compartments: expression of the cell cycle inhibitor p27Kip1 in normal, hyperplastic, and neoplastic cells. Am. J. Pathol. 153, 911–919 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yang, R. M. et al. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J. Urol. 159, 941–945 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Denicourt, C. & Dowdy, S. F. Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev. 18, 851–855 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

  150. Shen, M. M. & Abate-Shen, C. Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Dev. Dyn. 228, 767–778 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Ouyang, X., DeWeese, T. L., Nelson, W. G. & Abate-Shen, C. Loss-of-function of Nkx3.1 promotes increased oxidative damage in prostate carcinogenesis. Cancer Res. 65, 6773–6779 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Parsons, J. K. et al. GSTA1 expression in normal, preneoplastic, and neoplastic human prostate tissue. Prostate 49, 30–37 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Zha, S. et al. Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. Cancer Res. 61, 8617–8623 (2001).

    CAS  PubMed  Google Scholar 

  154. Knudsen, B. S. et al. Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate. Am. J. Pathol. 167, 255–266 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Dennis, L. K. & Dawson, D. V. Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology 13, 72–79 (2002).

    Article  PubMed  Google Scholar 

  156. Taylor, M. L., Mainous, A. G., 3rd & Wells, B. J. Prostate cancer and sexually transmitted diseases: a meta-analysis. Fam. Med. 37, 506–512 (2005).

    PubMed  Google Scholar 

  157. Sutcliffe, S. et al. Plasma antibodies against Trichomonas vaginalis and subsequent risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 15, 939–945 (2006). This is the first study linking objective evidence of exposure to Trichomonas vaginalis with prostate cancer risk.

    Article  CAS  PubMed  Google Scholar 

  158. Sutcliffe, S. et al. Sexually transmitted infections and prostatic inflammation/cell damage as measured by serum prostate specific antigen concentration. J. Urol. 175, 1937–1942 (2006).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Amelia K. Thomas for sketching the early concept designs for figure 2. Support was received from the Department of Defense Congressional Dir. Med. Research Program; The Public Health Services National Institutes of Health (NIH) and the National Cancer Institute, NIH and National Cancer Institute Specialized Programs of Research Excellence in Prostate Cancer, and philanthropic support from the Donald and Susan Sturm Foundation, B. L. Schwartz and R. A. Barry. A.M.D. is a Helen and Peter Bing Scholar through The Patrick C. Walsh Prostate Cancer Research Fund.

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Understanding Prostate Cancer

Glossary

Prostatic intraepithelial neoplasia

A lesion characterized by cells with neoplastic features, which line pre-existing acini and ducts. PIN represents the most likely precursor to many prostate cancers.

Benign prostatic hyperplasia

Non-cancerous enlargement consisting of excess glands and stroma affecting the transition zone of the prostate.

Urine reflux

During urination, urine flows from the bladder through the prostatic urethra and into the penile urethra. Urine reflux occurs when urine flows inadvertently into the prostatic ducts, permeating large portions of the prostatic acini.

Prostatitis

Technically means 'inflammation of the prostate'. However, it is usually referred to as a clinical syndrome largely characterized by pelvic pain that has several subtypes. Some symptomatic subtypes (I and II) are associated with bacterial infections, others with inflammation but no infection (IIIa), or no inflammation and no infection (IIIb). Type IV consists of chronic inflammation without clinical symptoms.

Expressed prostate fluid

Secretions obtained following prostate massage after digital rectal examination.

Prostate specific antigen

A polypeptide that is expressed at very high levels in prostate epithelial cells, whereas very low levels are detected in normal serum; however, several pathological conditions such as prostate cancer, prostate inflammation and benign prostatic hyperplasia can result in increased serum PSA levels.

Inflammasome

A multiprotein intracytoplasmic complex that activates pro-inflammatory caspases, which then cleave the precursor of interleukin-1β (pro-IL1β) into the active form, leading to a potent inflammatory response.

Corpora amylacea

Amorphous small nodules or concretions located in the lumen of benign prostate acini and ducts that accumulate with age.

Heterocyclic amines

Molecules that are produced as a result of cooking meats at high temperatures, and which can be metabolized to biologically active, DNA-damaging agents. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant HCA.

FOXP3

A nuclear transcription factor that is expressed specifically in regulatory T cells.

Odds ratio

The odds ratio is a way of comparing whether the probability of a certain event is the same for two groups, and is calculated using a 2×2 table. An odds ratio of one implies that an event is equally likely in both groups. An odds ratio greater than one implies that an event is more likely in the first group. An odds ratio less than one implies that the event is less likely in the first group.

Longitudinal study

A study in which repeated observations of a set of subjects are made over time with respect to one or more study variables.

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De Marzo, A., Platz, E., Sutcliffe, S. et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 7, 256–269 (2007). https://doi.org/10.1038/nrc2090

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