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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jemal, A. et al. Cancer statistics, 2005. CA Cancer J. Clin. 55, 10–30 (2005).
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.
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
ACS. Cancer Facts and FIGS 2005. American Cancer Society, 1–64 (2005).
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).
Nelson, W. G., De Marzo, A. M. & Isaacs, W. B. Prostate cancer. N. Engl. J. Med. 349, 366–381 (2003).
Platz, E. A. & De Marzo, A. M. Epidemiology of inflammation and prostate cancer. J. Urol. 171, S36–S40 (2004).
Gonzalgo, M. L. & Isaacs, W. B. Molecular pathways to prostate cancer. J. Urol. 170, 2444–2452 (2003).
Shand, R. L. & Gelmann, E. P. Molecular biology of prostate-cancer pathogenesis. Curr. Opin. Urol. 16, 123–131 (2006).
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).
Meeker, A. K. Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology. Urol. Oncol. 24, 122–130 (2006).
Bostwick, D. G. in Urologic Surgical Pathology (eds Bostwick, D. G. & Eble, J. N.) 423–456 (Mosby, St. Louis, 1997).
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).
Peto, J. Cancer epidemiology in the last century and the next decade. Nature 411, 390–395 (2001).
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).
Franks, L. M. Atrophy and hyperplasia in the prostate proper. J. Pathol. Bacteriol. 68, 617–621 (1954).
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.
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).
Rich, A. R. On the frequency of occurrence of occult carcinoma of the prostate. J. Urol. 33, 215–223 (1934).
McNeal, J. E. Normal histology of the prostate. Am. J. Surg. Pathol. 12, 619–633 (1988).
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).
Ruska, K. M., Sauvageot, J. & Epstein, J. I. Histology and cellular kinetics of prostatic atrophy. Am. J. Surg. Pathol. 22, 1073–1077 (1998).
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).
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).
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).
Putzi, M. J. & De Marzo, A. M. Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia. Urology 56, 828–832 (2000).
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).
Abate-Shen, C. & Shen, M. M. Mouse models of prostate carcinogenesis. Trends Genet. 18, S1–S5 (2002).
Pelouze, P. S. Gonorrhea in the male and female: a book for practitioners (W. B. Saunders Company, Philadelphia, 1935).
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).
Gardner, W. A. Jr, Culberson, D. E. & Bennett, B. D. Trichomonas vaginalis in the prostate gland. Arch. Pathol. Lab. Med. 110, 430–432 (1986).
Thomson, L. Syphilis of the prostate. Am. J. Syphilis 4, 323–341 (1920).
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).
Bushman, W. in Prostatic Diseases (ed. Lepor, H.) 550–557 (W. B. Saunders Company, Philadelphia, 2000).
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).
Strickler, H. D. & Goedert, J. J. Sexual behavior and evidence for an infectious cause of prostate cancer. Epidemiol Rev. 23, 144–151 (2001).
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).
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).
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).
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.
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).
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).
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).
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).
Dennis, L. K., Lynch, C. F. & Torner, J. C. Epidemiologic association between prostatitis and prostate cancer. Urology 60, 78–83 (2002).
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).
Sutcliffe, S. et al. Gonorrhea, syphilis, clinical prostatitis, and the risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 15, 2160–2166 (2006).
Nickel, J. C. et al. Consensus development of a histopathological classification system for chronic prostatic inflammation. BJU Int. 87, 797–805 (2001).
Feigl, P. et al. Design of the Prostate Cancer Prevention Trial (PCPT). Control Clin. Trials 16, 150–163 (1995).
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).
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).
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.
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).
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).
Meares, E. M. Jr. Infection stones of prostate gland. Laboratory diagnosis and clinical management. Urology 4, 560–566 (1974).
Joachim, H. La lithiase prostatique peut-elle etre consideree comme un facteur cancerogene? Urologia (Treviso) 28, 1–11 (1961).
Cristol, D. S. & Emmett, J. L. Incidence of coincident prostatic calculi, prostatic hyperplasia and carcinoma of prostate gland. JAMA 124, 646–652 (1944).
Sondergaard, G., Vetner, M. & Christensen, P. O. Prostatic calculi. Acta Pathol. Microbiol. Immunol. Scand. [A] 95, 141–145 (1987).
Isaacs, J. T. Prostatic structure and function in relation to the etiology of prostatic cancer. Prostate 4, 351–366 (1983).
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.
Chen, X., Zhao, J., Salim, S. & Garcia, F. U. Intraprostatic spermatozoa: zonal distribution and association with atrophy. Hum. Pathol. 37, 345–351 (2006).
Giovannucci, E. et al. A prospective study of dietary fat and risk of prostate cancer. J. Natl Cancer Inst. 85, 1571–1579 (1993).
Norrish, A. E. et al. Heterocyclic amine content of cooked meat and risk of prostate cancer. J. Natl Cancer Inst. 91, 2038–2044 (1999).
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).
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.
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.
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).
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).
Borowsky, A. D. et al. Inflammation and atrophy precede prostatic neoplasia in a PhIP-induced rat model. Neoplasia 8, 708–715 (2006).
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).
Choo-Kang, B. S. et al. TNF-blocking therapies: an alternative mode of action? Trends Immunol. 26, 518–522 (2005).
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).
Coffey, D. S. Similarities of prostate and breast cancer: Evolution, diet, and estrogens. Urology 57, 31–38 (2001).
Harkonen, P. L. & Makela, S. I. Role of estrogens in development of prostate cancer. J. Steroid Biochem. Mol. Biol. 92, 297–305 (2004).
Gilleran, J. P. et al. The role of prolactin in the prostatic inflammatory response to neonatal estrogen. Endocrinology 144, 2046–2054 (2003).
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).
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).
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).
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).
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).
Theyer, G. et al. Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. Lab. Invest. 66, 96–107 (1992).
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).
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).
Steiner, G. E. et al. The picture of the prostatic lymphokine network is becoming increasingly complex. Rev. Urol. 4, 171–177 (2002).
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).
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).
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).
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).
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.
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.
Schaid, D. J. The complex genetic epidemiology of prostate cancer. Hum. Mol. Genet. 13 Spec No 1, R103–R121 (2004).
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.
Carpten, J. et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature Genet. 30, 181–184 (2002).
Silverman, R. H. Implications for RNase L in prostate cancer biology. Biochemistry 42, 1805–1812 (2003).
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).
Wiklund, F. et al. Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer. Clin. Cancer Res. 10, 7150–7156 (2004).
Maier, C. et al. Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene. Br. J. Cancer 92, 1159–1164 (2005).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Wang, L. et al. No association of germline alteration of MSR1 with prostate cancer risk. Nature Genet. 35, 128–129 (2003).
Seppala, E. H. et al. Germ-line alterations in MSR1 gene and prostate cancer risk. Clin. Cancer Res. 9, 5252–5256 (2003).
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).
Lindmark, F. et al. Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer. Prostate 59, 132–140 (2004).
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).
Janeway, C. A. Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
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).
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).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
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).
Chen, Y. C. et al. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res. 65, 11771–11778 (2005).
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).
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).
Yamamoto, M., Takeda, K. & Akira, S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol. Immunol. 40, 861–868 (2004).
Takeuchi, O. et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933–940 (2001).
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).
Lindmark, F. et al. H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer. J. Natl Cancer Inst. 96, 1248–1254 (2004).
Lindmark, F. et al. Interleukin-1 receptor antagonist haplotype associated with prostate cancer risk. Br. J. Cancer 93, 493–497 (2005).
McCarron, S. L. et al. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res. 62, 3369–3372 (2002).
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).
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).
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).
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).
Amundadottir, L. T. et al. A common variant associated with prostate cancer in European and African populations. Nature Genet. 38, 652–658 (2006).
Groopman, J. D. & Kensler, T. W. Role of metabolism and viruses in aflatoxin-induced liver cancer. Toxicol. Appl. Pharmacol. 206, 131–137 (2005).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Lewis, C. E. & Pollard, J. W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605–612 (2006).
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).
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.
Neill, M. G. & Fleshner, N. E. An update on chemoprevention strategies in prostate cancer for 2006. Curr. Opin. Urol. 16, 132–137 (2006).
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).
Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nature Rev. Cancer 4, 11–22 (2004).
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).
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).
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).
Yildiz-Sezer, S. et al. Assessment of aberrations on chromosome 8 in prostatic atrophy. BJU Int. 98, 184–188 (2006).
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).
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).
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).
Yang, R. M. et al. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J. Urol. 159, 941–945 (1998).
Denicourt, C. & Dowdy, S. F. Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev. 18, 851–855 (2004).
Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).
Shen, M. M. & Abate-Shen, C. Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Dev. Dyn. 228, 767–778 (2003).
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).
Parsons, J. K. et al. GSTA1 expression in normal, preneoplastic, and neoplastic human prostate tissue. Prostate 49, 30–37 (2001).
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).
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).
Dennis, L. K. & Dawson, D. V. Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology 13, 72–79 (2002).
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).
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.
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).
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
FURTHER INFORMATION
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.
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1038/nrc2090
This article is cited by
-
Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies
Cell Communication and Signaling (2024)
-
Immune cell infiltration-based prognosis in prostate cancer: a review of current knowledge
Bulletin of the National Research Centre (2023)
-
“Stromal cells in prostate cancer pathobiology: friends or foes?”
British Journal of Cancer (2023)
-
Detection of high-risk Human Papillomavirus in prostate cancer from a UK based population
Scientific Reports (2023)
-
Exploring the role of the inflammasomes on prostate cancer: Interplay with obesity
Reviews in Endocrine and Metabolic Disorders (2023)