Understanding the Epidemiology, Natural History, and Key Pathways Involved in Prostate Cancer
2009; Elsevier BV; Volume: 73; Issue: 5 Linguagem: Inglês
10.1016/j.urology.2009.03.001
ISSN1527-9995
Autores Tópico(s)Glutathione Transferases and Polymorphisms
ResumoProstate cancer accounts for about 25% of all the newly diagnosed cancers in American men and was projected to cause >28 000 deaths in 2008. Black men are disproportionately affected; their incidence rate is about 1.6 times greater than the rate for white men. As the population ages, the number of new cases per year is expected to increase by >60% and reach 300 000 by 2015. This high incidence, coupled with the protracted onset of the disease, makes PCa a particularly appropriate candidate for prevention and early intervention strategies. Potential disease precursors, particularly high-grade prostatic intraepithelial neoplasia, might help identify men at high risk of developing PCa. Dihydrotestosterone, a product converted from testosterone by 5α-reductases, plays an important role in normal prostate growth and in the development of PCa. The 5α-reductase levels, particularly type 1, appear to increase during the disease course of prostatic intraepithelial neoplasia and PCa, with greater expression occurring as the disease progresses. Therefore, the inhibition of 5α-reductase could potentially reduce the risk of PCa development, slow or prevent disease progression, and/or treat existing disease. A substantial research effort has recently focused on understanding the pathways involved in the disease's emergence and progression, particularly the 5α-reductase pathway. Prostate cancer accounts for about 25% of all the newly diagnosed cancers in American men and was projected to cause >28 000 deaths in 2008. Black men are disproportionately affected; their incidence rate is about 1.6 times greater than the rate for white men. As the population ages, the number of new cases per year is expected to increase by >60% and reach 300 000 by 2015. This high incidence, coupled with the protracted onset of the disease, makes PCa a particularly appropriate candidate for prevention and early intervention strategies. Potential disease precursors, particularly high-grade prostatic intraepithelial neoplasia, might help identify men at high risk of developing PCa. Dihydrotestosterone, a product converted from testosterone by 5α-reductases, plays an important role in normal prostate growth and in the development of PCa. The 5α-reductase levels, particularly type 1, appear to increase during the disease course of prostatic intraepithelial neoplasia and PCa, with greater expression occurring as the disease progresses. Therefore, the inhibition of 5α-reductase could potentially reduce the risk of PCa development, slow or prevent disease progression, and/or treat existing disease. A substantial research effort has recently focused on understanding the pathways involved in the disease's emergence and progression, particularly the 5α-reductase pathway. Globally, prostate cancer (PCa) is highly prevalent. It is the most common noncutaneous cancer in men.1Jemal A. Siegel R. Ward E. et al.Cancer statistics, 2008.CA Cancer J Clin. 2008; 58: 71-96Crossref PubMed Scopus (10183) Google Scholar, 2Ries L. Melbert D. Drapcho M. et al.SEER cancer statistics review (based on November 2007 SEER data submission, posted to the SEER Web site, 2008).http://seer.cancer.gov/csr/1975_2005/Google Scholar An estimated 782 600 new cases and 254 000 deaths caused by the disease occurred in 2007.3Garcia M. Jemal A. Ward E. et al.Global cancer facts and figures 2007.http://www.cancer.org/downloads/STT/Global_Cancer_Facts_and_Figures_2007_rev.pdfGoogle Scholar The mortality rates for PCa have been decreasing in many developed countries (eg, the United States, the United Kingdom, and Canada), which has been attributed to improved treatment and early detection.3Garcia M. Jemal A. Ward E. et al.Global cancer facts and figures 2007.http://www.cancer.org/downloads/STT/Global_Cancer_Facts_and_Figures_2007_rev.pdfGoogle Scholar, 4Baade P.D. Coory M.D. Aitken J.F. International trends in prostate-cancer mortality: the decrease is continuing and spreading.Cancer Causes Control. 2004; 15: 237-241Crossref PubMed Scopus (76) Google Scholar In contrast, PCa mortality has been increasing in some Asian countries (eg, Japan, Singapore). The list of likely causes includes increased consumption of animal fat, obesity, and physical inactivity.3Garcia M. Jemal A. Ward E. et al.Global cancer facts and figures 2007.http://www.cancer.org/downloads/STT/Global_Cancer_Facts_and_Figures_2007_rev.pdfGoogle Scholar In the United States, in 2008, new cases of PCa were projected to account for approximately 25% (186 320) of all cancers diagnosed in men.1Jemal A. Siegel R. Ward E. et al.Cancer statistics, 2008.CA Cancer J Clin. 2008; 58: 71-96Crossref PubMed Scopus (10183) Google Scholar Despite the advances in early detection, PCa continues to cause substantial mortality in the United States.1Jemal A. Siegel R. Ward E. et al.Cancer statistics, 2008.CA Cancer J Clin. 2008; 58: 71-96Crossref PubMed Scopus (10183) Google Scholar, 2Ries L. Melbert D. Drapcho M. et al.SEER cancer statistics review (based on November 2007 SEER data submission, posted to the SEER Web site, 2008).http://seer.cancer.gov/csr/1975_2005/Google Scholar It ranked second (10%; 28 660) among the 10 leading cancer-related causes of death for men in 2008; cancer of the lung and bronchus were first (31%; 90 810). In the United States, the 5-year survival rate for localized or regional PCa is 100%. However, when it has already metastasized by the time of diagnosis, the 5-year survival rate has been as low as 32%.1Jemal A. Siegel R. Ward E. et al.Cancer statistics, 2008.CA Cancer J Clin. 2008; 58: 71-96Crossref PubMed Scopus (10183) Google Scholar The incidence of PCa generally increases with increasing age.2Ries L. Melbert D. Drapcho M. et al.SEER cancer statistics review (based on November 2007 SEER data submission, posted to the SEER Web site, 2008).http://seer.cancer.gov/csr/1975_2005/Google Scholar, 5Boyle P. Severi G. Giles G.G. The epidemiology of prostate cancer.Urol Clin North Am. 2003; 30: 209-217Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 6Yin M. Bastacky S. Chandran U. et al.Prevalence of incidental prostate cancer in the general population: a study of healthy organ donors.J Urol. 2008; 179: 892-895Abstract Full Text Full Text PDF Scopus (95) Google Scholar According to 1 analysis of U.S. incidence data from 2001 to 2005, approximately 37% of cases of PCa were diagnosed in men 50 years old have histologic evidence of PCa; however, most of these cases remain clinically "silent." Multiple genetic changes appear to be necessary for clinically aggressive PCa to develop.16Carter H.B. Piantadosi S. Isaacs J.T. Clinical evidence for and implications of the multistep development of prostate cancer.J Urol. 1990; 143: 742-746Abstract Full Text PDF PubMed Google Scholar How the disease develops when localized varies. Lower grade tumors (ie, highly or moderately differentiated tumors) tend to have a more protracted course. In contrast, some high-grade tumors progress more rapidly to metastatic disease.17Chodak G.W. Thisted R.A. Gerber G.S. et al.Results of conservative management of clinically localized prostate cancer.N Engl J Med. 1994; 330: 242-248Crossref PubMed Scopus (808) Google Scholar, 18Johansson J.E. Andrén O. Andersson S.O. et al.Natural history of early, localized prostate cancer.JAMA. 2004; 291: 2713-2719Crossref PubMed Scopus (586) Google Scholar A pooled analysis of 828 patients from 6 nonrandomized studies found that highly or moderately differentiated tumors yielded a 10-year disease-specific survival rate of 87%, but poorly differentiated tumors were associated with a 34% survival rate. Similarly, the 5- and 10-year metastasis-free survival rates were greater among men with lower disease grades (ie, grades indicating greater differentiation).17Chodak G.W. Thisted R.A. Gerber G.S. et al.Results of conservative management of clinically localized prostate cancer.N Engl J Med. 1994; 330: 242-248Crossref PubMed Scopus (808) Google Scholar A population-based cohort study examined the natural history of untreated, early-stage PCa during a mean observation period of 21 years. The study included 223 patients (mean age 72 years, range 41-91). Of these patients, 106 cases of PCa were detected by examination of the histologic specimens collected during operations performed because of suspected benign prostatic hyperplasia, and 117 were identified as palpable clinical disease that was localized to the prostate. The disease progressed in 89 patients (40%), and 39 (17% of the cohort) developed metastatic disease. However, the study did not consider PCa cases detected through prostate-specific antigen (PSA) testing, because it had not been available at the time of diagnosis, and PSA screening did not occur during the period when this cohort had been recruited (1977-1984). In most cases, the disease moved slowly during the first 10-15 years after diagnosis.18Johansson J.E. Andrén O. Andersson S.O. et al.Natural history of early, localized prostate cancer.JAMA. 2004; 291: 2713-2719Crossref PubMed Scopus (586) Google Scholar As reported by Chodak et al.,17Chodak G.W. Thisted R.A. Gerber G.S. et al.Results of conservative management of clinically localized prostate cancer.N Engl J Med. 1994; 330: 242-248Crossref PubMed Scopus (808) Google Scholar tumors that were highly differentiated at diagnosis were associated with lower rates of progression and PCa death. However, 15-20 years after diagnosis, substantial decreases occurred in the cumulative progression-free survival (from 45.0% at 15 years to 36.0% at 20 years), metastasis-free survival (from 76.9% to 51.2%), and PCa-specific survival (from 78.7% to 54.5%) rates. An increase in PCa mortality rate was also seen between the first 15 years of follow-up (15 per 1000 person-years) and the subsequent follow-up (44 per 1000 person-years).18Johansson J.E. Andrén O. Andersson S.O. et al.Natural history of early, localized prostate cancer.JAMA. 2004; 291: 2713-2719Crossref PubMed Scopus (586) Google Scholar These findings highlight the importance of time in the development of PCa—time that offers opportunities for interventions (strategies to prevent or reduce risk) that might be able to alter the usual course, the standard natural history, of the disease. Almost all cases of PCa are adenocarcinoma.15Scardino P.T. The Gordon Wilson lecture: natural history and treatment of early stage prostate cancer.Trans Am Clin Climatol Assoc. 2000; 111: 201-241PubMed Google Scholar, 19Miller G.J. Torkko K.C. Natural history of prostate cancer—epidemiologic considerations.Epidemiol Rev. 2001; 23: 14-18Crossref Scopus (21) Google Scholar About 4% of PCa cases exhibit transitional cell morphology and are believed to have developed from the urogenital lining of the prostatic urethra. Few cases of PCa have neuroendocrine morphology. These are thought to derive from either neuroendocrine stem cells normally present in the prostate or processes of aberrant transformation that occur during cell transformation.20Theodorescu D. Prostate cancer, clinical oncology.in: Schwab M. Encyclopedic Reference of Cancer. 1st ed. Springer Verlag, New York2001Google Scholar Figure 2 illustrates the different zones of the prostate.15Scardino P.T. The Gordon Wilson lecture: natural history and treatment of early stage prostate cancer.Trans Am Clin Climatol Assoc. 2000; 111: 201-241PubMed Google Scholar In the young adult, the transition zone typically constitutes about 5%-10% of the mass of the glandular prostate and surrounds the urethra proximal to the entry of the ejaculatory ducts. The central zone accounts for approximately 20%-25% of the mass of the normal glandular prostate and is positioned below the proximal urethral segment.15Scardino P.T. The Gordon Wilson lecture: natural history and treatment of early stage prostate cancer.Trans Am Clin Climatol Assoc. 2000; 111: 201-241PubMed Google Scholar, 21McNeal J.E. The zonal anatomy of the prostate.Prostate. 1981; 2: 35-49Crossref PubMed Scopus (437) Google Scholar The ejaculatory ducts pass through the central zone before entering the urethra.15Scardino P.T. The Gordon Wilson lecture: natural history and treatment of early stage prostate cancer.Trans Am Clin Climatol Assoc. 2000; 111: 201-241PubMed Google Scholar About 70%-75% of the normal glandular structure of the adult prostate consists of the peripheral zone, a double row of duct buds that surround the central zone laterally and occupy the apical region of the prostate. The anterior fibromuscular stroma is nonglandular and constitutes about one third of the mass within the prostatic capsule.15Scardino P.T. The Gordon Wilson lecture: natural history and treatment of early stage prostate cancer.Trans Am Clin Climatol Assoc. 2000; 111: 201-241PubMed Google Scholar, 21McNeal J.E. The zonal anatomy of the prostate.Prostate. 1981; 2: 35-49Crossref PubMed Scopus (437) Google Scholar This anatomic region is intermingled, with fibers descending from the bladder neck, as well as from the striated urethral sphincter.15Scardino P.T. The Gordon Wilson lecture: natural history and treatment of early stage prostate cancer.Trans Am Clin Climatol Assoc. 2000; 111: 201-241PubMed Google Scholar The transitional zone and other periurethral glands are where benign prostatic hyperplasia (BPH) develops.21McNeal J.E. The zonal anatomy of the prostate.Prostate. 1981; 2: 35-49Crossref PubMed Scopus (437) Google Scholar Most PCa cases (about 70%) begin in the peripheral zone.15Scardino P.T. The Gordon Wilson lecture: natural history and treatment of early stage prostate cancer.Trans Am Clin Climatol Assoc. 2000; 111: 201-241PubMed Google Scholar, 20Theodorescu D. Prostate cancer, clinical oncology.in: Schwab M. Encyclopedic Reference of Cancer. 1st ed. Springer Verlag, New York2001Google Scholar, 21McNeal J.E. The zonal anatomy of the prostate.Prostate. 1981; 2: 35-49Crossref PubMed Scopus (437) Google Scholar About 10%-15% of PCa cases develop in the transitional zone and 15%-20% in the central zone.20Theodorescu D. Prostate cancer, clinical oncology.in: Schwab M. Encyclopedic Reference of Cancer. 1st ed. Springer Verlag, New York2001Google Scholar Most cases are multifocal (ie, multiple independent malignant clones are present in the same gland). These multicentric lesions are often present in different zones of the prostate and typically are of different grades.19Miller G.J. Torkko K.C. Natural history of prostate cancer—epidemiologic considerations.Epidemiol Rev. 2001; 23: 14-18Crossref Scopus (21) Google Scholar, 22Byar D.P. Mostofi F.K. Carcinoma of the prostate: prognostic evaluation of certain pathologic features in 208 radical prostatectomies: examined by the step-section technique.Cancer. 1972; 30: 5-13Crossref PubMed Scopus (348) Google Scholar, 23Miller G.J. Cygan J.M. Morphology of prostate cancer: the effects of multifocality on histological grade, tumor volume and capsule penetration.J Urol. 1994; 152: 1709-1713Google Scholar Because multicentric lesions can have different characteristics, one cannot be sure that the characteristics of a carcinoma identified at biopsy represent the status of the gland as a whole until the prostate has been removed and thoroughly examined.19Miller G.J. Torkko K.C. Natural history of prostate cancer—epidemiologic considerations.Epidemiol Rev. 2001; 23: 14-18Crossref Scopus (21) Google Scholar Testosterone is the main circulating androgen in men.24Zhu Y.S. Sun G.H. 5α-Reductase isozymes in the prostate.J Med Sci. 2005; 25: 1-12Google Scholar In the prostate and other organs, testosterone functions as a prohormone; it is converted to dihydrotestosterone (DHT) in the prostatic stromal and basal cells by 5α-reductase (5AR), an intracellular enzyme present in the prostate, skin, and liver.24Zhu Y.S. Sun G.H. 5α-Reductase isozymes in the prostate.J Med Sci. 2005; 25: 1-12Google Scholar, 25Thigpen A.E. Silver R.I. Guileyardo J.M. et al.Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression.J Clin Invest. 1993; 92: 903-910Crossref PubMed Scopus (636) Google Scholar In serum, the ratio of testosterone to DHT is approximately 10:1. This ratio is reversed in the prostate.26Marks L.S. 5α-Reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar DHT is the primary prostatic androgen and plays an essential role in prostate development and growth. DHT has as much as 10 times more affinity for the androgen receptor (AR) than does testosterone.27Wilbert D.M. Griffin J.E. Wilson J.D. Characterization of the cytosol androgen receptor of the human prostate.J Clin Endocrinol Metab. 1983; 56: 113-120Crossref PubMed Scopus (133) Google Scholar DHT exhibits different functions according to the developmental stage of an individual. In utero, DHT plays a critical role in the normal differentiation of the male external genitalia and prostate. Evidence supporting the role of DHT in prostate development derives from observations of the Guevedoce (Dominican pseudohermaphrodites), a population characterized by male internal urogenital tracts but female-appearing external genitalia until age 12 and small prostates as adults.26Marks L.S. 5α-Reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar, 28Imperato-McGinley J. Guerrero L. Gautier T. et al.Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism.Science. 1974; 186: 1213-1215Crossref PubMed Scopus (1029) Google Scholar, 29Imperato-McGinley J. Zhu Y.S. Androgens and male physiology the syndrome of 5α-reductase-2 deficiency.Mol Cell Endocrinol. 2002; 198: 51-59Crossref PubMed Scopus (220) Google Scholar In Guevedoce, 5AR is deficient.26Marks L.S. 5α-Reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar, 30Andersson S. Berman D.M. Jenkins E.P. et al.Deletion of steroid 5 α-reductase 2 gene in male pseudohermaphroditism.Nature. 1991; 354: 159-161Crossref PubMed Scopus (624) Google Scholar The testosterone levels are normal, but the DHT levels are markedly suppressed.28Imperato-McGinley J. Guerrero L. Gautier T. et al.Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism.Science. 1974; 186: 1213-1215Crossref PubMed Scopus (1029) Google Scholar Prostatic diseases such as PCa and BPH have not been reported in these individuals, an important consequence of suppressed DHT levels. Administration of DHT can produce enlargement of the prostate in these individuals, underscoring the role of DHT in prostate development. DHT is also responsible for facial hair, acne, male pattern baldness, and prostate growth.26Marks L.S. 5α-Reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar, 29Imperato-McGinley J. Zhu Y.S. Androgens and male physiology the syndrome of 5α-reductase-2 deficiency.Mol Cell Endocrinol. 2002; 198: 51-59Crossref PubMed Scopus (220) Google Scholar Three isoforms of 5AR have been identified; a separate gene encodes each isoform.31Andersson S. Russell D.W. Structural and biochemical properties of cloned and expressed human and rat steroid 5α-reductases.Proc Natl Acad Sci USA. 1990; 87: 3640-3644Crossref PubMed Scopus (497) Google Scholar, 32Jenkins E.P. Andersson S. Imperato-McGinley J. et al.Genetic and pharmacological evidence for more than one human steroid 5α-reductase.J Clin Invest. 1992; 89: 293-300Crossref PubMed Scopus (374) Google Scholar, 33Uemura M. Tamura K. Chung S. et al.Novel 5α-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer.Cancer Sci. 2008; 99: 81-86PubMed Google Scholar The type 1 isoform is prevalent in extraprostatic tissue (ie, nongenital skin, liver, and certain brain regions) and is present throughout life. Although conflicting results have been reported,25Thigpen A.E. Silver R.I. Guileyardo J.M. et al.Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression.J Clin Invest. 1993; 92: 903-910Crossref PubMed Scopus (636) Google Scholar several studies have suggested that type 1 5AR is also expressed in the prostate and preputial skin. This isoform appears to be most strongly expressed in the prostatic epithelium and predominantly localized in nuclei of luminal secretory cells.34Bonkhoff H. Stein U. Aumuller G. et al.Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas.Prostate. 1996; 29: 261-267Crossref PubMed Scopus (107) Google Scholar, 35Iehle C. Radvanyi F. Diezde G. et al.Differences in steroid 5alpha-reductase iso-enzymes expression between normal and pathological human prostate tissue.J Steroid Biochem Mol Biol. 1999; 68: 189-195Crossref PubMed Scopus (113) Google Scholar, 36Pelletier G. Luu-The V. Huang X.F. et al.Localization by in situ hybridization of steroid 5alpha-reductase isozyme gene expression in the human prostate and preputial skin.J Urol. 1998; 160: 577-582Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Its expression increases in PCa (relative to BPH tissue).35Iehle C. Radvanyi F. Diezde G. et al.Differences in steroid 5alpha-reductase iso-enzymes expression between normal and pathological human prostate tissue.J Steroid Biochem Mol Biol. 1999; 68: 189-195Crossref PubMed Scopus (113) Google Scholar Its expression is low in BPH tissue but increases steadily in prostatic intraepithelial neoplasia and in primary, recurrent, and metastatic PCa.37Tindall D.J. Rittmaster R.S. The rationale for inhibiting 5α-reductase isoenzymes in the prevention and treatment of prostate cancer.J Urol. 2008; 179: 1235-1242Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Type 2 5AR is prevalent in the prostate and is also present in the seminal vesicles and epididymis, as well as in the fetal genital skin. In the skin and scalp, a single wave of expression of type 2 5AR begins at or just before birth and ends at around 2-3 years of age.25Thigpen A.E. Silver R.I. Guileyardo J.M. et al.Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression.J Clin Invest. 1993; 92: 903-910Crossref PubMed Scopus (636) Google Scholar The type 2 isoform is deficient in the Guevedoce owing to a deletion in the gene.26Marks L.S. 5α-Reductase: history and clinical importance.Rev Urol. 2004; 6: S11-S21Google Scholar, 30Andersson S. Berman D.M. Jenkins E.P. et al.Deletion of steroid 5 α-reductase 2 gene in male pseudohermaphroditism.Nature. 1991; 354: 159-161Crossref PubMed Scopus (624) Google Scholar Recently, a novel 5AR (type 3) has been reported specifically in hormone-refractory PCa cells with little or no expression in normal adult organs; it appears to play a role in hormone-refractory PCa growth and progression.33Uemura M. Tamura K. Chung S. et al.Novel 5α-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer.Cancer Sci. 2008; 99: 81-86PubMed Google Scholar Its potential role as a therapeutic target in PCa remains to be elucidated. The activity of 5AR is different in various ethnic groups and greater among groups with greater rates of PCa.38Ross R.K. Bernstein L. Lobo R.A. et al.5-Alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males.Lancet. 1992; 339: 887-889Abstract PubMed Scopus (403) Google Scholar Studies indirectly estimating 5AR activity by measuring levels of 5α-reduced androgen metabolites have provided evidence of elevated 5AR activity among white men compared with Chinese-American men39Lookingbill D.P. Demers L.M. 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