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Mukherjee AG, V G A. Sex hormone-binding globulin and its critical role in prostate cancer: A comprehensive review. J Steroid Biochem Mol Biol 2025; 245:106606. [PMID: 39181189 DOI: 10.1016/j.jsbmb.2024.106606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/13/2024] [Accepted: 08/19/2024] [Indexed: 08/27/2024]
Abstract
Prostate cancer (PC) is a common and widespread cancer that affects men globally. A complicated interaction of hormonal variables influences its development. Sex hormone-binding globulin (SHBG) is a crucial element in controlling the availability of sex hormones, especially androgens, which have a notable impact on the development and progression of PC. SHBG controls the levels of free, active androgens in the body, which helps regulate androgen-dependent processes associated with PC. The equilibrium between SHBG and androgens plays a critical role in maintaining the stability of the prostate. When this balance is disrupted, it is associated with the development and advancement of PC. The processes responsible for SHBG's role in PC are complex and have multiple aspects. SHBG primarily binds to androgens, preventing them from interacting with androgen receptors (ARs) in prostate cells. It reduces the activation of androgen signaling pathways essential for tumor development and survival. In addition, SHBG can directly affect prostate cells by interacting with specific receptors on the cell surface. This review thoroughly examines the role of SHBG in PC, including its physiological activities, methods of action, and clinical consequences.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India
| | - Abilash V G
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India.
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Santos PB, Patel H, Henrique R, Félix A. Can epigenetic and inflammatory biomarkers identify clinically aggressive prostate cancer? World J Clin Oncol 2020; 11:43-52. [PMID: 32133274 PMCID: PMC7046922 DOI: 10.5306/wjco.v11.i2.43] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023] Open
Abstract
Prostate cancer (PCa) is a highly prevalent malignancy and constitutes a major cause of cancer-related morbidity and mortality. It emerges through the acquisition of genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications and microRNA deregulation. These generate heritable transformations in the expression of genes but do not change the DNA sequence. Alterations in DNA methylation (hypo and hypermethylation) are the most characterized in PCa. They lead to genomic instability and inadequate gene expression. Major and minor-specific modifications in chromatin recasting are involved in PCa, with signs suggesting a dysfunction of enzymes modified by histones. MicroRNA deregulation also contributes to the initiation of PCa, including involvement in androgen receptor signalization and apoptosis. The influence of inflammation on prostate tumor carcinogenesis is currently much better known. Recent discoveries about microbial species resident in the urinary tract suggest that these are the initiators of chronic inflammation, promoting prostate inflammatory atrophy and eventually leading to PCa. Complete characterization of the relationship between the urinary microbiome and prostatic chronic inflammation will be crucial to develop plans for the prevention of PCa. The prevalent nature of epigenetic and inflammatory alterations may provide potential biomarkers for PCa diagnosis, treatment decisions, evaluation of prognosis and posttreatment surveillance.
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Affiliation(s)
- Pedro Bargão Santos
- Department of Urology, Prof. Doutor Fernando Fonseca Hospital, Amadora 2720-276, Portugal
| | - Hitendra Patel
- Department of Urology, University Hospital North Norway, Tromsø 9019, Norway
- Department of Urology, St George’s University Hospitals, Tooting, London SW17 0QT, United Kingdom
| | - Rui Henrique
- Departments of Pathology and Cancer Biology and Epigenetics Group-Research Center, Portuguese Oncology Institute of Porto, Porto 4200-072, Portugal
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto 4099-002, Portugal
| | - Ana Félix
- Department of Pathology, Portuguese Oncology Institute of Lisbon, Lisbon 1099-023, Portugal
- Department of Pathology, NOVA Medical School, Lisbon 1169-056, Portugal
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3
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Fawzy MS, Elfayoumi AR, Mohamed RH, Fatah IRA, Saadawy SF. Cyclooxygenase 2 (rs2745557) Polymorphism and the Susceptibility to Benign Prostate Hyperplasia and Prostate Cancer in Egyptians. Biochem Genet 2016; 54:326-336. [PMID: 26920155 DOI: 10.1007/s10528-016-9722-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Accepted: 02/14/2016] [Indexed: 10/22/2022]
Abstract
Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, has been reported to be correlated with tumorigenesis, tumor progression, and metastasis. We aimed to evaluate the association between COX-2 (rs2745557) polymorphism and prostate cancer (PCa), benign prostate hyperplasia (BPH) risk. We also assessed the influence of other risk factors such as obesity, smoking, diabetes in modulating the risk of PCa in Egyptian men. COX-2 (rs2745557) was genotyped in 112 PC patients, 111 BPH and 120 subjects as a control group. COX-2 and PSA levels were measured by ELISA. We found that GG genotype was associated with a 17-fold increased risk for PCa and 20-fold increased the risk for BPH more than AA genotype. Also, G allele carriers of COX-2 were associated with metastatic cancer (OR = 1.3, P < 0.05) and disease aggressiveness (OR = 3.5, P < 0.001). The coexistence of obesity, smoking, or diabetes with GG genotype may lead to increasing the risk of developing BPH (OR = 3.3, 4, and 2.7, respectively) and of developing PCa (OR = 2.9, 4.9, and 3.2, respectively). Our results showed evidence suggesting the involvement of the COX-2 (rs2745557) polymorphism and its protein in PCa or BPH initiation and progression. Also, the coexistence of COX-2 (rs2745557) and obesity, smoking, or diabetes may lead to the development of PCa or BPH.
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Affiliation(s)
- Mohamed S Fawzy
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Randa H Mohamed
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Ihab R Abdel Fatah
- Urology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sara F Saadawy
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Esfahani M, Ataei N, Panjehpour M. Biomarkers for evaluation of prostate cancer prognosis. Asian Pac J Cancer Prev 2016; 16:2601-11. [PMID: 25854335 DOI: 10.7314/apjcp.2015.16.7.2601] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Prostate cancer, with a lifetime prevalence of one in six men, is the second cause of malignancy-related death and the most prevalent cancer in men in many countries. Nowadays, prostate cancer diagnosis is often based on the use of biomarkers, especially prostate-specific antigen (PSA) which can result in enhanced detection at earlier stage and decreasing in the number of metastatic patients. However, because of the low specificity of PSA, unnecessary biopsies and mistaken diagnoses frequently occur. Prostate cancer has various features so prognosis following diagnosis is greatly variable. There is a requirement for new prognostic biomarkers, particularly to differentiate between inactive and aggressive forms of disease, to improve clinical management of prostate cancer. Research continues into finding additional markers that may allow this goal to be attained. We here selected a group of candidate biomarkers including PSA, PSA velocity, percentage free PSA, TGFβ1, AMACR, chromogranin A, IL-6, IGFBPs, PSCA, biomarkers related to cell cycle regulation, apoptosis, PTEN, androgen receptor, cellular adhesion and angiogenesis, and also prognostic biomarkers with Genomic tests for discussion. This provides an outline of biomarkers that are presently of prognostic interest in prostate cancer investigation.
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Affiliation(s)
- Maryam Esfahani
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran E-mail :
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5
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Gnanapragasam VJ. Molecular markers to guide primary radical treatment selection in localized prostate cancer. Expert Rev Mol Diagn 2014; 14:871-81. [DOI: 10.1586/14737159.2014.936851] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Lewinshtein DJ, Porter CR, Nelson PS. Genomic predictors of prostate cancer therapy outcomes. Expert Rev Mol Diagn 2014; 10:619-36. [DOI: 10.1586/erm.10.53] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Lazarini M, Traina F, Machado-Neto JA, Barcellos KSA, Moreira YB, Brandão MM, Verjovski-Almeida S, Ridley AJ, Saad STO. ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1832:365-74. [PMID: 23200924 DOI: 10.1016/j.bbadis.2012.11.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Revised: 10/15/2012] [Accepted: 11/16/2012] [Indexed: 01/30/2023]
Abstract
BACKGROUND Several Rho GTPase-activating proteins (RhoGAPs) are implicated in tumor progression through their effects on Rho GTPase activity. ARHGAP21 is a RhoGAP with increased expression in head and neck squamous cell carcinoma and with a possible role in glioblastoma tumor progression, yet little is known about the function of ARHGAP21 in cancer cells. Here we studied the role of ARHGAP21 in two prostate adenocarcinoma cell lines, LNCaP and PC3, which respectively represent initial and advanced stages of prostate carcinogenesis. RESULTS ARHGAP21 is located in the nucleus and cytoplasm of both cell lines and its depletion resulted in decreased proliferation and increased migration of PC3 cells but not LNCaP cells. In PC3 cells, ARHGAP21 presented GAP activity for RhoA and RhoC and induced changes in cell morphology. Moreover, its silencing altered the expression of genes involved in cell proliferation and cytoskeleton organization, as well as the endothelin-1 canonical pathway. CONCLUSIONS Our results reveal new functions and signaling pathways regulated by ARHGAP21, and indicate that it could contribute to prostate cancer progression.
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Affiliation(s)
- Mariana Lazarini
- Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, INCTS, Campinas, São Paulo, Brazil.
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Ohno Y, Nakashima J, Izumi M, Ohori M, Hashimoto T, Tachibana M. Association of legumain expression pattern with prostate cancer invasiveness and aggressiveness. World J Urol 2012; 31:359-64. [PMID: 23124822 DOI: 10.1007/s00345-012-0977-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Accepted: 10/16/2012] [Indexed: 01/26/2023] Open
Abstract
OBJECTIVES To investigate the clinical implication of legumain, an asparaginyl endopeptidase that is highly expressed in several types of cancer, expression in prostate cancer. METHODS Legumain expression in prostate cancer cell lines was determined by real-time reverse transcriptase PCR and Western blot. Furthermore, legumain expression in 88 prostatectomy specimens was evaluated by immunohistochemistry. The association between legumain expression and clinicopathological factors was analyzed. RESULTS Legumain expression was confirmed at the mRNA and protein levels in all the cells. Although all the cancer tissues were positive for legumain, 2 staining patterns were observed in the cytoplasm: diffuse cytoplasmic and vesicular positivity. The rates of Gleason score ≥8, extracapsular extension, and perineural invasion in the group with vesicular staining were significantly higher than those in the diffuse cytoplasmic group (p < 0.05). The maximum size of the tumor with vesicular staining was significantly greater than that of the tumor with diffuse cytoplasmic staining (p = 0.0302). The 5-year biochemical recurrence-free rate in the patients with vesicular legumain staining was 53.2%; this rate was significantly lower than that (78.8%) in the patients with diffuse cytoplasmic staining (p = 0.0269). CONCLUSIONS Tumors that showed a vesicular staining pattern of legumain had the potential of being highly invasive and aggressive in patients with prostate cancer who were treated with radical prostatectomy. This suggests that legumain might contribute to the invasiveness and aggressiveness of prostate cancer.
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Affiliation(s)
- Yoshio Ohno
- Department of Urology, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
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Foahom Kamwa AD, Vian E, Agoua G, Sénéchal C, Bentaleb Y, Fofana M, Manip-M'ebobisse N, Blanchet P. [Radiotherapy with androgen deprivation in high-risk prostate cancer: what outcomes on a Caribbean population?]. Prog Urol 2012; 22:954-62. [PMID: 23102018 DOI: 10.1016/j.purol.2012.07.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Revised: 03/26/2012] [Accepted: 07/11/2012] [Indexed: 10/28/2022]
Abstract
OBJECTIVE To analyze in a Caribbean population at 90% of African descent, the results of radiotherapy with androgen deprivation (AD) in high-risk prostate cancer (PCa). PATIENTS AND METHODS Fifty-nine consecutive patients with a high-risk PCa as defined by the D'AMICO classification and treated by radiotherapy with AD between January 2003 and April 2009 in our center were analyzed. The median dose of radiation and the median duration of AD were 70Gy and 37months respectively. Biochemical recurrence (BF), as primary outcome was defined according to the PHOENIX criteria (nadir PSA+2ng/mL). Multivariate analysis was performed to identify predictive factors of BF. The median follow-up was 47months. RESULTS Eight (13.6%) patients had BF and four (6.8%) developed metastases. Six (10.2%) died during the follow-up. The 5years acturial biochemical disease-free survival was 79.7%. Multivariate analyses have shown that Gleason sum (GS) superior to 7 (P=0.029), AD duration less than 24months (P=0.004) and the rate of Nadir PSA greater or equal to 0.5ng/mL (P=0.011) were independent predictive factors of BF. CONCLUSION This study was the first to our knowledge, to provide that radiotherapy associate with AD for HRPC among Caribbean men is effective as observed in other populations. Patients with GS superior to 7 could be considered for more aggressive treatments in clinical trials.
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Affiliation(s)
- A D Foahom Kamwa
- Service d'urologie andrologie, CHU Caremeau, Nîmes cedex, France.
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Miyake H, Fujisawa M. Prognostic prediction following radical prostatectomy for prostate cancer using conventional as well as molecular biological approaches. Int J Urol 2012; 20:301-11. [DOI: 10.1111/j.1442-2042.2012.03175.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 08/29/2012] [Indexed: 11/29/2022]
Affiliation(s)
- Hideaki Miyake
- Division of Urology; Kobe University Graduate School of Medicine; Kobe; Japan
| | - Masato Fujisawa
- Division of Urology; Kobe University Graduate School of Medicine; Kobe; Japan
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Predictive value of Sp1/Sp3/FLIP signature for prostate cancer recurrence. PLoS One 2012; 7:e44917. [PMID: 23028678 PMCID: PMC3441693 DOI: 10.1371/journal.pone.0044917] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 08/09/2012] [Indexed: 01/20/2023] Open
Abstract
Prediction of prostate cancer prognosis is challenging and predictive biomarkers of recurrence remain elusive. Although prostate specific antigen (PSA) has high sensitivity (90%) at a PSA level of 4.0 ng/mL, its low specificity leads to many false positive results and considerable overtreatment of patients and its performance at lower ranges is poor. Given the histopathological and molecular heterogeneity of prostate cancer, we propose that a panel of markers will be a better tool than a single marker. We tested a panel of markers composed of the anti-apoptotic protein FLIP and its transcriptional regulators Sp1 and Sp3 using prostate tissues from 64 patients with recurrent and non-recurrent cancer who underwent radical prostatectomy as primary treatment for prostate cancer and were followed with PSA measurements for at least 5 years. Immunohistochemical staining for Sp1, Sp3, and FLIP was performed on these tissues and scored based on the proportion and intensity of staining. The predictive value of the FLIP/Sp1/Sp3 signature for clinical outcome (recurrence vs. non-recurrence) was explored with logistic regression, and combinations of FLIP/Sp1/Sp3 and Gleason score were analyzed with a stepwise (backward and forward) logistic model. The discrimination of the markers was identified by sensitivity-specificity analysis and the diagnostic value of FLIP/Sp1/Sp3 was determined using area under the curve (AUC) for receiver operator characteristic curves. The AUCs for FLIP, Sp1, Sp3, and Gleason score for predicting PSA failure and non-failure were 0.71, 0.66, 0.68, and 0.76, respectively. However, this increased to 0.93 when combined. Thus, the “biomarker signature” of FLIP/Sp1/Sp3 combined with Gleason score predicted disease recurrence and stratified patients who are likely to benefit from more aggressive treatment.
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Fromont G, Rozet F, Cathelineau X, Ouzzane A, Doucet L, Fournier G, Cussenot O. BCAR1 expression improves prediction of biochemical reccurence after radical prostatectomy. Prostate 2012; 72:1359-65. [PMID: 22241677 DOI: 10.1002/pros.22485] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 12/13/2011] [Indexed: 11/07/2022]
Abstract
BACKGROUND Because prostate cancer exhibits a great variability in clinical outcome, biomarkers that can be used in daily practice are needed to better stratify patients into prognostic groups. Since steroid hormones play a central role in the development and progression of prostate cancer, we aimed to analyze in a matched nested case-control study the value of molecules involved in steroid signaling, to predict recurrence after radical prostatectomy, independently from standard prognostic tools. METHODS Among 1,200 patients treated by radical prostatectomy with negative margins with at least 4 years follow-up, 121 prostate cancers with biochemical relapse were matched after pathological reassessment with 121 cancers with identical clinicopathological features but without relapse. Immunohistochemistry was performed on tissue microarrays, using antibodies directed against molecules involved in androgen and estrogen signaling, including hormone receptors, enzymes (such as the five alpha reductases 1,2 and 3, aromatase, alpha-keto reductase 1C3 and squalene epoxidase), the breast cancer antiestrogen resistance 1 (BCAR1), and the proliferation marker Ki67. RESULTS The median follow-up for patients without recurrence was 7 years. Both cell proliferation and BCAR1 expression were significantly associated with biochemical relapse, in univariate and multivariate analysis. In subgroup analysis, the sole predictive marker in patients with well-differentiated prostate cancer was BCAR1 (P = 0.004), whereas only proliferation (P = 0.001) was significantly associated with relapse in less-differentiated prostate cancer patients. CONCLUSIONS BCAR1 is an independent predictor of recurrence after radical prostatectomy for "low risk" prostate cancer. The use of this biomarker may enable more individualized treatment approaches.
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Affiliation(s)
- Gaelle Fromont
- Department of Pathology, CHU/Universite de Poitiers, 86000 Poitiers, France.
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Ribeiro da Silva MN, Tobias-Machado M, Lima-Pompeo AC, Reis LO, da Silva Pinhal MA. [Prostate cancer: promising biomarkers related to aggressive disease]. Actas Urol Esp 2012; 36:484-490. [PMID: 22520043 DOI: 10.1016/j.acuro.2011.11.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Revised: 11/21/2011] [Accepted: 11/24/2011] [Indexed: 12/25/2022]
Abstract
BACKGROUND Although a rapidly growing number of candidate biological markers of prognosis and/or response to specific treatments in prostate cancer, none have to date showed ability to completely prognosticate prostate cancer on evidence based urology. OBJECTIVE To review the pertinent literature on the issue. ACQUISITION OF EVIDENCE A comprehensive review of the current literature was done focusing on promising biomarkers related to aggressive prostate cancer. SUMMARY OF EVIDENCE Combined with the heterogeneous nature of the disease, mixed case series are the most common study design, impeding robust results and the development of an effective therapeutic strategy. Improvement in prostate cancer patient survival requires not only the identification of new therapeutic target based on detailed understanding of the biological mechanisms involved in metastatic dissemination and tumor growth but strong clinical studies as well. CONCLUSION Better study design involving potential markers and including well-classified and staged patients with robust methodology and adequate outcomes (mainly survival) are necessary to the field evolution.
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Hayes GM, Simko J, Holochwost D, Kuchinsky K, Busch R, Misell L, Murphy EJ, Carroll P, Chan J, Shinohara K, Hellerstein MK. Regional cell proliferation in microdissected human prostate specimens after heavy water labeling in vivo: correlation with prostate epithelial cells isolated from seminal fluid. Clin Cancer Res 2012; 18:3250-60. [PMID: 22553345 DOI: 10.1158/1078-0432.ccr-11-2988] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Prostate cancer is detected with increasing frequency but has a highly variable natural history and prognosis and active surveillance of men with low-risk prostate cancer would benefit greatly from minimally invasive methods to identify progression. We describe here two novel in vivo metrics of cell proliferation in men with prostate neoplasia. EXPERIMENTAL DESIGN Three groups of men drank heavy water, a nonradioactive, stable isotopic tracer for 14 to 28 days: (i) healthy men, (ii) men scheduled for transrectal core needle biopsy, and (iii) men scheduled for radical prostatectomy. Prostate epithelial cells (PEC) were isolated from ejaculated seminal fluid in all subjects. Histologically graded lesions were microdissected from tissue slides obtained from subjects undergoing surgery and proliferation rates were measured from isolated cells via mass spectrometry. RESULTS Proliferation rates of seminal PEC in healthy men (0.10%-0.27%/d) were stable on repeat sampling. Rates above 0.34%/d were seen only in patients with cancer where rates increased progressively from normal tissue through benign prostate hyperplasia, prostate intraepithelial neoplasia, and tumor grades III and IV in all subjects. Seminal PEC kinetics correlated highly with the most proliferative microdissected region in each subject (r(2) = 0.94). CONCLUSIONS Prostate cell proliferation can be measured in vivo from microdissected histopathology sections or noninvasively from seminal fluid where the latter reflects the most proliferative region of the gland. This approach may allow monitoring of progression in men with low-risk prostate cancer.
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The effects of short-term genistein intervention on prostate biomarker expression in patients with localised prostate cancer before radical prostatectomy. Br J Nutr 2012; 108:2138-47. [PMID: 22397815 DOI: 10.1017/s0007114512000384] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Nutritionally relevant levels of genistein, the predominant isoflavone in soyabean associated with lower risk of prostate cancer (PCa), may modulate the expression of prostate tissue biomarkers associated with cancer prediction and progression. A phase 2 placebo-controlled, randomised, double-blind clinical trial was conducted in forty-seven Norwegian patients before prostatectomy. Intervention was 30 mg genistein or placebo capsules daily for 3-6 weeks. Luminal cells from malignant and benign glands were isolated with laser capture microdissection and the mRNA levels of androgen-related biomarkers (androgen receptor, NK3 homeobox 1, kallikrein-related peptide 4 (KLK4)) and cell cycle-related genes (p21 Waf1/Cip1 , p27 Kip1 , p53) were analysed with real-time semiquantitative PCR. Immunohistochemistry of androgen-, cell cycle-, proliferative- (Ki67 nuclear antigen), apoptotic- (B-cell CLL/lymphoma 2 (BCL-2) and BCL-2-associated X protein) and neuroendocrine differentiation-related biomarkers (neuron-specific enolase and cytoplasmic chromogranin A) was performed using tissue microarrays containing normal, Gleason grade 3 and grade 4 prostate tissues. There were no significant effects by genistein intervention on proliferation-, cell cycle-, apoptosis- or neuroendocrine biomarkers. Genistein intervention, however, significantly reduced the mRNA level of KLK4 in tumour cells (P = 0·033) and there was a non-significant reduction in androgen and cell cycle-related biomarkers, except for p27Kip1, whose expression in the nuclear compartment was increased. Genistein intervention modulated the expression of several biomarkers which may be related to PCa prediction and progression. The present study supports genistein as a chemopreventive agent in PCa. Further investigation is warranted in larger and longer-duration studies.
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Cancer/testis antigens: novel tools for discerning aggressive and non-aggressive prostate cancer. Asian J Androl 2012; 14:400-4. [PMID: 22343492 DOI: 10.1038/aja.2011.144] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The introduction of serum prostate-specific antigen (PSA) in the 1980s has dramatically altered and benefited the initial diagnosis of prostate cancer. However, the widespread use of PSA testing has resulted in overdetection and overtreatment of potentially indolent disease. Thus, a clinical dilemma today in the management of prostate cancer is to discern men with aggressive disease who need definitive treatment from men whose disease are not lethal. Although several serum and tissue biomarkers have been evaluated during the past decade, improved markers are still needed to enhance the accuracy, with which patients at risk can be discerned and treated more aggressively. The cancer/testis antigens (CTAs) are a group of proteins that are restricted to the testis in the normal adult, but are aberrantly expressed in several types of cancers. Because of their restricted expression pattern, the CTAs represent attractive biomarker candidates for cancer diagnosis/prognosis. Furthermore, several studies to date have reported the differential expression of CTAs in prostate cancer. Here, we review recent developments that demonstrate the potential of the CTAs as biomarkers to discern the aggressive phenotype of prostate cancer.
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Canacci AM, Izumi K, Zheng Y, Gordetsky J, Yao JL, Miyamoto H. Expression of semenogelins I and II and its prognostic significance in human prostate cancer. Prostate 2011; 71:1108-14. [PMID: 21557275 DOI: 10.1002/pros.21323] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 11/23/2010] [Indexed: 01/22/2023]
Abstract
BACKGROUND Little is known about the role of semenogelins, seminal plasma proteins that play critical roles in semen clotting and subsequent liquefaction in the presence of zinc and prostate-specific antigen, in human malignancies. METHODS We investigated the expression of semenogelins in four human prostate cancer lines by RT-PCR and Western blotting as well as in 70 radical prostatectomy specimens by immunohistochemistry. Effects of semenogelin overexpression on prostate cancer cell proliferation were also assessed. RESULTS mRNA/protein signals for semenogelins I (SgI) and II (SgII) were detected only in androgen-sensitive LNCaP cells cultured with zinc. Transfection of SgI/SgII increased/decreased cell growth of androgen receptor (AR)-positive/semenogelin-negative CWR22Rv1 in the presence of zinc, whereas it showed marginal effects in AR-negative/semenogelin-negative PC-3 and DU145. Immunohistochemical studies showed that SgI and SgII stain positively in 55 (79%) and 31 (44%) cancer tissues, respectively, which was significantly higher than in corresponding benign tissues [SgI-positive in 13 (19%) cases (P < 0.0001) and SgII-positive in 15 (21%) cases (P = 0.0066)]. Among the histopathological parameters available for our patient cohort, there was an inverse association only between Gleason score (GS) and SgII expression (GS ≤ 7 vs. GS ≥ 8: P = 0.0150; GS7 vs. GS ≥ 8: P = 0.0111). Kaplan-Meier and log-rank tests further revealed that patients with SgI-positive/SgII-negative tumor have the highest risk for biochemical recurrence (P = 0.0242). CONCLUSIONS These results suggest the involvement of semenogelins in prostate cancer and their prognostic values in predicting cancer progression after radical prostatectomy. Additional functional analyses of semenogelins are necessary to determine their biological significance in prostate cancer.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Blotting, Western
- Cell Line, Tumor
- Cell Proliferation
- Humans
- Immunohistochemistry
- Kaplan-Meier Estimate
- Male
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/pathology
- Prostate/metabolism
- Prostate/pathology
- Prostatic Neoplasms/genetics
- Prostatic Neoplasms/metabolism
- Prostatic Neoplasms/pathology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Seminal Vesicle Secretory Proteins/genetics
- Seminal Vesicle Secretory Proteins/metabolism
- Statistics, Nonparametric
- Zinc/metabolism
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Affiliation(s)
- Anastasia M Canacci
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA
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19
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Prognostic relevance of cyclooxygenase-2 (COX-2) expression in Chinese patients with prostate cancer. Acta Histochem 2011; 113:131-6. [PMID: 19836060 DOI: 10.1016/j.acthis.2009.09.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2009] [Revised: 09/13/2009] [Accepted: 09/14/2009] [Indexed: 12/25/2022]
Abstract
Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, has been reported to be correlated with tumorigenesis, tumor progression and metastasis. The present study was designed to investigate the clinicopathological and prognostic significance of COX-2 in Chinese patients with prostate cancer. Firstly, RT-PCR and Western blot assays were performed to detect the expression of COX-2 mRNA and protein in prostate cancer cell lines and 20 tissue samples (tumor or corresponding non-tumor). Next, immunohistochemistry was performed to detect the expression of COX-2 protein in 88 prostate cancer tissue samples. Finally, the correlation between COX-2 expression and clinicopathological factors and patient survival was evaluated. We found that the expression levels of COX-2 mRNA and protein showed significant difference among four prostate cancer cell lines. Moreover, the levels of COX-2 mRNA and protein were significantly higher in prostate cancer tissues than in corresponding non-tumor tissues. COX-2 staining was positive in the cytoplasm of prostate cancer cells. High-COX-2 expression was correlated with the Gleason score (P=0.009), tumor stage (P=0.012), and lymph-node status (P=0.036). Furthermore, patients with high-COX-2 expression showed lower disease-free (P=0.014) and overall survival (P=0.047) rates than those with low-COX-2 expression. Univariate and multivariate analyses suggested that the status of COX-2 protein expression was an independent prognostic indicator for patients' survival. Taken together, higher COX-2 protein expression might provide an independent prognostic marker for Chinese patients with prostate cancer who have undergone surgery.
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20
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Thysell E, Surowiec I, Hörnberg E, Crnalic S, Widmark A, Johansson AI, Stattin P, Bergh A, Moritz T, Antti H, Wikström P. Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol. PLoS One 2010; 5:e14175. [PMID: 21151972 PMCID: PMC2997052 DOI: 10.1371/journal.pone.0014175] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 11/04/2010] [Indexed: 11/30/2022] Open
Abstract
Background Metastasis to the bone is one clinically important features of prostate cancer (PCa). Current diagnostic methods cannot predict metastatic PCa at a curable stage of the disease. Identification of metabolic pathways involved in the growth of bone metastases therefore has the potential to improve PCa prognostication as well as therapy. Methodology/Principal Findings Metabolomics was applied for the study of PCa bone metastases (n = 20) in comparison with corresponding normal bone (n = 14), and furthermore of malignant (n = 13) and benign (n = 17) prostate tissue and corresponding plasma samples obtained from patients with (n = 15) and without (n = 13) diagnosed metastases and from men with benign prostate disease (n = 30). This was done using gas chromatography-mass spectrometry for sample characterization, and chemometric bioinformatics for data analysis. Results were verified in a separate test set including metastatic and normal bone tissue from patients with other cancers (n = 7). Significant differences were found between PCa bone metastases, bone metastases of other cancers, and normal bone. Furthermore, we identified metabolites in primary tumor tissue and in plasma which were significantly associated with metastatic disease. Among the metabolites in PCa bone metastases especially cholesterol was noted. In a test set the mean cholesterol level in PCa bone metastases was 127.30 mg/g as compared to 81.06 and 35.85 mg/g in bone metastases of different origin and normal bone, respectively (P = 0.0002 and 0.001). Immunohistochemical staining of PCa bone metastases showed intense staining of the low density lipoprotein receptor and variable levels of the scavenger receptor class B type 1 and 3-hydroxy-3-methylglutaryl-coenzyme reductase in tumor epithelial cells, indicating possibilities for influx and de novo synthesis of cholesterol. Conclusions/Significance We have identified metabolites associated with PCa metastasis and specifically identified high levels of cholesterol in PCa bone metastases. Based on our findings and the previous literature, this makes cholesterol a possible therapeutic target for advanced PCa.
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Affiliation(s)
- Elin Thysell
- Department of Chemistry, Umeå University, Umeå, Sweden
| | | | - Emma Hörnberg
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Sead Crnalic
- Department of Pathology, Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Anders Widmark
- Department of Urology and Andrology and Orthopedics, and Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Annika I. Johansson
- Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Pär Stattin
- Department of Pathology, Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Anders Bergh
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Thomas Moritz
- Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Henrik Antti
- Department of Chemistry, Umeå University, Umeå, Sweden
- * E-mail: ;
| | - Pernilla Wikström
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
- * E-mail: ;
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21
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Rabien A, Fritzsche FR, Jung M, Tölle A, Diamandis EP, Miller K, Jung K, Kristiansen G, Stephan C. KLK15 is a prognostic marker for progression-free survival in patients with radical prostatectomy. Int J Cancer 2010; 127:2386-94. [PMID: 20473923 DOI: 10.1002/ijc.25435] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
In search of biomarkers for prostate cancer, we evaluated the expression of the human kallikrein-related peptidase KLK15 in samples of prostatic adenocarcinomas from radical prostatectomies. Twenty-five pairs of cancerous and adjacent normal prostatic tissue were selected by laser capture microdissection. The tissue was used for quantification of KLK15 mRNA by reverse-transcriptase polymerase chain reaction. Immunohistochemical expression of the KLK15 protein in 193 samples of prostatic adenocarcinoma was analysed in relation to clinicopathological parameters of the patients and disease progression. Expression of KLK15 correlated with the pathological tumour stage and Gleason score of the cases, both at mRNA and at protein level. While mRNA expression in the tumour was elevated, the protein level of KLK15 was reduced compared with adjacent normal tissue and to prostatic intraepithelial neoplasia. Univariate Kaplan-Meier analysis showed a significant association of dichotomised KLK15 levels with disease progression defined by prostate-specific antigen relapse (p = 0.001). Multivariate analysis according to the Cox proportional hazards regression model identified dichotomised KLK15 expression, corrected for the patient parameters age, preoperative prostate-specific antigen level, pathological tumour stage, Gleason score and surgical margin status, as an independent prognostic factor for poor outcome (inclusion model, hazard ratio 1.802, 95% confidence interval 1.037-3.132, p = 0.037). We suggest KLK15 as a new independent tumour marker for patients at risk for disease progression after radical prostatectomy.
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Affiliation(s)
- Anja Rabien
- Department of Urology, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
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22
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Long-term results after high-dose radiotherapy and adjuvant hormones in prostate cancer: how curable is high-risk disease? Int J Radiat Oncol Biol Phys 2010; 81:1279-85. [PMID: 20932659 DOI: 10.1016/j.ijrobp.2010.07.1975] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2010] [Revised: 07/01/2010] [Accepted: 07/19/2010] [Indexed: 11/21/2022]
Abstract
PURPOSE To analyze long-term outcome and prognostic factors for high-risk prostate cancer defined by National Comprehensive Cancer Network criteria treated with high-dose radiotherapy and androgen deprivation in a single institution. METHODS AND MATERIALS A total of 306 patients treated between 1995 and 2007 in a radiation dose-escalation program fulfilled the National Comprehensive Cancer Network high-risk criteria. Median International Commission on Radiation Units and Measurements radiation dose was 78 Gy (range, 66.0-84.1 Gy). Long-term androgen deprivation (LTAD) was administered in 231 patients, short-term androgen deprivation (STAD) in 59 patients, and no hormones in 16 patients. The Phoenix (nadir plus 2 ng/mL) consensus definition was used for biochemical control. Multivariate analysis was performed to determine the independent prognostic impact of clinical and treatment factors. Median follow-up time was 64 months (range, 24-171 months). RESULTS The actuarial overall survival at 5 and 10 years was 95.7% and 89.8%, respectively, and the corresponding biochemical disease-free survival (bDFS) was 89.5% and 67.2%, respectively. Fourteen patients (4.6%) developed distant metastasis. Multivariate analysis showed that Gleason score>7 (p=0.001), pretreatment prostate-specific antigen (PSA) level>20 ng/mL (p=0.037), higher radiation dose (p=0.005), and the use of adjuvant LTAD vs. STAD (p=0.011) were independent prognostic factors affecting bDFS in high-risk disease. The 5-year bDFS for patients treated with LTAD plus radiotherapy dose>78 Gy was 97%. CONCLUSIONS For high-risk patients the present series showed that the use of LTAD in conjunction with higher doses (>78 Gy) of radiotherapy was associated with improved biochemical tumor control. We observed that the presence of Gleason sum>7 and pretreatment PSA level>20 ng/mL in the same patient represents a 6.8 times higher risk of PSA failure. These men could be considered for clinical trials with addition of novel agents.
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23
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Salonia A, Gallina A, Briganti A, Zanni G, Suardi N, Capitanio U, Colombo R, Bertini R, Freschi M, Guazzoni G, Rigatti P, Montorsi F. Sex hormone-binding globulin is a significant predictor of extracapsular extension in men undergoing radical prostatectomy. BJU Int 2010; 107:1243-9. [DOI: 10.1111/j.1464-410x.2010.09582.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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24
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Molecular circuits of solid tumors: prognostic and predictive tools for bedside use. Nat Rev Clin Oncol 2010; 7:367-80. [PMID: 20551944 DOI: 10.1038/nrclinonc.2010.84] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The explosion of knowledge in cancer biology in the past two decades has led to the identification of specific molecular circuits in solid tumors. These pathways reflect specific abnormalities thought to drive malignant progression. This knowledge has also generated a vast panel of cancer biomarkers although many of these biomarkers lack sufficient research and validation to be used in the clinic. This Review discusses relevant molecular prognostic and/or predictive biomarkers in the six leading tumors with the highest contribution to cancer mortality: breast, lung, colorectal, prostate, pancreatic and ovarian cancer. Each biomarker is described according to its associated clinicopathological presentation and specific associated molecular interactions. Despite only few biomarkers being currently implemented in clinical practice, a new generation of predictors is emerging that could modify the classic organ-based cancer classification (for example, defects in DNA repair, aberrant MAPK signaling and aberrant PI3K/Akt/mTOR signaling). The advent of high-throughput strategies will also probably substitute monobiomarker strategies.
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25
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Clarke RA, Schirra HJ, Catto JW, Lavin MF, Gardiner RA. Markers for detection of prostate cancer. Cancers (Basel) 2010; 2:1125-54. [PMID: 24281110 PMCID: PMC3835122 DOI: 10.3390/cancers2021125] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 06/02/2010] [Accepted: 06/03/2010] [Indexed: 12/15/2022] Open
Abstract
Early detection of prostate cancer is problematic, not just because of uncertainly whether a diagnosis will benefit an individual patient, but also as a result of the imprecise and invasive nature of establishing a diagnosis by biopsy. Despite its low sensitivity and specificity for identifying patients harbouring prostate cancer, serum prostate specific antigen (PSA) has become established as the most reliable and widely-used diagnostic marker for this condition. In its wake, many other markers have been described and evaluated. This review focuses on the supporting evidence for the most prominent of these for detection and also for predicting outcome in prostate cancer.
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Affiliation(s)
- Raymond A. Clarke
- Prostate Cancer Institute, Cancer Care Centre, St George Hospital Clinical School of Medicine, University of New South Wales, Kogarah, NSW 2217, Australia; E-Mail:
| | - Horst J. Schirra
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane QLD, 4072, Australia; E-Mail:
| | - James W. Catto
- Academic Urology Unit and Institute for Cancer Studies, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; E-Mail:
| | - Martin F. Lavin
- Queensland Institute of Medical Research, Radiation Biology and Oncology, Brisbane, QLD 4029, Australia; E-Mail:
- University of Queensland Centre for Clinical Research, Brisbane, Australia
| | - Robert A. Gardiner
- University of Queensland Centre for Clinical Research, Brisbane, Australia
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Current Opinion in Endocrinology, Diabetes & Obesity. Current world literature. Curr Opin Endocrinol Diabetes Obes 2010; 17:293-312. [PMID: 20418721 DOI: 10.1097/med.0b013e328339f31e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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