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      The Present and Future of Prostate Cancer Urine Biomarkers

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          Abstract

          In order to successfully cure patients with prostate cancer (PCa), it is important to detect the disease at an early stage. The existing clinical biomarkers for PCa are not ideal, since they cannot specifically differentiate between those patients who should be treated immediately and those who should avoid over-treatment. Current screening techniques lack specificity, and a decisive diagnosis of PCa is based on prostate biopsy. Although PCa screening is widely utilized nowadays, two thirds of the biopsies performed are still unnecessary. Thus the discovery of non-invasive PCa biomarkers remains urgent. In recent years, the utilization of urine has emerged as an attractive option for the non-invasive detection of PCa. Moreover, a great improvement in high-throughput “omic” techniques has presented considerable opportunities for the identification of new biomarkers. Herein, we will review the most significant urine biomarkers described in recent years, as well as some future prospects in that field.

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          Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

          Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
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            Estimates of cancer incidence and mortality in Europe in 2008.

            Up-to-date statistics on cancer occurrence and outcome are essential for the planning and evaluation of programmes for cancer control. Since the relevant information for 2008 is not generally available as yet, we used statistical models to estimate incidence and mortality data for 25 cancers in 40 European countries (grouped and individually) in 2008. The calculations are based on published data. If not collected, national rates were estimated from national mortality data and incidence and mortality data provided by local cancer registries of the same or neighbouring country. The estimated 2008 rates were applied to the corresponding country population estimates for 2008 to obtain an estimate of the numbers of cancer cases and deaths in Europe in 2008. There were an estimated 3.2 million new cases of cancer and 1.7 million deaths from cancer in 2008. The most common cancers were colorectal cancers (436,000 cases, 13.6% of the total), breast cancer (421,000, 13.1%), lung cancer (391,000, 12.2%) and prostate cancer (382,000, 11.9%). The most common causes of death from cancer were lung cancer (342,000 deaths, 19.9% of the total), colorectal cancer (212,000 deaths, 12.3%), breast cancer (129,000, 7.5%) and stomach cancer (117,000, 6.8%). Copyright 2009 Elsevier Ltd. All rights reserved.
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              Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter.

              The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter. Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less--levels generally thought to be in the normal range. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                Molecular Diversity Preservation International (MDPI)
                1422-0067
                June 2013
                17 June 2013
                : 14
                : 6
                : 12620-12649
                Affiliations
                [1 ]Research Unit in Biomedicine and Translational Oncology, Vall d’Hebron Research Institute and Hospital and Autonomous University of Barcelona, 08035 Barcelona, Spain; E-Mails: marina.rigau@ 123456vhir.org (M.R.); mireia.olivan@ 123456vhir.org (M.O.); marta.garcia.lopez@ 123456vhir.org (M.G.); tamara.sequeiros@ 123456vhir.org (T.S.); melania.montes@ 123456vhir.org (M.M.); eva.colas@ 123456vhir.org (E.C.); marta.llaurado@ 123456vhir.org (M.L.); jaume.reventos@ 123456vhir.org (J.R.)
                [2 ]Department of Urology, Vall d’Hebron University Hospital and Autonomous University of Barcelona, 08035 Barcelona, Spain; E-Mails: jplanas@ 123456vhebron.net (J.P.); jmorote@ 123456vhebron.net (J.M.)
                [3 ]Department of Pathology, Vall d’Hebron University Hospital Autonomous University of Barcelona, 08035 Barcelona, Spain; E-Mail: itorres@ 123456vhebron.net
                [4 ]Cancer Genetics, University of East Anglia, Norwich Norfolk, NR4 7TJ, UK; E-Mails: colin.cooper@ 123456uea.ac.uk (C.C.); jeremy.clark@ 123456uea.ac.uk (J.C.)
                [5 ]Department of Basic Sciences, International University of Catalonia, 08017 Barcelona, Spain
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Author to whom correspondence should be addressed; E-Mail: andreas.doll@ 123456vhir.org ; Tel.: +34-93-489-4067; Fax: +34-93-274-6708.
                Article
                ijms-14-12620
                10.3390/ijms140612620
                3709804
                23774836
                82ded6c4-0016-4256-a698-997113c192f2
                © 2013 by the authors; licensee MDPI, Basel, Switzerland

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 23 April 2013
                : 27 May 2013
                : 03 June 2013
                Categories
                Review

                Molecular biology
                prostate cancer,biomarker,urine,non-invasive
                Molecular biology
                prostate cancer, biomarker, urine, non-invasive

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