Abstract
Due to its significant applicability for early detection, risk prediction and follow-up evaluation, prostate specific antigen (PSA) has revolutionized our ability to treat prostate cancer patients. With the prevalent use of PSA for early detection during the last two decades, disease characteristics have been altered towards early detected, localized tumors with a high chance of cure following local therapy. This advantage faces the risk of overdetection and overtreatment. In addition, PSA lacks both, sensitivity and specificity to accurately detect patients at risk of prostate cancer. Therefore, novel biomarkers are urgently needed to improve identification of men at risk of having the disease and to predict the natural behaviour of the tumor. Recent advances in the evaluation of high-throughput technologies have led to the discovery of novel candidate markers for prostate cancer. This article will briefly discuss current PSA-based strategies and review several novel biomarkers for prostate cancer, detectable in blood.
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Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, Oesterling JE, Scardino PT, Pearson JD (1997) Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. Jama 277:1445–1451
Kattan MW, Eastham JA, Stapleton AM, Wheeler TM, Scardino PT (1998) A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 90:766–771
Bunting PS (2002) Screening for prostate cancer with prostate-specific antigen: beware the biases. Clin Chim Acta 315:71–97
Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA Jr (2004) Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per milliliter. N Engl J Med 350:2239–2246
Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, Vernon SW, Cronin K, Edwards BK (2000) The annual report to the nation on the status of cancer, 1973–1997, with a special section on colorectal cancer. Cancer 88:2398–2424
Stamey TA, Johnstone IM, McNeal JE, Lu AY, Yemoto CM (2002) Preoperative serum prostate specific antigen levels between 2 and 22 ng/ml correlate poorly with post-radical prostatectomy cancer morphology: prostate specific antigen cure rates appear constant between 2 and 9 ng/ml J Urol 167:103–111
Lilja H, Ulmert D, Björk T, Charlotte B, Serio AM, Nilsson JA, Abrahamsson PA, Vickers AJ, Berglund G (2007) Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44–50 years. J Clin Oncol 25(4):431–436
Oesterling JE (1996) Age-specific reference ranges for serum PSA. N Engl J Med 335:345–346
Catalona WJ, Beiser JA, Smith DS (1997) Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol 158:2162–2167
Catalona WJ, Richie JP, deKernion JB, Ahmann FR, Ratliff TL, Dalkin BL, Kavoussi LR, MacFarlane MT, Southwick PC (1994) Comparison of prostate specific antigen concentration versus prostate specific antigen density in the early detection of prostate cancer: receiver operating characteristic curves. J Urol 152:2031–2036
Catalona WJ, Richie JP, deKernion JB, Ahmann FR, Ratliff TL, Dalkin BL, Kavoussi LR, MacFarlane MT, Southwick PC (1994) Comparison of prostate specific antigen concentration versus prostate specific antigen density in the early detection of prostate cancer: receiver operating characteristic curves. J Urol 152:2031–2036
Brawer MK, Beatie J, Wener MH, Vessella RL, Preston SD, Lange PH (1993) Screening for prostatic carcinoma with prostate specific antigen: results of the second year. J Urol 150:106–109
D’Amico AV, Chen MH, Roehl KA, Catalona WJ (2004) Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 351:125–135
Lilja H, Christensson A, Dahlen U, Matikainen MT, Nilsson O, Pettersson K, Lovgren T (1991) Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem 37:1618–1625
Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, deKernion JB, Walsh PC, Scardino PT, Lange PH, Subong EN, Parson RE, Gasior GH, Loveland KG, Southwick PC (1998) Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. Jama 279:1542–1547
Karakiewicz PI, Benayoun S, Kattan MW, Perrotte P, Valiquette L, Scardino PT, Cagiannos I, Heinzer H, Tanguay S, Aprikian AG, Huland H, Graefen M (2005) Development and validation of a nomogram predicting the outcome of prostate biopsy based on patient age, digital rectal examination and serum prostate specific antigen. J Urol 173:1930–1934
Chun FK, Briganti A, Graefen M, Porter C, Montorsi F, Haese A, Scattoni V, Borden L, Steuber T, Salonia A, Schlomm T, Latchemsetty K, Walz J, Kim J, Eichelberg C, Currlin E, Ahyai SA, Erbersdobler A, Valiquette L, Heinzer H, Rigatti P, Huland H, Karakiewicz PI (2007) Development and external validation of an extended repeat biopsy nomogram. J Urol 177:510–515
Brawer MK, Meyer GE, Letran JL, Bankson DD, Morris DL, Yeung KK, Allard WJ (1998) Measurement of complexed PSA improves specificity for early detection of prostate cancer. Urology 52:372–378
Partin AW, Brawer MK, Bartsch G, Horninger W, Taneja SS, Lepor H, Babaian R, Childs SJ, Stamey T, Fritsche HA, Sokoll L, Chan DW, Thiel RP, Cheli CD (2003) Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. J Urol 170:1787–1791
Canto EI, Singh H, Shariat SF, Lamb DJ, Mikolajczyk SD, Linton HJ, Rittenhouse HG, Kadmon D, Miles BJ, Slawin KM (2004) Serum BPSA outperforms both total PSA and free PSA as a predictor of prostatic enlargement in men without prostate cancer. Urology 63:905–910; discussion 910–901
Steuber T, Nurmikko P, Haese A, Pettersson K, Graefen M, Hammerer P, Huland H, Lilja H (2002) Discrimination of benign from malignant prostatic disease by selective measurements of single chain, intact free prostate specific antigen. J Urol 168:1917–1922
Catalona WJ, Bartsch G, Rittenhouse HG, Evans CL, Linton HJ, Amirkhan A, Horninger W, Klocker H, Mikolajczyk SD (2003) Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. J Urol 170:2181–2185
Lein M, Semjonow A, Graefen M, Kwiatkowski M, Abramjuk C, Stephan C, Haese A, Chun F, Schnorr D, Loening SA, Jung K (2005) A multicenter clinical trial on the use of (−5, −7) pro prostate specific antigen. J Urol 174:2150–2153
Darson MF, Pacelli A, Roche P, Rittenhouse HG, Wolfert RL, Saeid MS, Young CY, Klee GG, Tindall DJ, Bostwick DG (1999) Human glandular kallikrein 2 expression in prostate adenocarcinoma and lymph node metastases. Urology 53:939–944
Lintula S, Stenman J, Bjartell A, Nordling S, Stenman UH (2005) Relative concentrations of hK2/PSA mRNA in benign and malignant prostatic tissue. Prostate 63:324–329
Becker C, Piironen T, Pettersson K, Hugosson J, Lilja H (2000) Clinical value of human glandular kallikrein 2 and free and total prostate-specific antigen in serum from a population of men with prostate-specific antigen levels 3.0 ng/mL or greater. Urology 55:694–699
Becker C, Piironen T, Pettersson K, Bjork T, Wojno KJ, Oesterling JE, Lilja H (2000) Discrimination of men with prostate cancer from those with benign disease by measurements of human glandular kallikrein 2 (HK2) in serum. J Urol 163:311–316
Haese A, Graefen M, Steuber T, Becker C, Noldus J, Erbersdobler A, Huland E, Huland H, Lilja H (2003) Total and Gleason grade 4/5 cancer volumes are major contributors of human kallikrein 2, whereas free prostate specific antigen is largely contributed by benign gland volume in serum from patients with prostate cancer or benign prostatic biopsies. J Urol 170:2269–2273
Haese A, Graefen M, Steuber T, Becker C, Pettersson K, Piironen T, Noldus J, Huland H, Lilja H (2001) Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml. Prostate 49:101–109
Steuber T, Vickers AJ, Serio AM, Vaisanen V, Haese A, Pettersson K, Eastham JA, Scardino PT, Huland H, Lilja H (2006) Comparison of free and total forms of serum human Kallikrein 2 and prostate-specific antigen for prediction of locally advanced and recurrent prostate cancer. Clin Chem 53(2):233–240
Steuber T, Vickers AJ, Haese A, Becker C, Pettersson K, Chun FK, Kattan MW, Eastham JA, Scardino PT, Huland H, Lilja H (2006) Risk assessment for biochemical recurrence prior to radical prostatectomy: significant enhancement contributed by human glandular kallikrein 2 (hK2) and free prostate specific antigen (PSA) in men with moderate PSA-elevation in serum. Int J Cancer 118:1234–1240
Horoszewicz JS, Kawinski E, Murphy GP (1987) Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res 7:927–935
Chang SS, Gaudin PB, Reuter VE, Heston WD (2000) Prostate-specific membrane antigen: present and future applications. Urology 55:622–629
Elgamal AA, Holmes EH, Su SL, Tino WT, Simmons SJ, Peterson M, Greene TG, Boynton AL, Murphy GP (2000) Prostate-specific membrane antigen (PSMA): current benefits and future value. Semin Surg Oncol 18:10–16
Nanus DM, Milowsky MI, Kostakoglu L, Smith-Jones PM, Vallabahajosula S, Goldsmith SJ, Bander NH (2003) Clinical use of monoclonal antibody HuJ591 therapy: targeting prostate specific membrane antigen. J Urol 170:S84–S88; discussion S88–89
Pappot H, Hoyer-Hansen G, Ronne E, Hansen HH, Brunner N, Dano K, Grondahl-Hansen J (1997) Elevated plasma levels of urokinase plasminogen activator receptor in non-small cell lung cancer patients. Eur J Cancer 33:867–872
Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius-Ussing O, Sorensen S, Dano K, Brunner N (1999) Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 91:869–874
McCabe NP, Angwafo FF 3rd, Zaher A, Selman SH, Kouinche A, Jankun J (2000) Expression of soluble urokinase plasminogen activator receptor may be related to outcome in prostate cancer patients. Oncol Rep 7:879–882
Piironen T, Laursen B, Pass J, List K, Gardsvoll H, Ploug M, Dano K, Hoyer-Hansen G (2004) Specific immunoassays for detection of intact and cleaved forms of the urokinase receptor. Clin Chem 50:2059–2068
Steuber T, Vickers A, Haese A, Kattan MW, Eastham JA, Scardino PT, Huland H, Lilja H (2007) Free PSA isoforms and intact and cleaved forms of urokinase plasminogen activator receptor in serum improve selection of patients for prostate cancer biopsy. Int J Cancer 120(7):1499–1504
Uetsuki H, Tsunemori H, Taoka R, Haba R, Ishikawa M, Kakehi Y (2005) Expression of a novel biomarker, EPCA, in adenocarcinomas and precancerous lesions in the prostate. J Urol 174:514–518
Paul B, Dhir R, Landsittel D, Hitchens MR, Getzenberg RH (2005) Detection of prostate cancer with a blood-based assay for early prostate cancer antigen. Cancer Res 65:4097–4100
Bradley SV, Oravecz-Wilson KI, Bougeard G, Mizukami I, Li L, Munaco AJ, Sreekumar A, Corradetti MN, Chinnaiyan AM, Sanda MG, Ross TS (2005) Serum antibodies to huntingtin interacting protein-1: a new blood test for prostate cancer. Cancer Res 65:4126–4133
Minelli A, Ronquist G, Carlsson L, Mearini E, Nilsson O, Larsson A (2005) Antiprostasome antibody titres in benign and malignant prostate disease. Anticancer Res 25:4399–4402
Wang X, Yu J, Sreekumar A, Varambally S, Shen R, Giacherio D, Mehra R, Montie JE, Pienta KJ, Sanda MG, Kantoff PW, Rubin MA, Wei JT, Ghosh D, Chinnaiyan AM (2005) Autoantibody signatures in prostate cancer. N Engl J Med 353:1224–1235
Shariat SF, Shalev M, Menesses-Diaz A, Kim IY, Kattan MW, Wheeler TM, Slawin KM (2001) Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol 19:2856–2864
Wolff JM, Fandel TH, Borchers H, Jakse G (1999) Serum concentrations of transforming growth factor-beta 1 in patients with benign and malignant prostatic diseases. Anticancer Res 19:2657–2659
Lee SO, Lou W, Hou M, de Miguel F, Gerber L, Gao AC (2003) Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clin Cancer Res 9:370–376
Tan D, Wu X, Hou M, Lee SO, Lou W, Wang J, Janarthan B, Nallapareddy S, Trump DL, Gao AC (2005) Interleukin-6 polymorphism is associated with more aggressive prostate cancer. J Urol 174:753–756
Kattan MW, Shariat SF, Andrews B, Zhu K, Canto E, Matsumoto K, Muramoto M, Scardino PT, Ohori M, Wheeler TM, Slawin KM (2003) The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol 21:3573–3579
Fidler IJ (1990) Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50(19):6130–6138
Moreno JG, Croce CM, Fischer R, Monne M, Vihko P, Mulholland SG, Gomella LG (1992) Detection of hematogenous micrometastasis in patients with prostate cancer. Cancer Res 52(21):6110–6112
Katz AE, Olsson CA, Raffo AJ, Cama C, Perlman H, Seaman E, O’Toole KM, McMahon D, Benson MC, Buttyan R (1994) Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay. Urology 43(6):765–775
Shariat SF, Kattan MW, Song W, Bernard D, Gottenger E, Wheeler TM, Slawin KM (2003) Early postoperative peripheral blood reverse transcription PCR assay for prostate-specific antigen is associated with prostate cancer progression in patients undergoing radical prostatectomy. Cancer Res 63(18):5874–5878
de la Taille A, Olsson CA, Buttyan R, Benson MC, Bagiella E, Cao Y, Burchardt M, Chopin DK, Katz AE (1999) Blood-based reverse transcriptase polymerase chain reaction assays for prostatic specific antigen. Long term follow-up confirms the potential utility of this assay in identifying patients more likely to have biochemical recurrence (rising PSA) following radical prostatectomy. Int J Cancer 84(4):360–364
Hara N, Kasahara T, Kawasaki T, Bilim V, Obara K, Takahashi K, Tomita Y (2002) Reverse transcription-polymerase chain reaction detection of prostate-specific antigen, prostate-specific membrane antigen, and prostate stem cell antigen in one milliliter of peripheral blood: value for the staging of prostate cancer. Clin Cancer Res 8(6):1794–1799
Grasso YZ, Gupta MK, Levin HS, Zippe CD, Klein EA (1998) Combined nested RT-PCR assay for prostate-specific antigen and prostate-specific membrane antigen in prostate cancer patients: correlation with pathological stage. Cancer Res 58(7):1456–1459
Olsson CA, de Vries GM, Raffo AJ, Benson MC, O’Toole K, Cao Y, Buttyan RE, Katz AE (1996) Preoperative reverse transcriptase polymerase chain reaction for prostate specific antigen predicts treatment failure following radical prostatectomy. J Urol 155(5):1557–1562
Rissanen M, Helo P, Vaananen RM, Wahlroos V, Lilja H, Nurmi M, Pettersson K, Nurmi J (2007) Novel homogenous time-resolved fluorometric RT-PCR assays for quantification of PSA and hK2 mRNAs in blood. Clin Biochem 40(1–2):111–118. Epub 2006 Oct 19
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Steuber, T., Helo, P. & Lilja, H. Circulating biomarkers for prostate cancer. World J Urol 25, 111–119 (2007). https://doi.org/10.1007/s00345-007-0160-0
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DOI: https://doi.org/10.1007/s00345-007-0160-0