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DOI: 10.1160/TH13-04-0275
Prostate-specific kallikrein-related peptidases and their relation to prostate cancer biology and detection
Established relevance and emerging rolesPublication History
Received:
02 April 2013
Accepted after major revision:
17 July 2013
Publication Date:
01 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201303/lookinside/thumbnails/10-1160-th13-04-0275-1.jpg)
summary
Kallikreins are a family of serine proteases with a range of tissue-specific and essential proteolytic functions. Among the best studied are the prostate tissue-specific KLK2 and KLK3 genes and their secreted protease products, human kallikrein 2, hk2, and prostate-specific antigen (PSA). Members of the so-called classic kallikreins, these highly active trypsin-like serine proteases play established roles in human reproduction. Both hK2 and PSA expression is regulated by the androgen receptor which has a fundamental role in prostate tissue development and progression of disease. This feature, combined with the ability to sensitively detect different forms of these proteins in blood and biopsies, result in a crucially important biomarker for the presence and recurrence of cancer. Emerging evidence has begun to suggest a role for these kallikreins in critical vascular events. This review discusses the established and developing biological roles of hK2 and PSA, as well as the historical and advanced use of their detection to accurately and non-invasively detect and guide treatment of prostatic disease.
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References
- 1 Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem 2007; 53: 1423-1432.
- 2 Kim J, Coetzee GA. Prostate specific antigen gene regulation by androgen receptor. J Cell Biochem 2004; 93: 233-241.
- 3 Siegel R. et al. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11-30.
- 4 Lundwall A. et al. A comprehensive nomenclature for serine proteases with homology to tissue kallikreins. Biol Chem 2006; 387: 637-641.
- 5 Clements JA. et al. The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers. Crit Rev Clin Lab Sci 2004; 41: 265-312.
- 6 Olsson AY. et al. Taxon-specific evolution of glandular kallikrein genes and identification of a progenitor of prostate-specific antigen. Genomics 2004; 84: 147-156.
- 7 Marques PI. et al. Birth-and-death of KLK3 and KLK2 in primates: evolution driven by reproductive biology. Genome Biol Evol 2012; 04: 1331-1338.
- 8 Lovgren J. et al. Activation of the zymogen form of prostate-specific antigen by human glandular kallikrein 2. Biochem Biophys Res Commun 1997; 238: 549-555.
- 9 Lilja H, Laurell CB. The predominant protein in human seminal coagulate. Scand J Clin Lab Invest 1985; 45: 635-641.
- 10 Denmeade SR. et al. Activation of latent protease function of pro-hK2, but not pro-PSA, involves autoprocessing. Prostate 2001; 48: 122-126.
- 11 Lilja H. et al. Seminal vesicle-secreted proteins and their reactions during gelation and liquefaction of human semen. J Clin Invest 1987; 80: 281-285.
- 12 Lilja H. et al. Semenogelin, the predominant protein in human semen. Primary structure and identification of closely related proteins in the male accessory sex glands and on the spermatozoa. J Biol Chem 1989; 264: 1894-1900.
- 13 Frenette G. et al. Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. Int J Cancer 1997; 71: 897-899.
- 14 Rehault S. et al. Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. Eur J Biochem 2001; 268: 2960-2968.
- 15 Cohen P. et al. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J Endocrinol 1994; 142: 407-415.
- 16 Cohen P. et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J Clin Endocrinol Metab 1992; 75: 1046-1053.
- 17 Iwamura M. et al. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology 1996; 48: 317-325.
- 18 Christensson A. et al. Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem 1990; 194: 755-763.
- 19 Misra UK. et al. Ligation of prostate cancer cell surface GRP78 activates a proproliferative and antiapoptotic feedback loop: a role for secreted prostate-specific antigen. J Biol Chem 2011; 286: 1248-1259.
- 20 Saraswati S. et al. Galectin-3 is a substrate for prostate specific antigen (PSA) in human seminal plasma. Prostate 2011; 71: 197-208.
- 21 Nangia-Makker P. et al. Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol 2000; 156: 899-909.
- 22 Mahabeer R, Bhoola KD. Kallikrein and kinin receptor genes. Pharmacol Ther 2000; 88: 77-89.
- 23 Deperthes D. et al. Human kallikrein hK2 has low kininogenase activity while prostate-specific antigen (hK3) has none. Biochim Biophys Acta 1997; 1343: 102-106.
- 24 Fortier AH. et al. Recombinant prostate specific antigen inhibits angiogenesis in vitro and in vivo. Prostate 2003; 56: 212-219.
- 25 Fortier AH. et al. Antiangiogenic activity of prostate-specific antigen. J Natl Cancer Inst 1999; 91: 1635-1640.
- 26 Koistinen H. et al. Novel small molecule inhibitors for prostate-specific antigen. Prostate 2008; 68: 1143-1151.
- 27 Mattsson JM. et al. The antiangiogenic role of prostate-specific antigen. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research. 2010. Washington, DC: AACR;
- 28 Mattsson JM. et al. Peptides binding to prostate-specific antigen enhance its antiangiogenic activity. Prostate 2012; 72: 1588-1594.
- 29 Ankerst DP. Prostate cancer screening. 2nd ed. 2009. New York: Humana Press;
- 30 Stamey TA. et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987; 317: 909-916.
- 31 Catalona WJ. et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991; 324: 1156-1161.
- 32 Savblom C. et al. Blood levels of free-PSA but not complex-PSA significantly correlates to prostate release of PSA in semen in young men, while blood levels of complex-PSA, but not free-PSA increase with age. Prostate 2005; 65: 66-72.
- 33 Lilja H. et al. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer 2008; 08: 268-278.
- 34 Lilja H. et al. Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem 1991; 37: 1618-1625.
- 35 Zhang WM. et al. Prostate-specific antigen forms a complex with and cleaves alpha 1-protease inhibitor in vitro. Prostate 1997; 33: 87-96.
- 36 Christensson A, Lilja H. Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. Eur J Biochem 1994; 220: 45-53.
- 37 Stenman UH. et al. A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res 1991; 51: 222-226.
- 38 Christensson A. et al. Serum prostate specific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993; 150: 100-105.
- 39 Mikolajczyk SD. et al. A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer. Cancer Res 2001; 61: 6958-6963.
- 40 Vaisanen V. et al. Characterisation and processing of prostate specific antigen (hK3) and human glandular kallikrein (hK2) secreted by LNCaP cells. Prostate Cancer Prostatic Dis 1999; 02: 91-97.
- 41 Nurmikko P. et al. Production and characterisation of novel anti-prostate-specific antigen (PSA) monoclonal antibodies that do not detect internally cleaved Lys145-Lys146 inactive PSA. Clin Chem 2000; 46: 1610-1618.
- 42 Vaisanen V. et al. Intact free prostate-specific antigen and free and total human glandular kallikrein 2. Elimination of assay interference by enzymatic digestion of antibodies to F(ab’)2 fragments. Anal Chem 2006; 78: 7809-7815.
- 43 Nurmikko P. et al. Discrimination of prostate cancer from benign disease by plasma measurement of intact, free prostate-specific antigen lacking an internal cleavage site at Lys145-Lys146. Clin Chem 2001; 47: 1415-1423.
- 44 Mikolajczyk SD. et al. Free prostate-specific antigen in serum is becoming more complex. Urology 2002; 59: 797-802.
- 45 Steuber T. et al. 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 2007; 53: 233-240.
- 46 Roddam AW. et al. Use of prostate-specific antigen (PSA) isoforms for the detection of prostate cancer in men with a PSA level of 2-10 ng/ml: systematic review and meta-analysis. Eur Urol 2005; 48: 386-399.
- 47 Filella X, Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013; 51: 729-739.
- 48 Vickers AJ. et al. A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening. Cancer Epidemiol Biomarkers Prev 2011; 20: 255-261.
- 49 Amarapurkur DN, Trivedi MH, Desai HG. Metoclopramide in variceal bleeding. Indian J Gastroenterol 1991; 10: 71-72.
- 50 de Koning HJ. et al. Large-scale randomized prostate cancer screening trials: program performances in the European Randomized Screening for Prostate Cancer trial and the Prostate, Lung, Colorectal and Ovary cancer trial. Int J Cancer 2002; 97: 237-244.
- 51 Hugosson J. et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010; 11: 725-732.
- 52 Schroder FH. et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: 981-990.
- 53 Schroder FH, Roobol MJ. ERSPC and PLCO prostate cancer screening studies: what are the differences?. Eur Urol 2010; 58: 46-52.
- 54 Andriole GL. et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: 1310-1319.
- 55 Gulati R. et al. The impact of PLCO control arm contamination on perceived PSA screening efficacy. Cancer Causes Control 2012; 23: 827-835.
- 56 Andriole GL. et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012; 104: 125-132.
- 57 Schroder FH. et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol 2012; 62: 745-752.
- 58 Heijnsdijk EA. et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med 2012; 367: 595-605.
- 59 Moyer VA. U. S.P.S.T. Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: 120-134.
- 60 Roobol MJ, Carlsson SV. Risk stratification in prostate cancer screening. Nat Rev Urol 2012; 10: 38-48.
- 61 Gomella LG. et al. Screening for prostate cancer: the current evidence and guidelines controversy. Can J Urol 2011; 18: 5875-5883.
- 62 Horwich A. et al. and Panel Members. ESMO Consensus Conference Guidelines 2012. Ann Oncol 2013; 24: 1141-1162.
- 63 Nilsson PM. et al. Social mobility, marital status, and mortality risk in an adult life course perspective: the Malmo Preventive Project. Scand J Public Health 2005; 33: 412-423.
- 64 Ulmert D. et al. Prostate-specific antigen at or before age 50 as a predictor of advanced prostate cancer diagnosed up to 25 years later: a case-control study. BMC Med 2008; 06: 6
- 65 Lilja H. et al. Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years. J Clin Oncol 2007; 25: 431-436.
- 66 Lilja H. et al. Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50. Cancer 2011; 117: 1210-1219.
- 67 Vickers AJ. et al. The predictive value of prostate cancer biomarkers depends on age and time to diagnosis: towards a biologically-based screening strategy. Int J Cancer 2007; 121: 2212-2217.
- 68 LeBeau AM. et al. Potent and selective peptidyl boronic acid inhibitors of the serine protease prostate-specific antigen. Chem Biol 2008; 15: 665-674.
- 69 LeBeau AM. et al. Prostate-specific antigen is a „chymotrypsin-like“ serine protease with unique P1 substrate specificity. Biochemistry 2009; 48: 3490-3496.
- 70 Cosgrove 3rd DM. et al. Aprotinin therapy for reoperative myocardial revascularisation: a placebo-controlled study. Ann Thorac Surg 1992; 54: 1031-1038.
- 71 Denmeade SR. et al. Specific and efficient peptide substrates for assaying the proteolytic activity of prostate-specific antigen. Cancer Res 1997; 57: 4924-4930.
- 72 Denmeade SR. et al. Enzymatic activation of a doxorubicin-peptide prodrug by prostate-specific antigen. Cancer Res 1998; 58: 2537-2540.
- 73 Denmeade SR. et al. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. J Natl Cancer Inst 2003; 95: 990-1000.
- 74 Ulmert D. et al. Imaging androgen receptor signalling with a radiotracer targeting free prostate-specific antigen. Cancer Discov 2012; 02: 320-327.
- 75 LeBeau AM. et al. Optimisation of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer. Bioorg Med Chem 2009; 17: 4888-4893.
- 76 Miyamoto DT. et al. Androgen receptor signalling in circulating tumour cells as a marker of hormonally responsive prostate cancer. Cancer Discov 2012; 02: 995-1003.