Prostate-specific antigen

edit
Kallikrein-related peptidase 3
Identifiers
Symbols KLK3; APS; KLK2A1; PSA; hK3
External IDs OMIM: 176820 MGI: 892021 HomoloGene: 84789 GeneCards: KLK3 Gene
RNA expression pattern
PBB GE KLK3 204582 s at tn.png
PBB GE KLK3 204583 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 354 16617
Ensembl ENSG00000142515 ENSMUSG00000063713
UniProt P07288 O35307
RefSeq (mRNA) NM_001030047 XM_001000656
RefSeq (protein) NP_001025218 XP_001000656
Location (UCSC) Chr 19:
56.05 - 56.06 Mb		 Chr 7:
44.06 - 44.06 Mb
PubMed search [1] [2]

Prostate-specific antigen (PSA) is a protein produced by the cells of the prostate gland. PSA is present in small quantities in the serum of normal men, and is often elevated in the presence of prostate cancer and in other prostate disorders. A blood test to measure PSA is considered the most effective test currently available for the early detection of prostate cancer, but this effectiveness has also been questioned.[1][2][3]

Rising levels of PSA over time are associated with both localized and metastatic prostate cancer (CaP).

Contents

Biochemistry

Prostate-specific antigen (PSA), also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen) is a 34 kD glycoprotein manufactured almost exclusively by the prostate gland; PSA is produced for the ejaculate where it liquifies the semen in the seminal coagulum and allows sperm to swim freely.[4] It is also believed to be instrumental in dissolving the cervical mucous cap, allowing the entry of sperm.[5]

It is a serine protease (EC 3.4.21.77) enzyme, the gene of which is located on the nineteenth chromosome (19q13).[6]

Discovery

The discovery of prostate-specific antigen (PSA) is beset with controversy; as PSA is present in prostatic tissue and semen, it was independently discovered and given different names, thus adding to the controversy.[7] Flocks was the first to experiment with antigens in the prostate[8] and 10 years later Ablin reported the presence of precipitation antigens in the prostate.[9] In 1971, Hara characterized a unique protein in the semen fluid, gamma-seminoprotein. Li and Beling, in 1973, isolated a protein, E1, from human semen in an attempt to find a novel method to achieve fertility control.[10][11] In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source.[12] In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen').[13] PSA was first measured quantitatively in the blood by Papsidero in 1980, and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer.

Serum PSA

Risk of prostate cancer in two age groups based on Free PSA as % of Total PSA [14]

PSA is normally present in the blood at very low levels. The reference range of less than 4 ng/mL for the first commercial PSA test, the Hybritech Tandem-R PSA test released in February 1986, was based on a study that found 99% of 472 apparently healthy men had a total PSA level below 4 ng/mL—the upper limit of normal is much less than 4 ng/mL.[15] Increased levels of PSA may suggest the presence of prostate cancer. However, prostate cancer can also be present in the complete absence of an elevated PSA level, in which case the test result would be a false negative.[16] Obesity has been reported to reduce serum PSA levels.[17] Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.[18]

PSA levels can be also increased by prostate infection, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation,[19][20] producing a false positive result. Digital rectal examination (DRE) has been shown in several studies[21] to produce an increase in PSA. However, the effect is clinically insignificant, since DRE causes the most substantial increases in patients with PSA levels already elevated over 4.0 ng/mL.

The "normal" reference ranges for prostate-specific antigen increase with age, as do the usual ranges in cancer:[22]

Age <50 50 - 59 60 - 69 >70 (years)
Cancer No cancer Cancer No cancer Cancer No cancer Cancer No cancer
5th percentile 0.4 0.3 1.2 0.3 1.7 0.3 2.3 0.4 (ng/mL)
95th percentile 163.0 2.5 372.5 4.7 253.2 8.3 613.2 17.8

Despite earlier findings,[23] recent research suggests that the rate of increase of PSA (the PSA velocity) is not a more specific marker for prostate cancer.[24] However, the PSA rate of rise may have value in prostate cancer prognosis. Men with prostate cancer whose PSA level increased by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing radical prostatectomy.[25]

Most PSA in the blood is bound to serum proteins. A small amount is not protein bound and is called free PSA. In men with prostate cancer the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%. (See graph at right.) The lower the ratio the greater the probability of prostate cancer. Measuring the ratio of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL.[26] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.[19]

PSA in other biologic fluids & tissues

Concentration of PSA in human body fluids
Fluid PSA (ng/mL)
semen
200,000 to 5.5 million
amniotic fluid
0.60-8.98
breast milk
0.47-100
saliva
0
female urine
0.12-3.72
female serum
0.01-.53

It is now clear that the term prostate-specific antigen is a misnomer. It is neither an antigen nor specific to the prostate. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues.[27]

In women, PSA is found in female ejaculate at concentrations roughly equal to that found in male semen.[28] Other than semen and female ejaculate, the greatest concentrations of PSA in biological fluids are detected in breast milk and amniotic fluid. Low concentrations of PSA have been identified in the urethral glands, endometrium, normal breast tissue and salivary gland tissue. PSA also is found in the serum of women with breast, lung, or uterine cancer and in some patients with renal cancer.[29]

Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized.[30]

Uses of PSA

Prostate cancer

Screening

The U.S. Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men of age 50 and older. PSA levels between 4 and 10 ng/mL (nanograms per milliliter) are considered to be suspicious and should be followed by rectal ultrasound imaging and, if indicated, prostate biopsy. PSA is false positive-prone (7 out of 10 men in this category will still not have prostate cancer) and false negative-prone (2.5 out of 10 men with prostate cancer have no elevation in PSA).[31] Recent reports indicate that refraining from ejaculation 24 hours or more prior to testing will improve test accuracy.[19]

Risk Stratification & Staging

Post-Treatment Monitoring

Each year, up to 70,000 men in the U.S. will have a "biochemical recurrence," a rising PSA level after failed definitive therapy. The ideal salvage therapy for these men is not clear and includes salvage local therapies and systemic approaches, of which the mainstay is hormonal therapy. Treatment needs to be individualized based on the individual's risk of progression as well as the likelihood of success and the risks of the treatment.[32]

Forensic identification of semen

PSA was first identified by researchers attempting to find a substance in seminal fluid that would aid in the investigation of rape cases.[33] PSA is now used to indicate the presence of semen in forensic serology.[34] The semen of adult males has PSA levels far in excess of those found in other tissues; therefore, a high level of PSA found in a sample is an indicator that semen may be present. Because PSA is a biomarker that is expressed independently of spermatozoa, it remains useful in identifying semen from vasectomized and azoospermic males.[35]

It is important to note that PSA can also be found at low levels in other body fluids, such as urine and breast milk, thus setting a high minimum threshold of interpretation to rule out false positive results and conclusively state that semen is present.[27] While traditional tests such as crossover electrophoresis have a sufficiently low sensitivity to detect only seminal PSA, newer diagnostics tests developed from clinical prostate cancer screening methods have lowered the threshold of detection down to 4 ng/mL.[36] This level of antigen has been shown to be present in the peripheral blood of males with prostate cancer, and rarely in female urine samples and breast milk.[27] No studies have been performed to assess the PSA levels in the tissues and secretions of pre-pubescent children. Therefore, the presence of PSA from a high sensitivity (4 ng/mL) test cannot conclusively identify the presence of semen, so care must be taken with the interpretation of such results.

Interactions

Prostate-specific antigen has been shown to interact with Protein C inhibitor.[37][38]

See also

References

  1. ↑ Andriole GL, Grubb RL, Buys SS, et al. (2009). "Mortality Results from a Randomized Prostate-Cancer Screening Trial". New Eng. J. Med. 360 (13): 1310. doi:10.1056/NEJMoa0810696. PMID 19297565. 
  2. ↑ Schröder FH, Hugosson J, Roobol MJ, et al. (2009). "Screening and Prostate-Cancer Mortality in a Randomized European Study". New Eng. J. Med. 360 (13): 1320. doi:10.1056/NEJMoa0810084. PMID 19297566. 
  3. ↑ Ablin RJ (2010-03-09). "The Great Prostate Mistake". The New York Times. http://www.nytimes.com/2010/03/10/opinion/10Ablin.html. Retrieved 2010-03-11. 
  4. ↑ Balk SP, Ko YJ, Bubley GJ (January 2003). "Biology of prostate-specific antigen". J. Clin. Oncol. 21 (2): 383–91. doi:10.1200/JCO.2003.02.083. PMID 12525533. 
  5. ↑ edited by Wayne J.G. Hellstrom. (1999). "Chapter 8: What is the prostate and what is its function?". American Society of Andrology Handbook. San Francisco, Calif.: American Society of Andrology. ISBN 1891276026. http://www.andrologysociety.com/resources/handbook/ch.8.asp. Retrieved 2006-09-17. 
  6. ↑ Lilja H (November 2003). "Biology of prostate-specific antigen". Urology 62 (5 Suppl 1): 27–33. doi:10.1016/S0090-4295(03)00775-1. PMID 14607215. 
  7. ↑ Rao AR, Motiwala HG, Karim OM (January 2008). "The discovery of prostate-specific antigen". BJU Int. 101 (1): 5–10. doi:10.1111/j.1464-410X.2007.07138.x. PMID 17760888. 
  8. ↑ Flocks RH, Boatman DL, Hawtrey CE (November 1972). "Tissue specific isoantigens in the dog prostate". Invest Urol 10 (3): 215–20. PMID 4629646. 
  9. ↑ Ablin RJ, Soanes WA, Gonder MJ (July 1969). "Immunologic studies of the prostate. A review". Int Surg 52 (1): 8–21. PMID 4977978. 
  10. ↑ Li TS, Beling CG (February 1973). "Isolation and characterization of two specific antigens of human seminal plasma". Fertil. Steril. 24 (2): 134–44. PMID 4631694. 
  11. ↑ Li TS, Beling CG (October 1974). "The effect of antibodies to two human seminal plasma-specific antigens on human sperm". Fertil. Steril. 25 (10): 851–6. PMID 4213812. 
  12. ↑ Sensabaugh GF (January 1978). "Isolation and characterization of a semen-specific protein from human seminal plasma: a potential new marker for semen identification". J. Forensic Sci. 23 (1): 106–15. PMID 744956. 
  13. ↑ Wang MC, Valenzuela LA, Murphy GP, Chu TM (September 1979). "Purification of a human prostate specific antigen". Invest Urol 17 (2): 159–63. PMID 89106. 
  14. ↑ Catalona W, Partin A, Slawin K, Brawer M, Flanigan R, Patel A, Richie J, deKernion J, Walsh P, Scardino P, Lange P, Subong E, Parson R, Gasior G, Loveland K, Southwick P (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 (19): 1542–7. doi:10.1001/jama.279.19.1542. PMID 9605898. 
  15. ↑ Kolota, Gina (May 30, 2004). "It Was Medical Gospel, but It Wasn't True". The New York Times: p. 47. http://www.nytimes.com/2004/05/30/weekinreview/it-was-medical-gospel-but-it-wasn-t-true.html. 
    Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA (May 2004). "Prevalence of prostate cancer among men with a prostate-specific antigen level < or &#61;4.0 ng per milliliter". N. Engl. J. Med. 350 (22): 2239–46. doi:10.1056/NEJMoa031918. PMID 15163773. 
    Carter HB (May 2004). "Prostate cancers in men with low PSA levels--must we find them?". N. Engl. J. Med. 350 (22): 2292–4. doi:10.1056/NEJMe048003. PMID 15163780. 
    Mytrle JF, Klimley PG, Ivor L, Bruni JF (1986). "Clinical utility of prostate specific antigen (PSA) in the management of prostate cancer". Advances in Cancer Diagnostics. San Diego: Hybritech Inc. 
    Mytrle JF, Ivor L (1989). "Measurement of Prostate-Specific Antigen (PSA) in Serum by a Two-Site Immunometric Method (Hybritech Tandem-R/Tandem-E PSA)". In Catalona WJ, Coffey DS, Karr JP (eds.). Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16–19, 1988 at Prout's Neck, Maine, U.S.A.. New York: Elsevier. pp. 161–71. ISBN 0-444-01514-0. 
    Mytrle JF (1989). "Normal Levels of Prostate-Specific Antigen (PSA)". In Catalona WJ, Coffey DS, Karr JP (eds.). Clinical Aspects of Prostate Cancer. Assessment of New Diagnostic and Management Procedures. Proceedings of a workshop of the Prostate Cancer Working Group of the National Cancer Institute's Organ Systems Program, held October 16–19, 1988 at Prout's Neck, Maine, U.S.A.. New York: Elsevier. pp. 183–9. ISBN 0-444-01514-0. 
    Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL (April 1991). "Measurement of prostate-specific antigen in serum as a screening test for prostate cancer". N. Engl. J. Med. 324 (17): 1156–61. PMID 1707140. 
    Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL (May 1994). "Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men". J. Urol. 151 (5): 1283–90. PMID 7512659. 
  16. ↑ Thompson I, Pauler D, Goodman P, Tangen C, Lucia M, Parnes H, Minasian L, Ford L, Lippman S, Crawford E, Crowley J, Coltman C (2004). "Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter". N Engl J Med 350 (22): 2239–46. doi:10.1056/NEJMoa031918. PMID 15163773. 
  17. ↑ Bañez LL, Hamilton RJ, Partin AW, Vollmer RT, Sun L, Rodriguez C, Wang Y, Terris MK, Aronson WJ, Presti JC Jr, Kane CJ, Amling CL, Moul JW, Freedland SJ. (2004). "Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer". JAMA 350 (19): 2275–80. doi:10.1001/jama.298.19.2275. PMID 18029831. 
  18. ↑ Robert Dreicer (2007-11-20). "Why Do Obese Men Have Lower PSA Concentrations?". Journal Watch (New England Journal of Medicine) 2007 (1120): 1. http://oncology-hematology.jwatch.org/cgi/content/full/2007/1120/1. Retrieved 2008-04-27. 
  19. ↑ 19.0 19.1 19.2 Herschman JD, Smith DS, Catalona WJ (August 1997). "Effect of ejaculation on serum total and free prostate-specific antigen concentrations". Urology 50 (2): 239–43. doi:10.1016/S0090-4295(97)00209-4. PMID 9255295. 
  20. ↑ Nadler RB, Humphrey PA, Smith DS, Catalona WJ, Ratliff TL (August 1995). "Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels". J. Urol. 154 (2 Pt 1): 407–13. doi:10.1016/S0022-5347(01)67064-2. PMID 7541857. 
  21. ↑ Crawford ED, Schutz MJ, Clejan S, Drago J, Resnick MI, Chodak GW, Gomella LG, Austenfeld M, Stone NN, Miles BJ (1992). "The effect of digital rectal examination on prostate-specific antigen levels". JAMA 267 (16): 2227–8. doi:10.1001/jama.267.16.2227. PMID 1372943. 
    Chybowski FM, Bergstralh EJ, Oesterling JE (July 1992). "The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study". J. Urol. 148 (1): 83–6. PMID 1377290. 
    Collins GN, Martin PJ, Wynn-Davies A, Brooman PJ, O'Reilly PH (May 1997). "The effect of digital rectal examination, flexible cystoscopy and prostatic biopsy on free and total prostate specific antigen, and the free-to-total prostate specific antigen ratio in clinical practice". J. Urol. 157 (5): 1744–7. doi:10.1016/S0022-5347(01)64849-3. PMID 9112518. 
    Tarhan F, Orçun A, Küçükercan I, Camursoy N, Kuyumcuoğlu U (December 2005). "Effect of prostatic massage on serum complexed prostate-specific antigen levels". Urology 66 (6): 1234–8. doi:10.1016/j.urology.2005.06.077. PMID 16360449. 
  22. ↑ Population based age-specific reference ranges for PSA. D. J. Connolly, A. Black, L. J. Murray, A. Gavin, P. F. Keane. 2007 Prostate Cancer Symposium.
  23. ↑ Carter H, Pearson J, Metter E, Brant L, Chan D, Andres R, Fozard J, Walsh P (1992). "Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease". JAMA 267 (16): 2215–20. doi:10.1001/jama.267.16.2215. PMID 1372942. 
  24. ↑ H. Ballentine Carter (2006). "Assessing Risk: Does This Patient Have Prostate Cancer?" (Editorial). Journal of the National Cancer Institute 98 (8): 506–7. doi:10.1093/jnci/djj155. PMID 16622114. 
  25. ↑ D'Amico A, Chen M, Roehl K, Catalona W (2004). "Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy". N Engl J Med 351 (2): 125–35. doi:10.1056/NEJMoa032975. PMID 15247353. 
  26. ↑ Catalona W, Smith D, Ornstein D (1997). "Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements". JAMA 277 (18): 1452–5. doi:10.1001/jama.277.18.1452. PMID 9145717. 
  27. ↑ 27.0 27.1 27.2 Dale L. Laux, M.S. & Sarah E. Custis (PDF). Forensic Detection of Semen III. Detection of PSA Using Membrane Based Tests: Sensitivity Issues with Regards to the Presence of PSA in Other Body Fluids. Midwestern Association of Forensic Scientists. http://mafs.net/pdf/forensicdetectionsemen3.pdf. Retrieved 2008-05-11. 
  28. ↑ Wimpissinger F, Stifter K, Grin W, Stackl W (September 2007). "The female prostate revisited: perineal ultrasound and biochemical studies of female ejaculate". J Sex Med 4 (5): 1388–93; discussion 1393. doi:10.1111/j.1743-6109.2007.00542.x. PMID 17634056. 
  29. ↑ Stanley A Brosman. eMedicine: Prostate-Specific Antigen. WebMD. http://www.emedicine.com/med/TOPIC3465.HTM#section~CharacteristicsofProstateSpecificAntigen. Retrieved 2008-05-11. 
  30. ↑ Chuang AY, DeMarzo AM, Veltri RW, Sharma RB, Bieberich CJ, Epstein JI (August 2007). "Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma". Am. J. Surg. Pathol. 31 (8): 1246–55. doi:10.1097/PAS.0b013e31802f5d33. PMID 17667550. 
  31. ↑ Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA (May 2004). "Prevalence of prostate cancer among men with a prostate-specific antigen level < or &#61;4.0 ng per milliliter". N. Engl. J. Med. 350 (22): 2239–46. doi:10.1056/NEJMoa031918. PMID 15163773. 
  32. ↑ Moul JW, Banez LL, Freedland SJ (2007). "Rising PSA in Nonmetastatic Prostate Cancer". Oncology 21 (12). http://www.cancernetwork.com/display/article/10165/63133. 
  33. ↑ Hara M, Inorre T, Fukuyama T. (1971). "Some physicochemical characteristics of gamma-seminoprotein, an antigenic component specific for human seminal plasma". Jpn J Legal Med. 25: 322–324. 
  34. ↑ Bill O. Gartside, Kevin J. Brewer & Carmella L. Strong (April 2003). "Estimation of Prostate-Specific Antigen (PSA) Extraction Efficiency from Forensic Samples Using the Seratecâ PSA Semiquant Semiquantitative Membrane Test". Forensic Science Communications 5 (2). http://www.fbi.gov/hq/lab/fsc/backissu/april2003/gartside.htm. Retrieved 2008-05-11. 
  35. ↑ M. Hochmeister, O. Rudin, U.V.Borer, A. Kratzer, Ch. Gehrig and R. Dirnhofer (1997). Evaluation of Prostate-Specific Antigen (PSA) Membrane Tests for the Forensic Identification of Semen. Eighth International Symposium on Human Identification. http://www.promega.com/geneticidproc/ussymp8proc/33.html. Retrieved 2008-05-11. 
  36. ↑ Manfred N. Hochmeister, Bruce Budowle, Oskar Rudin, Christian Gehrig, Urs Borer, Michael Thali, and Richard Dirnhofer (1999). "Evaluation of Prostate-Specific Antigen (PSA) Membrane Test Assays for the Forensic Identification of Seminal Fluid" (PDF). Journal of Forensic Science 44: 1057–60. http://projects.nfstc.org/workshops/resources/articles/Evaluation%20of%20prostate-specific%20antigen%20(PSA)%20membrane%20test%20assays%20for%20the%20forensic%20identification%20of%20seminal%20fluid.pdf. Retrieved 2008-05-11. 
  37. ↑ Christensson, A; Lilja H (February 1994). "Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen". Eur. J. Biochem. (GERMANY) 220 (1): 45–53. doi:10.1111/j.1432-1033.1994.tb18597.x. ISSN 0014-2956. PMID 7509746. 
  38. ↑ Kise, H; Nishioka J, Kawamura J, Suzuki K (May. 1996). "Characterization of semenogelin II and its molecular interaction with prostate-specific antigen and protein C inhibitor". Eur. J. Biochem. (GERMANY) 238 (1): 88–96. doi:10.1111/j.1432-1033.1996.0088q.x. ISSN 0014-2956. PMID 8665956. 

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Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21)
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