| 释义 |
- Medical uses Prostate cancer Screening Risk stratification and staging Post-treatment monitoring Histology Forensic identification of semen
- Mechanism of action
- Biochemistry
- History
- Serum levels PSA velocity Free PSA Inactive PSA Complexed PSA
- PSA in other biologic fluids and tissues
- Interactions
- See also
- References
- Further reading
- External links
{{Infobox gene}}Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), is a glycoprotein enzyme encoded in humans by the KLK3 gene. PSA is a member of the kallikrein-related peptidase family and is secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows sperm to swim freely.[1] It is also believed to be instrumental in dissolving cervical mucus, allowing the entry of sperm into the uterus.[2]PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders.[3] PSA is not a unique indicator of prostate cancer, but may also detect prostatitis or benign prostatic hyperplasia.[4] Medical usesProstate cancerScreening{{main|Prostate cancer screening}}Clinical practice guidelines for prostate cancer screening vary and are controversial due to uncertainty as to whether the benefits of screening ultimately outweigh the risks of overdiagnosis and over treatment.[5] In the United States, 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. The patient needs to be informed of the risks and benefits of PSA testing prior to performing the test (see below). PSA levels between 4 and 10 ng/mL (nanograms per milliliter) are considered to be suspicious and consideration should be given to confirming the abnormal PSA with a repeat test. If indicated, prostate biopsy is performed to obtain tissue sample for histopathological analysis. In the United Kingdom, the National Health Service (2018) does not mandate, nor advise for PSA test, but allows patients to decide based on their doctor's advice.[6]As of 2018 the UK National Health Service did not offer general PSA screening, for similar reasons.[7] While PSA testing may help 1 in 1,000 avoid death due to prostate cancer, 4 to 5 in 1,000 would die from prostate cancer after 10 years even with screening. This means that PSA screening may reduce mortality from prostate cancer by up to 25%. Expected harms include anxiety for 100 – 120 receiving false positives, biopsy pain, and other complications from biopsy for false positive tests. Of those found to have prostate cancer, frequent overtreatment is common because most cases of prostate cancer are not expected to cause any symptoms. Therefore, many will experience the side effects of treatment, such as for every 1000 men screened, 29 will experience erectile dysfunction, 18 will suffer urinary incontinence, 2 will have serious cardiovascular events, 1 will suffer pulmonary embolus or deep venous thrombosis, and 1 perioperative death. Since the expected harm relative to risk of death are perceived by patients as minimal, men found to have prostate cancer usually (up to 90% of cases) elect to receive treatment.[8] Risk stratification and stagingMen with prostate cancer may be characterized as low-, intermediate-, or high-risk for having/developing metastatic disease or dying of prostate cancer. PSA level is one of three variables on which the risk-stratification is based; the others are the grade of prostate cancer (Gleason grading system) and the stage of cancer based on physical examination and imaging studies. D'Amico Criteria for each risk category are as follows:[9] Low-risk: PSA < 10, Gleason score ≤ 6, AND clinical stage ≤ T2a Intermediate-risk: PSA 10-20, Gleason score 7, OR clinical stage T2b/c High-risk: PSA > 20, Gleason score ≥ 8, OR clinical stage ≥ T3 Given the relative simplicity of the 1998 D’Amico criteria (above), other predictive models of risk stratification based on mathematical probability constructs exist or have been proposed to allow for better matching of treatment decisions with disease features.[10] Studies are being conducted into the incorporation of multiparametric MRI imaging results into nomograms that rely on PSA, Gleason grade and tumor stage.[11] Post-treatment monitoringPSA levels are monitored periodically (e.g., every 6–36 months) after treatment for prostate cancer - more frequently in patients with high-risk disease, less frequently in patients with lower-risk disease. If surgical therapy (i.e., radical prostatectomy) is successful at removing all prostate tissue (and prostate cancer), PSA becomes undetectable within a few weeks. A subsequent rise in PSA level above 0.2 ng/mL[12] L{{Disputed inline|Post-treatment_monitoring:_no_references._Incorrect_units.3F|date=February 2014|reason=Should units be ng/mL?}} is generally regarded as evidence of recurrent prostate cancer after a radical prostatectomy; less commonly, it may simply indicate residual benign prostate tissue.{{Citation needed|date=February 2014}} Following radiation therapy of any type for prostate cancer, some PSA levels might be detected, even when the treatment ultimately proves to be successful. This makes it more difficult to interpret the relationship between PSA levels and recurrence/persistence of prostate cancer after radiation therapy. PSA levels may continue to decrease for several years after radiation therapy. The lowest level is referred to as the PSA nadir. A subsequent increase in PSA levels by 2.0 ng/mL{{Disputed inline|Post-treatment_monitoring:_no_references._Incorrect_units.3F|date=February 2014|reason=Should units be ng/mL?}} above the nadir is the currently accepted definition of prostate cancer recurrence after radiation therapy.{{Citation needed|date=February 2014}} If recurrent prostate cancer is detected by a rise in PSA levels after curative treatment, it is referred to as a "biochemical recurrence". The likelihood of developing recurrent prostate cancer after curative treatment is related to the pre-operative variables described in the preceding section (PSA level and grade/stage of cancer). Low-risk cancers are the least likely to recur, but they are also the least likely to have required treatment in the first place.{{Citation needed|date=February 2014}} HistologyPSA is produced in the epithelial cells of the prostate, and can be demonstrated in biopsy samples or other histological specimens using immunohistochemistry. Disruption of this epithelium, for example in inflammation or benign prostatic hyperplasia, may lead to some diffusion of the antigen into the tissue around the epithelium, and is the cause of elevated blood levels of PSA in these conditions.[13] More significantly, PSA remains present in prostate cells after they become malignant. Prostate cancer cells generally have variable or weak staining for PSA, due to the disruption of their normal functioning. Thus, individual prostate cancer cells produce less PSA than healthy cells; the raised serum levels in prostate cancer patients is due to the greatly increased number of such cells, not their individual activity. However, in most cases of prostate cancer, the cells remain positive for the antigen, which can therefore be used to identify metastasis. Since some high-grade prostate cancers may be entirely negative for PSA, however, histological analysis to identify such cases usually uses PSA in combination with other antibodies, such as PSAP and CD57.[13] Forensic identification of semenPSA was first identified by researchers attempting to find a substance in seminal fluid that would aid in the investigation of rape cases.[14] PSA is now used to indicate the presence of semen in forensic serology.[15] 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.[16] 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.[18] 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.[17] 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.[18] 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. Mechanism of action The physiological function of KLK3 is the dissolution of the coagulum, the sperm entrapping gel composed of semenogelins and fibronectin. Its proteolytic action is effective in liquefying the coagulum so that the sperm can be liberated. The activity of PSA is well regulated. In the prostate it is present as an inactive pro-form which is activated through the action of KLK2, another kallikrein-related peptidase. In the prostate, zinc ion concentrations are ten times higher than in other bodily fluids. Zinc ions have a strong inhibitory effect on the activity of PSA and on that of KLK2, so that PSA is totally inactive. Further regulation is achieved through pH variations. Although its activity is increased by higher pH, the inhibitory effect of zinc also increases. The pH of semen is slightly alkaline and the concentrations of zinc are high. On ejaculation, semen is exposed to the acidic pH of the vagina, due to the presence of lactic acid. In fertile couples, the final vaginal pH after coitus approaches the 6-7 levels, which coincides well with reduced zinc inhibition of PSA. At these pH levels, the reduced PSA activity is countered by a decrease in zinc inhibition. Thus, the coagulum is slowly liquefied, releasing the sperm in a well regulated manner. Biochemistry Prostate-specific antigen (PSA, also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen) is a 34-kD glycoprotein produced almost exclusively by the prostate gland. It is a serine protease ({{EC number|3.4.21.77}}) enzyme, the gene of which is located on the 19th chromosome (19q13) in humans.[18] History 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.[19] Flocks was the first to experiment with antigens in the prostate[20] and 10 years later Ablin reported the presence of precipitation antigens in the prostate.[21] In 1971, Mitsuwo 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.[22][23] In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source.[24] In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen').[25] PSA was first measured quantitatively in the blood by Papsidero in 1980,[26] and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer. Serum levelsPSA 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. |archivedate = 2008-04-09}}
16. ^{{cite journal | vauthors = Hochmeister MN, Budowle B, Rudin O, Gehrig C, Borer U, Thali M, Dirnhofer R | title = Evaluation of prostate-specific antigen (PSA) membrane test assays for the forensic identification of seminal fluid | journal = Journal of Forensic Sciences | volume = 44 | issue = 5 | pages = 1057–60 | date = Sep 1999 | pmid = 10486959 }}
17. ^{{cite journal|vauthors=Hochmeister MN, Budowle B, Rudin O, Gehrig C, Borer U, Thali M, Dirnhofer R |title=Evaluation of prostate-specific antigen (PSA) membrane test assays for the forensic identification of seminal fluid |journal=Journal of Forensic Sciences |volume=44 |issue=5 |pages=1057–60 |date=Sep 1999 |pmid=10486959 |url=http://journalsip.astm.org/jofs/PAGES/3097.htm |archive-url=https://web.archive.org/web/20041024194221/http://journalsip.astm.org/jofs/PAGES/3097.htm |dead-url=yes |archive-date=2004-10-24 }}
18. ^{{cite journal | vauthors = Lilja H | title = Biology of prostate-specific antigen | journal = Urology | volume = 62 | issue = 5 Suppl 1 | pages = 27–33 | date = Nov 2003 | pmid = 14607215 | doi = 10.1016/S0090-4295(03)00775-1 }}
19. ^{{cite journal | vauthors = Rao AR, Motiwala HG, Karim OM | title = The discovery of prostate-specific antigen | journal = BJU International | volume = 101 | issue = 1 | pages = 5–10 | date = Jan 2008 | pmid = 17760888 | doi = 10.1111/j.1464-410X.2007.07138.x }}
20. ^{{cite journal | vauthors = Flocks RH, Boatman DL, Hawtrey CE | title = Tissue specific isoantigens in the dog prostate | journal = Investigative Urology | volume = 10 | issue = 3 | pages = 215–20 | date = Nov 1972 | pmid = 4629646 | doi = }}
21. ^{{cite journal | vauthors = Ablin RJ, Soanes WA, Gonder MJ | title = Immunologic studies of the prostate. A review | journal = International Surgery | volume = 52 | issue = 1 | pages = 8–21 | date = Jul 1969 | pmid = 4977978 | doi = }}
22. ^{{cite journal | vauthors = Li TS, Beling CG | title = Isolation and characterization of two specific antigens of human seminal plasma | journal = Fertility and Sterility | volume = 24 | issue = 2 | pages = 134–44 | date = Feb 1973 | pmid = 4631694 | doi = }}
23. ^{{cite journal | vauthors = Li TS, Beling CG | title = The effect of antibodies to two human seminal plasma-specific antigens on human sperm | journal = Fertility and Sterility | volume = 25 | issue = 10 | pages = 851–6 | date = Oct 1974 | pmid = 4213812 | doi = }}
24. ^{{cite journal | vauthors = Sensabaugh GF | title = Isolation and characterization of a semen-specific protein from human seminal plasma: a potential new marker for semen identification | journal = Journal of Forensic Sciences | volume = 23 | issue = 1 | pages = 106–15 | date = Jan 1978 | pmid = 744956 | doi = }}
25. ^{{cite journal | vauthors = Wang MC, Valenzuela LA, Murphy GP, Chu TM | title = Purification of a human prostate specific antigen | journal = Investigative Urology | volume = 17 | issue = 2 | pages = 159–63 | date = Sep 1979 | pmid = 89106 | doi = }}
26. ^{{cite journal | vauthors = Kuriyama M, Wang MC, Papsidero LD, Killian CS, Shimano T, Valenzuela L, Nishiura T, Murphy GP, Chu TM | title = Quantitation of prostate-specific antigen in serum by a sensitive enzyme immunoassay | journal = Cancer Research | volume = 40 | issue = 12 | pages = 4658–62 | date = Dec 1980 | pmid = 6159971 }}
27. ^{{cite news | first = Kolota | last = Gina | name-list-format = vanc |date=May 30, 2004 |title=It Was Medical Gospel, but It Wasn't True |work=The New York Times |page=47 |url=https://www.nytimes.com/2004/05/30/weekinreview/it-was-medical-gospel-but-it-wasn-t-true.html }}
* {{cite journal | vauthors = Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA | title = Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter | journal = The New England Journal of Medicine | volume = 350 | issue = 22 | pages = 2239–46 | date = May 2004 | pmid = 15163773 | doi = 10.1056/NEJMoa031918 }}* {{cite journal | vauthors = Carter HB | title = Prostate cancers in men with low PSA levels--must we find them? | journal = The New England Journal of Medicine | volume = 350 | issue = 22 | pages = 2292–4 | date = May 2004 | pmid = 15163780 | pmc = 3474980 | doi = 10.1056/NEJMe048003 }}*{{cite book |vauthors=Myrtle JF, Klimley PG, Ivor L, Bruni JF |year=1986 |chapter=Clinical utility of prostate specific antigen (PSA) in the management of prostate cancer |title=Advances in Cancer Diagnostics |location=San Diego |publisher=Hybritech Inc}}*{{cite book |vauthors=Mytrle JF, Ivor L |year=1989 |chapter=Measurement of Prostate-Specific Antigen (PSA) in Serum by a Two-Site Immunometric Method (Hybritech Tandem-R/Tandem-E PSA) |editors=Catalona WJ, Coffey DS, Karr JP (eds.) |title=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. |location=New York |publisher=Elsevier |isbn=978-0-444-01514-3 |pages=161–71}}*{{cite book |author=Mytrle JF |year=1989 |chapter=Normal Levels of Prostate-Specific Antigen (PSA) |editors=Catalona WJ, Coffey DS, Karr JP (eds.) |title=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. |location=New York |publisher=Elsevier |isbn=978-0-444-01514-3 |pages=183–9}}* {{cite journal | vauthors = Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL | title = Measurement of prostate-specific antigen in serum as a screening test for prostate cancer | journal = The New England Journal of Medicine | volume = 324 | issue = 17 | pages = 1156–61 | date = Apr 1991 | pmid = 1707140 | doi = 10.1056/NEJM199104253241702 }}* {{cite journal | vauthors = Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL | title = 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 | journal = The Journal of Urology | volume = 151 | issue = 5 | pages = 1283–90 | date = May 1994 | pmid = 7512659 | doi = }}
28. ^{{cite journal | vauthors = Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA | title = Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter | journal = The New England Journal of Medicine | volume = 350 | issue = 22 | pages = 2239–46 | date = May 2004 | pmid = 15163773 | doi = 10.1056/NEJMoa031918 }}
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30. ^{{cite journal | last = Robert Dreicer | title = Why do obese men have lower PSA concentrations? | journal = Journal Watch | date = 2007-11-20 | url = http://oncology-hematology.jwatch.org/cgi/content/full/2007/1120/1 | accessdate = 2008-04-27 | volume = 2007 | issue = 1120 | pages = 1 | archive-url = https://web.archive.org/web/20080217021312/http://oncology-hematology.jwatch.org/cgi/content/full/2007/1120/1 | archive-date = 2008-02-17 | dead-url = yes | df = }}
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{{cite journal | vauthors = Chybowski FM, Bergstralh EJ, Oesterling JE | title = The effect of digital rectal examination on the serum prostate specific antigen concentration: results of a randomized study | journal = The Journal of Urology | volume = 148 | issue = 1 | pages = 83–6 | date = Jul 1992 | pmid = 1377290 | doi = }}
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{{cite journal | vauthors = Tarhan F, Orçun A, Küçükercan I, Camursoy N, Kuyumcuoğlu U | title = Effect of prostatic massage on serum complexed prostate-specific antigen levels | journal = Urology | volume = 66 | issue = 6 | pages = 1234–8 | date = Dec 2005 | pmid = 16360449 | doi = 10.1016/j.urology.2005.06.077 }}
35. ^1 2 3 4 5 6 7 8 9 10 11 12 {{cite journal | vauthors = Connolly D, Black A, Murray L, Gavin A, Keane P | year = 2007 | title = 798 Population Based Age-Specific Reference Ranges for PSA |journal=European Urology Supplements |volume=6 |issue=2 |pages=222 |doi=10.1016/S1569-9056(07)60793-3}}
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56. ^{{cite journal | vauthors = Christensson A, Lilja H | title = Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen | journal = European Journal of Biochemistry / FEBS | volume = 220 | issue = 1 | pages = 45–53 | date = Feb 1994 | pmid = 7509746 | doi = 10.1111/j.1432-1033.1994.tb18597.x }}
57. ^{{cite journal | vauthors = Kise H, Nishioka J, Kawamura J, Suzuki K | title = Characterization of semenogelin II and its molecular interaction with prostate-specific antigen and protein C inhibitor | journal = European Journal of Biochemistry / FEBS | volume = 238 | issue = 1 | pages = 88–96 | date = May 1996 | pmid = 8665956 | doi = 10.1111/j.1432-1033.1996.0088q.x }}
Further reading {{Refbegin | 2}}- {{cite journal | vauthors = De Angelis G, Rittenhouse HG, Mikolajczyk SD, Blair Shamel L, Semjonow A | title = Twenty Years of PSA: From Prostate Antigen to Tumor Marker | journal = Reviews in Urology | volume = 9 | issue = 3 | pages = 113–23 | year = 2007 | pmid = 17934568 | pmc = 2002501 | doi = }}
- {{cite journal | vauthors = Henttu P, Vihko P | title = Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate | journal = Annals of Medicine | volume = 26 | issue = 3 | pages = 157–64 | date = Jun 1994 | pmid = 7521173 | doi = 10.3109/07853899409147884 }}
- {{cite journal | vauthors = Diamandis EP, Yousef GM, Luo LY, Magklara A, Obiezu CV | title = The new human kallikrein gene family: implications in carcinogenesis | journal = Trends in Endocrinology and Metabolism | volume = 11 | issue = 2 | pages = 54–60 | date = Mar 2000 | pmid = 10675891 | doi = 10.1016/S1043-2760(99)00225-8 }}
- {{cite journal | vauthors = Lilja H | title = Biology of prostate-specific antigen | journal = Urology | volume = 62 | issue = 5 Suppl 1 | pages = 27–33 | date = Nov 2003 | pmid = 14607215 | doi = 10.1016/S0090-4295(03)00775-1 }}
{{Refend}} External links - The MEROPS online database for peptidases and their inhibitors: S01.162
- American Cancer Society: Detailed Guide: Prostate Cancer [https://web.archive.org/web/20060901162604/http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_Can_prostate_cancer_be_found_early_36.asp Can Prostate Cancer Be Found Early?]
- National Cancer Institute: The Prostate-Specific Antigen (PSA) Test: Questions and Answers
- {{MeshName|Prostate-Specific+Antigen}}
- [https://web.archive.org/web/20090308005134/http://www.prostateuk.org/psa/psa.htm Prostate UK] Help us stop prostate diseases ruining lives
- PSA at Lab Tests Online
- Total PSA ELISA assay procedure
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