Prostate-specific antigen

Kallikrein-related peptidase 3

Crystallographic structure of human prostate-specific antigen (green/gold cartoon) covalently attached to an substrate acyl intermediate (multicolor sticks, carbon = white, nitrogen = blue, oxygen = red) and an glucosamine–manose disaccharide (spheres, carbon = yellow and oxygen = red).[1]
Identifiers
Symbols KLK3; APS; KLK2A1; PSA; hK3
External IDs OMIM: 176820 MGI: 892021 HomoloGene: 84789 GeneCards: KLK3 Gene
EC number 3.4.21.77
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 354 16617
Ensembl ENSG00000142515 ENSMUSG00000063713
UniProt P07288 O35307
RefSeq (mRNA) NM_001030047.1 XM_001000656
RefSeq (protein) NP_001025218.1 XP_001000656
Location (UCSC) Chr 19:
51.36 – 51.36 Mb		 Chr 7:
44.06 – 44.06 Mb
PubMed search [1] [2]

Prostate-specific antigen (PSA) also known as gamma-seminoprotein or kallikrein-3 (KLK3) is a glycoprotein that in humans is encoded by the KLK3 gene. KLK3 is a member of the kallikrein-related peptidase family secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate where it liquifies the semen in the seminal coagulum and allows sperm to swim freely.[2] It is also believed to be instrumental in dissolving the cervical mucous, allowing the entry of sperm.[3]

PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer and in other prostate disorders. While frequently used for prostate cancer screening, the United States Preventive Services Task Force (USPSTF) does not recommend its use in healthy men.[4] This USPSTF recommendation, released in October 2011, is based on "review of evidence" studies concluding that "Prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary."[5] In those with prostate cancer, rising levels of PSA over time are associated with both localized and metastatic prostate cancer (CaP). Prostate test screening is controversial and may lead to unnecessary, even harmful, consequences in some patients.[6]

Contents

Mechanism of action

The physiological function of KLK3 is the dissolution of the coagulum, the sperm entrapping gel composed of semenogelins and fibronectin. Its proteolic 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 liquified, 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 3.4.21.77) enzyme, the gene of which is located on the nineteenth chromosome (19q13) in humans.[7]

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.[8]

Flocks was the first to experiment with antigens in the prostate[9] and 10 years later Albin reported the presence of precipitation antigens in the prostate.[10]

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.[11][12]

In 1978, Sensabaugh identified semen-specific protein p30, but proved that it was similar to E1 protein, and that prostate was the source.[13] In 1979, Wang purified a tissue-specific antigen from the prostate ('prostate antigen').[14]

PSA was first measured quantitatively in the blood by Papsidero in 1980,[15] and Stamey carried out the initial work on the clinical use of PSA as a marker of prostate cancer.

Serum PSA

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.[16]

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.[17]

Obesity has been reported to reduce serum PSA levels.[18] Delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.[19]

PSA levels can be also increased by prostatitis, irritation, benign prostatic hyperplasia (BPH), and recent ejaculation,[20][21] producing a false positive result. Digital rectal examination (DRE) has been shown in several studies[22] 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:[23]

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

PSA velocity

Despite earlier findings,[25] recent research suggests that the rate of increase of PSA (the 'PSA velocity') is not a more specific marker for prostate cancer,[26] e.g. >0.35 ng/mL/yr [27]

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.[28]

Free PSA

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.[29] However, both total and free PSA increase immediately after ejaculation, returning slowly to baseline levels within 24 hours.[20]

Inactive PSA

The PSA test in 1994 failed to differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the commercial assay kits for PSA did not provide correct PSA values. [30] Thus with the introduction of the ratio of free to total PSA, the reliability of the test has improved and measuring the activity of the enzyme could add to the ratio of free to total PSA and further improve the diagnostic value of test. [31] Proteolytically active PSA has been shown to have an anti-angiogenic effect [32] and certain inactive subforms may be associated with prostate cancer, as shown by MAb 5D3D11, an antibody able to detect forms abundantly represented in sera from cancer patients. [33] The presence of inactive proenzyme forms of PSA is another potential indicator of disease. [34]

PSA in other biologic fluids and tissues

Concentration of PSA in human body fluids
Fluid PSA (ng/mL)
semen
200,000 - 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 - 0.53

It is now clear that the term prostate-specific antigen is a misnomer: it is an antigen but is not specific to the prostate. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues.[35]

In women, PSA is found in female ejaculate at concentrations roughly equal to that found in male semen.[36] 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.[37]

Tissue samples can be stained for the presence of PSA in order to determine the origin of malignant cells that have metastasized.[38]

Uses of PSA

Prostate cancer

Screening

Main article: Prostate cancer screening

A recent published study[39] concluded "After 20 years of follow-up the rate of death from prostate cancer did not differ significantly between men in the screening group and those in the control group".

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. 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. The independent US Preventive Services Task Force rated the PSA test as "I", meaning it "found insufficient evidence to recommend either for or against screening"; for men aged 75 years or older, the rating is "D", meaning it found more reasons to advise against it.[40] In the United Kingdom, the National Health Service does not mandate, nor advise for PSA test, but allows patients to decide based on their doctor's advice.[41] 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).[42] A 1997 report indicated that refraining from ejaculation 24 hours or more prior to testing would improve test accuracy.[20]

Risk stratification and staging

Patients with localized (non-metastatic) prostate cancer have traditionally been characterized as low-, intermediate-, or high-risk for failure of curative treatment and prostate cancer mortality. 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 clinical investigations (as opposed to examination of surgical pathology). Criteria for each risk category are as follows:

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

Researchers are working to identify more accurate prognostic variables for risk-stratification of men with prostate cancer.

Post-treatment monitoring

PSA levels are monitored periodically (usually every 6–12 months) after treatment for prostate cancer. 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/dL is generally regarded as evidence of recurrent prostate cancer after a radical prostatectomy; less commonly, it may simply indicate residual benign prostate tissue.

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/dL above the nadir is the currently accepted definition of prostate cancer recurrence after radiation therapy.

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 correlated to various risk factors, such as the grade of prostate cancer (Gleason score), PSA level prior to treatment, and the stage of disease prior to treatment. Patients with low-grade cancer (Gleason score ≤ 6), PSA < 10, and tumors that are not palpable by digital rectal examination are at the lowest risk of recurrence.

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.[43] PSA is now used to indicate the presence of semen in forensic serology.[44] 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.[45]

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.[35] 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.[46] 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.[35] 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.[47][48]

See also

References

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