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Twenty Years of Prostate-specific Antigen – An Historical View
European Oncology Review, 2005:54-6
The determination of prostate-specific antigen (PSA) is credited with dramatic advances in the early detection of prostate cancer. Although considerable efforts have been undertaken to improve the ability to diagnose prostate cancer, screening and staging abilities remain inadequate. PSA remains essential for prostate cancer diagnosis and management although it continues to be a source of controversy and debate when used as a screening tool. This article summarises the history of biochemical research and current status of PSA in tumour diagnostics.
Citation European Oncology Review, 2005:54-6
From Antigen to Tumour Marker
In the 1960s, antigens were characterised in prostate tissue extracts with properties of prostate organ specificity.1 Independently, between 1966 and 1971, the Japanese team of Hara et al. identified a prostatespecific protein in seminal fluid – gamma seminoprotein.2 An assay for gamma seminoprotein was developed for forensic use in rape cases. In 1978, Sensabaugh purified a prostate-specific protein from seminal fluid (p30), which was also used for forensic purposes.3 Following the discovery of prostate antigen in prostate cancer tissue and sera by Wang et al. at Roswell Park Memorial Institute in 1979, the question of whether gamma seminoprotein, p30 and a protein with similar properties, E1 antigen, represented the same protein as prostate antigen was the focus of numerous studies. In 1992 it was determined that all of these proteins had identical amino acid sequences and were therefore encoded by the same gene.4 It is now recognised that gamma seminoprotein, p30 and E1 are the same as ‘prostatic antigen protein’ identified by Dr Chu’s laboratory in prostate cancer patients and subsequently known as PSA. In 1979, for the first time, the working group headed by Wang reported on the immuno-precipitation of an antigen from a pool of normal hypertrophic and malignant prostate tissue. Wang et al. were able to show that this antigen is clearly prostate-localised, i.e. it is not detected in other tissues. It was also shown that PSA differed immunologically and chemically from prostatic acid phosphatase (PAP), which had been used since 1938 for diagnosis of prostate cancer.5
Lilja et al.6 revealed the probable physiological function of PSA. In the seminal fluid, PSA cleaves the gel-forming proteins from the seminal vesicles, initiating liquification of the gel-like ejaculate, thereby increasing the motility of sperm cells and aiding fertilisation. Due to the great similarity of PSA to other serine proteases Watt et al. proposed that PSA would be secreted from the cell like other serine proteases as a precursor form. It was not until much later in 1997 that the precursor form, proPSA, was indeed discovered in prostate tissue and serum. In 1997 Thomas Takayama,7 Abhay Kumar8 and Janita Lövgren9 produced the PSA precursor, proPSA, in recombinant form and reported that the secreted precursor form is activated extracellularily by hK2.
First Steps to Clinical Application
In 1980, Papsidero et al.10 found that PSA also occurs in the serum of patients with prostate cancer, i.e. not only in the prostate tissue and seminal plasma. Using an insensitive immunoelectrophoresis method that detected a minimum of 0.5µg/mL PSA. PSA was detected in the serum using this technique in only 17 of the 219 patients with prostate cancer. In 1980, Kuriyama et al. reported the first sensitive PSA immunoassay with a much higher clinical sensitivity for prostate cancer. However, it was soon discovered that elevated levels of PSA also often occurred in noncancer patients with enlarged prostate glands. The lack of specificity of PSA for prostate cancer significantly delayed clinical application, but many clinicians around the world started to use PSA in the late 1980s, mostly in conjunction with PAP. However, PAP has now been replaced by PSA for diagnosis and monitoring of prostate cancer.
- Ablin R J, “On the identification and characterization of prostate-specific antigen [letter]”, Hum. Pathol. (1993);24: pp. 811–812.
- Hara M, Inoue T, Koyanagi Y, “Preparation and immunoelectrophoretic assessment of antisera to human seminal plasma”, Jpn. J. Legal Med. (1966);20: p. 356.
- Sensabaugh G F, “Isolation and characterization of a semen-specific protein from human seminal plasma: A potential new marker for semen identification”, J. Forensic Sci. (1978);23: pp. 106–115.
- Sokoll L J, Chan D W, “Prostate-specific antigen. Its discovery and biochemical characteristics”, Urol. Clin. North Am. (1997);24: pp. 253–259.
- Wang M C, Valenzuela L A, Murphy G P, Chu T M, “Purification of a human prostate specific antigen”, Invest. Urol. (1979);17, pp. 159–163.
- Lilja H, “A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein”, J. Clin. Invest. (1985);76: pp. 1,899–1,903.
- Takayama T K, Fujikawa K, Davie E W, “Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein”, J. Biol. Chem. (1997);272: pp. 21,582–21,588.
- Kumar A, Mikolajczyk S D, Goel A S, Millar L S, Saedi M S, “Expression of pro form of prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallikrein 2”, Cancer Res. (1997);57: pp. 3,111–3,114.
- Lövgren J, Rajakoski K, Karp M, Lundwall A, Lilja H, “Activation of the zymogen form of prostate-specific antigen by human glandular kallikrein 2”, Biochemical & Biophysical Research Communications (1997);238: pp. 549–555.
- Papsidero L D, Wang M C, Valenzuela L A, Murphy G P, Chu T M, “A prostate antigen in sera of prostatic cancer patients”, Cancer Res. (1980);40: pp. 2,428–2,432.
- Semjonow A, De Angelis G, Oberpenning F, Schmid H-P, Brandt B, Hertle L, “The clinical impact of different assays for prostate specific antigen”, BJU Int. (2000);86: pp. 590–597.
- Semjonow A, Schmid H P, “The rise and fall of PSA: clinical implications of prostate specific antigen kinetics”, Urol. Res. (2002);30: pp. 85–88.
- Rittenhouse H G, Finlay J A, Mikolajczyk S D, Partin A W, “Human kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate”, Crit. Rev. Clin. Lab. Sci. (1998);35: pp. 275–368.
- Theodorescu D, Fliser D, Wittke S, Mischak H, Krebs R, Walden M, Ross M, Eltze E, Bettendorf O, Wülfing C, Semjonow A, “Pilot study of capillary electrophoresis coupled to mass spectrometry as a tool to define potential prostate cancer biomarkers in urine”, Electrophoresis (2005);26: pp. 2,797–2,808.