Discovery and validation of prostate cancer biomarkers

The prostate, derived from the Greek word προστάτης – prostates, meaning “the one who stands before”, is a walnut-sized exocrine gland, part of the male genitourinary tract. It produces and stores an alkaline fluid, which liquefies the semen and prolongs the life-span of the spermatozoa. Anatomically, the prostate is located underneath the bladder and in front of the rectum, surrounding the urethra. The prostate can be divided into four distinct zones: the peripheral zone, the central zone, the transition zone and the anterior fibromuscular zone. The majority of prostate cancers (PCa) originate from the peripheral zone. The transition zone is responsible for the disease of benign prostatic hyperplasia (BPH). The epithelial cells of the prostate gland produce prostate-specific antigen (PSA), a 34kD glycoprotein. It is also known as kallikrein III (KLK3), seminin, semenogelase, γ-seminoprotein or P-30 antigen. PSA is the protein in prostate fluid which is responsible for the lysis of the gel proteins, resulting in the liquefaction of the semen. In 1971, PSA was discovered by a Japanese research group as a result from a forensic search to identify specific proteins present in the ejaculate and was originally named γ-seminoprotein. Later, PSA was specifically linked to the prostate and prostatic disease and was shown to be almost exclusively present in the epithelial cells of the prostate. PSA was first measured quantitatively in human serum by Papsidero and Kuriyama et al. in 1980. Normally, PSA is confined within the prostate and only a minute amount leaks into the circulation. In men with PCa, PSA serum levels may be increased. Unlike what might be expected, these elevated serum concentrations in PCa patients are not the result of increased expression of PSA but of an increased release of PSA in the bloodstream, most likely resulting from disruption of the prostate architecture in PCa (Figure 1). As PSA is prostate-specific but not PCa-specific, increased PSA serum levels may also result from prostatitis, irritation or BPH. The clinical usefulness of PSA in PCa detection was first shown by Stamey et al. in 1987, who carried out the initial clinical validation.

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