Elsevier

Clinical Biochemistry

Volume 37, Issue 7, July 2004, Pages 519-528
Clinical Biochemistry

Review
Are multiple markers the future of prostate cancer diagnostics?

https://doi.org/10.1016/j.clinbiochem.2004.05.016Get rights and content

Abstract

Prostate specific antigen (PSA) is the most successful and widely employed cancer serum marker in use today. There is growing evidence that the introduction of wide PSA screening and earlier detection can result in decreased cancer mortality associated with a decline in metastatic disease. PSA circulates in a number of distinct forms. Measurement of these in addition to total PSA significantly increases diagnostic utility. Diagnostic utility is likely to be further increased by adding kallikreins, cytokines, growth factors, receptors and cellular adhesion factors to the biomarker panel. The need for multiple markers reflects the multidimensional nature of prostate disease which ranges from metastatic cancer to indolent cancer to benign hyperplasia and inflammation, all of which require distinct treatments and medical interventions.

Section snippets

Pro-PSA: a cancer-associated form of free PSA

Several investigations have demonstrated precursor forms of PSA (pPSA) in the serum of men with prostate cancer [20], [21], [22]. There are also significant levels of truncated pPSA, which refers to pPSA in which any of the normal 7 aa's in the proleader peptide have been removed. The truncated pPSA forms containing proleader peptides of 4 and 2 amino acids, [-4]pPSA and [-2]pPSA, respectively, are of particular interest. Truncated pPSA forms are more resistant to activation to mature PSA than

BPSA, a biomarker of benign prostate disease

The PSA in BPH tissues and seminal plasma has been shown to have higher levels of internal peptide bond cleavages and is more enzymatically inactive [30], [31], [32]. A distinct degraded form of PSA termed benign PSA (BPSA) has been identified in BPH tissue. BPSA concentrations were relatively lower in cancer tissue from the same prostate [33]. BPSA is highly correlated with the presence of BPH nodules in the prostate, the primary pathological feature of BPH [33]. BPSA contains two internal

Other forms of PSA in Serum

It is evident from preliminary studies using quantitative immunoassays for BPSA and pPSA that these PSA forms do not, in general, account for all of the free PSA forms in serum. Together the BPSA and sum of pPSA forms typically compose about 40–60% of the free PSA [13], though individual specimens can be much higher or lower. The remaining inactive forms of PSA are thought to be composed mainly of PSA that is intact but nonnative, or denatured, and has been designated intact, nonnative PSA

Prostatic kallikreins

The prostate-specific kallikrein hK2 is 80% identical with PSA but has distinct biochemical properties [47]. Several immunoassays specific for hK2 have now been developed [48], [49], [50], [51]. Serum hK2 typically represents 1–2% of serum PSA concentration. However, the hK2 is not directly proportional to PSA and it improves the discrimination of cancer in combination with total PSA and free PSA [52], [53]. HK2 also appears to serve as a marker for aggressiveness [54] and has shown some

Proteins associated with prostate cancer

Host response cytokines and growth factors may also be viable candidates for biomarker prostate panels. Transforming growth factor-beta has been shown to have multiple effects on epithelial cell proliferation in the prostate [64]. Plasma levels of TGF-beta in combination with interleukin 6 soluble receptor (IL6SR), which also can regulate cell proliferation [65], are markedly elevated in metastatic prostate cancer patients. Utilizing a biomarker panel containing PSA, TGF-beta, and IL6SR, Kattan

Multiplexed assay formats

In a multiplexed assay, several parameters or analytes are measured simultaneously in a single reaction, for example, performing a series of ELISAs for different cytokines within the same well of a microtiter plate, or carrying out PCR amplification of multiple alleles in genomic DNA within a single tube reaction by using a pool of primer sets. The concept of the multiplexed immunosorbent assay was first described by Ekins [73] more than a decade ago; while Dattagupta et al. [74] first

Selective proteomic profiles

The prostatic proteins and serum markers described in this review represent a diversity of candidates for the study and diagnostic evaluation of prostate disease. Some were identified through the newer genomic and proteomic techniques [97], while others were identified and investigated from existing paradigms. With the explosion in new potential markers discovered through genomic and proteomic technologies, the use of multiple markers to increase specificity is sure to become more common. In

Summary

It is unlikely that the use of the PSA test will diminish anytime soon and in fact should be bolstered and augmented by the myriad of new prostate cancer markers. PSA has already shown significant increases in diagnostic utility in combination with free PSA, complexed PSA, BPSA, and pro-PSA and is likely to provide even greater diagnostic value with additional prostate kallikreins such as hK2, hK4, and hK15 and with cytokines, growth factors, receptors, and cellular adhesion factors as

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    Present address: Gen-Probe, San Diego, CA 92121, USA.

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