ReviewAre multiple markers the future of prostate cancer diagnostics?
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
References (101)
- et al.
Early diagnosis and surgical management of prostate cancer
Cancer Treat. Rev.
(2003) - et al.
Observations on pathology trends in 62,537 prostate biopsies obtained from urology private practices in the United States
Urology
(1998) - et al.
Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria
Urology
(2001) - et al.
The Gleason score shift: score four and seven years ago
Int. J. Radiat. Oncol. Biol. Phys.
(2003) - et al.
The effect of prostatitis, urinary retention, ejaculation, and ambulation on the serum prostate-specific antigen concentration
Urol. Clin. North Am.
(1997) - et al.
Interpretation of free prostate specific antigen clinical research studies for the detection of prostate cancer
J. Urol.
(1998) - et al.
Free prostate-specific antigen in serum is becoming more complex
Urology
(2002) - et al.
Combinations of multiple serum markers are superior to individual assays for discriminating malignant from benign pelvic masses
Gynecol. Oncol.
(1995) - et al.
A precursor form of PSA (pPSA) is a component of the free PSA in prostate cancer serum
Urology
(1997) - et al.
Immunohistochemical staining of prostate cancer with monoclonal antibodies to the precursor of prostate-specific antigen
Urology
(2003)
Proenzyme PSA for the early detection of prostate cancer in the 2.5-4.0 ng/ml total PSA range: preliminary analysis
Urology
Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml
J. Urol.
Characterization of the precursor of prostate-specific antigen-activation by trypsin and by human glandular kallikrein
J. Biol. Chem.
Prostate specific antigen in benign prostatic hyperplasia: purification and characterization
J. Urol.
“BPSA,” a specific molecular form of free prostate-specific antigen, is found predominantly in the transition zone of patients with nodular benign prostatic hyperplasia
Urology
Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. PLESS Study Group
Urology
Prostate tissue composition and response to finasteride in men with symptomatic benign prostatic hyperplasia
J. Urol.
Isolation and characterization of free form prostate specific antigen (f-PSA) in sera of men with prostate cancer
J. Urol.
Measurement of complexed PSA improves specificity for early detection of prostate cancer
Urology
Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer
J. Urol.
Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: relationship to transition zone volume
J. Urol.
Discrimination of men with prostate cancer from those with benign disease by measurements of human glandular kallikrein 2 (HK2) in serum
J. Urol.
Use of human glandular kallikrein 2 for the detection of prostate cancer: preliminary analysis
Urology
In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic “gray zone” of total PSA 4 to 10 ng/mL
Urology
Performance of a neural network in detecting prostate cancer in the prostate-specific antigen reflex range of 2.5 to 4.0 ng/mL
Urology
E-cadherin expression in prostate cancer: a broad survey using high-density tissue microarray technology
Hum. Pathol.
Multi-analyte immunoassay
J. Pharm. Biomed. Anal.
Rapid identification of microorganisms by nucleic acid hybridization after labeling the test sample
Anal. Biochem.
Protein microarrays: meeting analytical challenges for clinical applications
Cancer Cell
High-throughput cell analysis using multiplexed array technologies
Drug Discov. Today
Protein microarray technology
Trends Biotechnol.
Simultaneous quantification of proinflammatory cytokines in human plasma using the LabMAP assay
J. Immunol. Methods
Multiplexed particle-based flow cytometric assays
J. Immunol. Methods
Toward optimized antibody microarrays: a comparison of current microarray support materials
Anal. Biochem.
Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut
BMJ
Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen
N. Engl. J. Med.
Preoperative serum prostate-specific antigen (PSA) below 10 microg/l predicts neither the presence of prostate cancer nor the rate of postoperative PSA failure
Clin. Chem.
Prostate-specific antigen in serum occurs predominantly in complex with α1-antichymotrypsin
Clin. Chem.
A complex between prostate specific antigen and α1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer
Cancer Res.
Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial
JAMA
Pro PSA: a more cancer specific form of prostate specific antigen for the early detection of prostate cancer
Keio J. Med.
The predictive value of a combination of tumor markers in monitoring patients with ovarian cancer
Cancer
Combining diagnostic test results to increase accuracy
Biostatistics
Combining biomarkers to detect disease with application to prostate cancer
Biostatistics
Human tissue kallikreins: a family of new cancer biomarkers
Clin. Chem.
A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue
Cancer Res.
Identification of precursor forms of prostate-specific antigen in serum of prostate cancer patients by immunosorption and mass spectrometry
Cancer Res.
A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer
Cancer Res.
Expression of pro form of Prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallikrein 2
Cancer Res.
Production and activation of recombinant hK2 with propeptide mutations resulting in high expression levels
Eur. J. Biochem.
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Present address: Gen-Probe, San Diego, CA 92121, USA.