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Articles |
Departments of
1
Urology,
2
Laboratory Medicine and Pathobiochemistry, and
3
Pathology, University Hospital Charité, Humboldt University, Schumannstrasse 20/21, D-10098 Berlin, Germany.
a Author for correspondence. Fax 49-30-2802-1402; e-mail klaus.jung{at}charite.de
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: Prostatic tissue samples were obtained after
cystoprostatectomy from patients with bladder cancer (n = 10),
from BPH patients (transurethral resection of the prostate, n =
10; adenomectomy, n = 10), and from the cancerous and noncancerous
parts of the same prostates removed surgically by prostatectomy because
of PCa (n = 20). PSA pattern was characterized by gel filtration,
immunoblotting, and immunoassays for tPSA, fPSA,
1-antichymotrypsin-PSA (ACT-PSA), and complexed PSA
(Bayer Immuno 1 assay). Comparisons were made with the PSA
concentrations in serum.
Results: The major portion of tPSA in all tissue samples was fPSA; complexed PSA forms were <2%. Samples from cystoprostatectomy patients had the lowest and those from adenomectomy patients the highest values of tPSA and fPSA. PSA concentrations were lower in cancerous than in the noncancerous parts of the prostate. No significant correlations were found between tumor stage or grade and the amounts of tPSA, fPSA, and ACT-PSA in tissue. Tissue PSA values were not correlated with the serum PSA concentrations nor with the ratios fPSA/tPSA and ACT-PSA/tPSA in sera.
Conclusions: The amounts of tPSA and the PSA isoforms in prostatic tissue explain neither the concentrations of tPSA and PSA isoforms in serum nor the behavior of the ratio fPSA/tPSA in patients with BPH and PCa.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-antichymotrypsin (ACT),
and a small amount is complexed with
1-antitrypsin and protein C. The portion of
PSA that is complexed with 2-macroglobulin can
be measured only if the complex is cleaved and the PSA epitopes become
accessible. Free PSA (fPSA), the portion of PSA not bound to serum
proteins, accounts for 10–30% of tPSA. A lower ratio of fPSA to tPSA
(fPSA/tPSA) in patients with prostate cancer (PCa) has been
demonstrated in numerous studies [reviewed in Ref. (3)].
This ratio has been considered as a helpful tool for distinguishing
between PCa and benign prostatic hyperplasia (BPH). Several factors that influence the ratio fPSA/tPSA in serum, e.g., age, prostate size, drug treatment, prostate manipulation, sample stability, or assay method, have been reviewed recently (4)(5). However, the reason for the changed ratio in PCa patients has not yet been clarified on a molecular basis, although some hypotheses exist (6). Thus, the reduced ratio may be attributable to differences at the cellular level: (a) a changed synthesis of ACT in neoplastic cells compared with benign cells (7), leading to increased formation of ACT-PSA complex early in malignant cells before release into circulation; (b) the release of different proportions of enzymatically inactive PSA that react differently with ACT in the circulation (6)(8); and (c) the alteration of the glycosylation rate of PSA in neoplastic cells, leading to characteristic differences of the elimination kinetics of the PSA isoforms from blood (9).
Because these models have not been clarified in detail, our investigation had three objectives: (a) to assess the pattern of the main intracellular PSA isoforms in both malignant and benign prostatic tissue, using various biochemical techniques; (b) to evaluate the relationships between the intracellular PSA pattern and the occurrence of the serum PSA isoforms in patients with PCa and BPH; and (c) to infer from these results whether the intracellular PSA pattern determines the typical fPSA/tPSA ratio in serum of patients with PCa and BPH.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Groups investigated.
A total of 50 men were studied,
including a group of 10 men (median age, 61 years; range, 44–72 years)
undergoing cystoprostatectomy for bladder cancer with a histologically
confirmed absence of PCa (group CYS), 20 patients with BPH (median age,
71 years; range, 63–81 years), and 20 with PCa (median age, 65 years;
range, 57–71 years). Ten of the BPH patients underwent transurethral
resection of the prostate (group TUR-P), and 10 had open adenomectomies
(group ADE). Each PCa patient had been classified according to the TNM
system, and the histological grade had been classified as grade 1, 2,
or 3. The number of patients in each classification according to
pathological stages and grades were as follows: pT2 pN0M0, n = 14;
pT3 pN0M0, n = 6; G1, n = 2; G2, n = 14; and G3, n
= 4.
Blood samples.
Blood samples were taken before diagnostic
procedures of the prostate or 4 weeks (at the earliest) after digital
rectal examination, prostatic biopsy, and transrectal ultrasound. The
samples were collected in evacuated tubes (Monovette 03.1528; Sarstedt
GmbH) and were centrifuged at 1600g for 15 min at 4 °C
after the blood had clotted for 1 h at room temperature. The sera
were frozen at -80 °C within 2 h after collection and were not
thawed (and refrozen) before being tested within 12 weeks.
Tissue samples.
Prostate tissue samples were obtained from the
cancerous and noncancerous parts of the same prostates that had
been surgically removed by radical prostatectomy so that matched pairs
were used. Small pieces of tissue were dissected immediately after
removal of the prostate and stored in liquid nitrogen until analysis.
The cut edges within the prostate were inked so that the dissected
pieces could easily be assigned to the adjacent prostate tissue
examined histopathologically. Similarly, prostate tissue material from
cystoprostatectomies, adenomectomies, and transurethral resections were
collected. Histological analysis from all tissue pieces used was
performed by clinical pathologists (B.R. and G.K.) as described
previously in detail to ensure that the material used was either
malignant or nonmalignant tissue (4).
Preparation of tissue extracts.
Tissue samples (~30–50 mg)
were thawed, cut into small pieces, and homogenized in 100 µL of 10
mmol/L sodium phosphate buffer, pH 7.46, containing 2.5 mL/L
Triton X-100 with a Wheaton glass homogenizer by 10 strokes on ice and
were additionally sonicated. The homogenate was transferred into a
1.5-mL tube (Eppendorf GmbH). The homogenizer was rinsed twice
with 100 µL of Triton solution. This mixture of 300 µL was
centrifuged at 23 000g for 15 min at 4 °C. The
supernatant was removed. To investigate the effect of the
extraction procedure, the pellet was resuspended and the extraction was
repeated several times. The recommended final extraction procedure
consisted of three extractions with Triton solution and the
measurements of the analytes in the combined supernatants. All
supernatants were stored at -80 °C until analysis.
Additional samples investigated.
To compare the results
obtained with samples described in the study groups, the following
specimens were used: a serum with high PSA concentration (2170 µg/L)
from a patient with advanced PCa; seminal plasma; and purified PSA from
human seminal fluid (Calbiochem-Novabiochem) incubated at 37 °C for
3 h with either 50 mmol/L phosphate buffer, pH 7.4, containing 50
g/L human serum albumin (Serva Feinbiochemica) or with a female serum
pool. All samples were stored at -80 °C until used.
procedures
Immunoassays for PSA.
As indicated in the text, tPSA was
measured with the Roche Elecsys PSA Immunoassay (Roche Diagnostics),
the IMMULITE PSA assay (Diagnostic Products), the AxSYM PSA assay
(Abbott Diagnostics), or the Bayer Immuno 1 PSA Assay (Bayer
Diagnostics). fPSA was measured with the IMMULITE Free PSA kit, the
Roche Elecsys Free PSA Immunoassay, or the AxSYM Free PSA assay.
According to the information provided by the manufacturers, all tests
are equimolar assays for determining PSA. To measure complexed PSA
(cPSA), a recently introduced immunoassay ( product no. T01-3982-51;
Bayer Diagnostics) for the Bayer Immuno 1 system was used
(10). This assay is based on the unique binding properties
of the capture monoclonal antibody MM1 used in the Bayer Immuno 1 assay
for tPSA. That antibody fails to bind fPSA in the presence of specific
antibodies against epitope E, which is exposed only in fPSA, so that
all cPSA forms such ACT-PSA and minor forms except PSA complexed to
2-macroglobulin are detected.
To measure ACT-PSA, two prototype assays on the ES immunoanalyzer (Roche Diagnostics) were used. The principle of the tests was described previously and is based on the two-step sandwich technique (11). Samples are incubated in the first step with specific monoclonal biotinylated antibodies, forming a PSA-antibody sandwich complex that is bound by the biotinylated antibodies to the streptavidin-coated tubes. After washing, an horseradish peroxidase-labeled mouse anti-ACT conjugate for determining ACT-PSA is added and bound to the PSA-antibody complex in a second incubation cycle. The two assays differed in the use of different antibodies. After incubation, the tubes are emptied and washed. The substrate diammonium 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonate) is then added, and the absorbance is measured after 30 min.
To measure PSA and its isoforms in tissue extracts, the supernatants were removed from the freezer and thawed by agitation at room temperature. Necessary dilutions were made either with 50 mmol/L phosphate buffer, pH 7.4, containing 50 g/L human serum albumin or with special dilution solutions supplied with the corresponding test kits.
Gel filtration chromatography.
Samples containing 1.3–2.5
µg of tPSA were loaded on a Sephacryl S-200 column (1.6 x 90
cm; Pharmacia) and eluted with 20 mmol/L phosphate buffer, pH 7.4,
containing 150 mmol/L NaCl and 5 mmol/L NaN3 at a
flow rate of 9.6 mL/h. Fractions (1.6-mL) were collected, aliquoted,
and stored at -80 °C until analysis within 12 weeks. The column was
calibrated with ferritin (450 kDa), catalase (240 kDa), bovine serum
albumin (65 kDa), egg albumin (45 kDa), chymotrypsinogen A (25 kDa),
and equine myoglobin (17.8 kDa) by measuring the absorbance at 280 nm
in the fractions.
Electrophoresis and immunoblotting.
Sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed
under reducing conditions on the Midget Electrophoresis Unit 2050 (LKB)
according to the standard method of Laemmli (12). Samples
heated at 95 °C for 5 min in sample buffer containing 50 mL/L
2-mercaptoethanol and 20 g/L SDS were applied to a 4% stacking
gel and electrophoresed through a 10% SDS polyacrylamide gel
containing 1 g/L SDS. After electrophoresis, the proteins were
transferred to polyvinylidene difluoride membranes (Hybond-P; Amersham
Life Science) by the Multiblot Electrophoresis Transfer Unit 2051
(LKB). The transfer buffer contained 25 mmol/L Tris, 192 mmol/L
glycine, 200 mL/L methanol, and 0.375 g/L SDS. The blots were
blocked with 50 g/L powdered nonfat milk in phosphate-buffered saline
containing 1 mL/L Tween 20 for 1 h at room temperature,
washed, and then incubated for 1 h with a 2000-fold dilution of
primary antibody (rabbit anti-PSA, cat. no. A0562; rabbit anti-ACT,
cat. no. A022; Dako). Bands were visualized with horseradish peroxidase
conjugated to anti-mouse IgG (diluted 3000-fold; Amersham) and a
chemiluminescence reaction according to the instructions of the
manufacturer (ECL-Plus system; Amersham). The Perfect Protein Western
Blot Kit (Calbiochem-Novabiochem) consisting of seven recombinant
proteins was used as the molecular marker set.
Other determinations.
Protein concentrations in tissue
extracts were measured with Coomassie Brilliant Blue assay reagent,
using bovine serum albumin as the calibrator (13). DNA was
assayed using the fluorescence dye Hoechst 33258 in phosphate-buffered
saline solution (14).
statistical analysis
Data were analyzed with the statistical software SPSS 8.0 for
Windows (SPSS) and GraphPad Prism 3.00 for Windows (GraphPad Software).
The Kruskal–Wallis nonparametric ANOVA with Dunn’s post test, the
Mann–Whitney U-test, the Wilcoxon test for paired data, and
the calculation of rank correlation coefficients according to Spearman
(rS) were performed. Regression
analysis for method evaluation was performed using the software EVAPAK
3.01 for Windows according to Passing and Bablok (15).
P 
0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The scatter plots and medians of the tPSA, fPSA, ACT-PSA, and cPSA
values in the various tissue samples are shown in Fig. 1
. These data and respective comparisons can be summarized as
follows:
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• fPSA was the major form of PSA in prostatic tissue, independent of the source of the tissue. ACT-PSA yielded only a negligible amount of <0.5% of the tPSA. The minor occurrence of ACT-PSA was verified in comparative measurements by two different ACT-PSA assays based on different anti-PSA antibodies and by the low values of cPSA. The cPSA values were ~3- to 14-fold higher than ACT-PSA but did not exceed 2% of the total PSA.
• The fPSA values were significantly correlated with tPSA (rS = 0.964–0.964; P <0.01) and with ACT-PSA (rS = 0.454–0.648; P <0.05) in all tissue samples.
• Total and free PSA were partly different in the various sources of the prostatic tissue and showed large ranges. The samples obtained from cystoprostatectomy patients and histologically confirmed as nondiseased had the lowest values, and the samples from adenomectomy patients the highest values. tPSA and fPSA were significantly lower in tissue material obtained from transurethral resection of the prostate than in tissue from adenomectomies, although a similar pattern might be expected. PSA probably is damaged in tissue specimens by heat when the cauterizing loop is used for resection of the prostate.
• tPSA and fPSA were lower in cancerous than in noncancerous parts of prostate glands from patients with PCa. These differences were not observed for ACT-PSA and cPSA. No significant correlations were found between tumor stage and the tissue concentrations of tPSA, fPSA, and ACT-PSA (rS = 0.054, 0.108, and 0.225, respectively; P >0.05) and also between tumor grade and tPSA, fPSA, and ACT-PSA (rS = -0.13, -0.168, and -0.310, respectively; P >0.05).
• The sum of fPSA plus ACT-PSA or cPSA was ~90% of the tPSA, not varying significantly between the different sources of prostatic tissues (ANOVA; P >0.05; means, 84.5–92.9%). To further elucidate this phenomenon of incomplete recovery, comparative measurements of total and free PSA were performed with two additional assay systems (Abbott AxSYM and DPC IMMULITE). The fPSA/tPSA ratios obtained with the test systems (Roche, 85.4. ± 12.1; Abbott, 97.8 ± 8.1; DPC, 81.9 ± 6.6) differed significantly (ANOVA; P <0.05).
psa electrophoresis pattern of prostatic tissue
Fig. 2
A shows the PSA patterns representative of healthy prostatic
tissue (lane 5) and tissue obtained from PCa (lanes 6 and 7) compared
with patterns observed in seminal plasma (lane 2), purified PSA (lane
3), and serum from a patient with advanced PCa (lane 4). The
immunoassay detected PSA in the serum at ~30 kDa and ~90 kDa, which
corresponded to fPSA and the ACT-PSA complex, respectively. The PSA
bands detected at >150 kDa are characteristic of
PSA-2-macroglobulin complexes (16).
These complexes were not found in prostatic tissue samples, although
ACT was present in prostatic tissue from cancerous and noncancerous
sources (Fig. 2B
). However, distinct PSA bands below 30 kDa (lanes
5–7) also occurred in all prostatic tissue samples and in seminal
plasma. These bands represent internally cleaved PSA molecules
(17)(18)(19).
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psa gel filtration pattern of prostatic tissue
Gel filtration on Sephacryl S-200 revealed typical PSA profiles
for the various prostatic tissue samples studied in comparison with
serum, seminal plasma, and purified PSA incubated with serum albumin or
female serum (Fig. 3
). The peak at ~30 kDa corresponds to fPSA. The peak at ~90
kDa in serum of a patient with advanced PCa (Fig. 3A
) and in female
serum incubated with purified PSA (Fig. 3C
) corresponds to the ACT-PSA
complex. All prostatic tissue samples of cancerous or noncancerous
origin (Fig. 3
, E-H) displayed only peaks of fPSA.
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tPSA, fPSA, cPSA, ANDACT-PSA IN SERUM
The serum PSA concentrations and the corresponding percentage
ratios of fPSA/tPSA and ACT-PSA/tPSA are shown in Table 1
. The characteristic pattern of a lower fPSA/tPSA ratio and
higher ACT-PSA/tPSA ratio in PCa patients compared with BPH patients
was evident. However, no correlations were found between the serum and
tissue tPSA concentrations in controls and patients with BPH and PCa
(rS = -0.091, 0.307, and 0.241;
P >0.10). In addition, the fPSA/tPSA and ACT-PSA/tPSA
ratios in sera did not correlate with the tissue PSA concentrations
(rS between 0.05 and 0.340;
P >0.10).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been postulated that PSA is more extensively complexed in PCa
cells than in nondiseased prostatic or BPH cells (7).
Consequently, the lower fPSA/tPSA ratio in the serum of PCa patients
has been assumed to reflect these cellular peculiarities after PSA is
released into the blood stream (7). However, our data for
the multiple PSA isoforms in various specimens of prostatic tissue and
serum of the same patients (Fig. 1
and Table 1
) clearly contradict that
hypothesis.
The major form of prostatic tissue PSA is fPSA, whereas ACT-PSA or cPSA
are <2% of tPSA. The tissue cPSA concentration is 3- to 14-fold
higher than that of ACT-PSA. We believe that these differences are
caused by additional PSA complexes that occur in prostatic tissue
rather than by a slight cross-reaction of fPSA in the cPSA assay
(10). For example, prostatic tissue contains high
concentrations of 1-antitrypsin
(20), which can form a complex with PSA (21).
Thus, although ACT-PSA or cPSA contributes <2% of the total tissue
PSA, the main proportion of the tPSA in serum is bound to ACT (Table 1
)
or measured as cPSA (10). In addition, no correlations were
found between tissue and serum PSA isoforms patterns. These
quantitative data were corroborated by chromatographic and
electrophoretic analyses of PSA and ACT in tissue extracts. Although
the tPSA and fPSA were lower in cancerous than in noncancerous parts of
the prostate (Fig. 1
), no changed pattern of tissue PSA isoforms was
observed (Figs. 2
and 3
). Moreover, the immunoblots (Fig. 2B
) and the
immunostaining data by Igawa et al. (22) did not confirm a
higher expression of ACT in malignant than in benign prostatic tissue,
as described by Björk et al. (7). These data make it
unlikely that the isoform pattern of the serum PSA is a simple
reflection of the tissue PSA pattern. Other molecular mechanisms such
as the changed proportions of enzymatically active and inactive PSA or
posttranslational modification by glycosylation should be considered as
possible explanations of the different fPSA/tPSA ratio in the
serum of BPH and PCa patients (9)(23).
Enzymatically inactive PSA, also called "nicked PSA", is formed by
internal proteolytic cleavage and is unable to bind ACT and other
protease inhibitors (23). This nicking process for PSA
probably takes place in the extracellular space before PSA reaches the
circulation (6). It is assumed that PSA is subjected to this
process in healthy and BPH tissue for longer periods of time than in
PCa tissue, which additionally secretes PSA directly into the blood
stream because of the altered tissue architecture (6).
However, nicked PSA forms have also been found in BPH nodule
fluid (8). These PSA forms also occurred in the tissue
extracts from both PCa and BPH tissue (Fig. 2
). Whatever the reason,
PCa serum shows a lower proportion of the cleaved forms than BPH serum
(19). This phenomenon could be of great diagnostic
significance (19).
The tissue PSA concentrations measured in our study were in the same range as reported by others but somewhat higher (24)(25). These differences could be explained by the use of different PSA assays. Our comparative experiments with various PSA assays support the view that the assays are not completely interchangeable, although all assays were exclusively calibrated against the Stanford 90:10 PSA Calibrator (26). The differences may be related to calibration problems or to the different immunoreactivities of the antibodies used in the assays for detecting free and total PSA (27). In addition, the different fPSA/tPSA ratios obtained with the three assay systems suggest that the differences of ~10% between the sum of fPSA plus ACT-PSA or cPSA and tPSA may be a result of incorrect calibration of the assays, e.g., for fPSA, rather than incomplete recovery of the PSA isoforms.
There are several reports on PSA expression in BPH and PCa tissue specimens based on immunohistochemistry (22)(28)(29)(30)(31)(32), whereas only a few studies determined tPSA with immunoassays (24)(25)(33). The present study thus is the first to date to analyze in detail different sources of prostatic tissue for the molecular PSA forms. Immunohistochemical studies generally indicated a decreased PSA immunoreactivity in PCa tissue compared with benign prostatic tissue. In addition, a dedifferentiation of PCa was found to be associated with a decrease in PSA staining (28)(31). These findings are only partly consistent with quantitative PSA values determined by ELISA techniques in corresponding tissue extracts (24)(33)(34). For example, Pretlow et al. (24) found a decreased PSA content in tumor tissue but did not find relationships between tissue PSA content and the cell differentiation, as Stege et al. (33) did. Our data also showed significant differences between the PSA contents in cancerous and noncancerous parts of the prostate, but no association of tissue PSA concentration with the tumor grade was observed. For a long time, Stege et al. (33) and Pousette et al. (34) recommended tissue PSA as good predictor of the outcome of PCa. However, a recent study showing even higher concentrations of PSA in malignant tissue and no significant differences of tissue PSA in well, moderately, and poorly differentiated PCa tissue challenges these data (25). The reasons for these differences observed between PSA histochemistry and ELISA measurements are not known (24), but it may be easier to relate PSA staining to tumor differentiation when using immunohistochemistry than when measuring PSA in extracts from macroscopic tissue samples. In addition to these contradictory data, the quite variable and overlapping PSA values presumably caused by PSA heterogeneity in malignant prostatic tissue makes it difficult to use tissue PSA as diagnostic marker.
In summary, the amounts of tPSA and the isoforms fPSA, ACT-PSA, and cPSA in prostatic tissue specimens explains neither the concentrations of these analytes in serum nor the characteristics of the fPSA/tPSA ratio in patients with BPH and PCa. In addition, the determination of these analytes in prostatic tissue does not seem to possess diagnostic significance.
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Acknowledgments |
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Footnotes |
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1-antichymotrypsin; fPSA, free, noncomplexed form of PSA; PCa, prostate cancer; BPH, benign prostatic hyperplasia; cPSA, complexed form of PSA; and SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis. 
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References |
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