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The Prostate 39:123–129 (1999)
Elevation of Serum Levels of Urokinase-Type
Plasminogen Activator and Its Receptor Is
Associated With Disease Progression and
Prognosis in Patients With Prostate Cancer
Hideaki Miyake,* Isao Hara, Kazuki Yamanaka, Kazuo Gohji,
Soichi Arakawa, and Sadao Kamidono
Department of Urology, Kobe University School of Medicine, Kobe, Japan
BACKGROUND. Several investigators have revealed that urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are overexpressed in serum as well as in tumor tissues
in patients with various types of cancer. In this study, we examined whether the serum levels
of uPA and uPAR could be used as predictors of the progression and prognosis of prostate
cancer.
METHODS. Serum levels of uPA and uPAR in 54 healthy controls, 62 patients with benign
prostatic hypertrophy (BPH), and 72 patients with prostate cancer were measured by a sandwich enzyme immunoassay.
RESULTS. The mean serum levels of uPA and uPAR in patients with prostate cancer were
significantly higher than those in healthy controls and patients with BPH. Furthermore, the
serum uPA and uPAR levels in prostate cancer patients with metastasis were significantly
elevated compared with those in patients without metastasis. Among patients who underwent radical prostatectomy, the serum levels of uPA and uPAR in patients with pathologically organ-confined disease were significantly lower than in those with advanced disease.
The overall survival rate of prostate cancer patients with elevated serum levels of either uPA
or uPAR, or of both, was significantly lower than that of patients with normal serum levels
of uPA and uPAR.
CONCLUSIONS. The results of this study indicate that the elevation of serum levels of either
uPA or uPAR, or of both, could be used as new predictors of progression and prognosis in
patients with prostate cancer. Prostate 39:123–129, 1999. © 1999 Wiley-Liss, Inc.
KEY WORDS:
prostate cancer; serum; uPA; uPA receptor; progression; prognosis
INTRODUCTION
Prostate cancer is the most frequent malignancy in
men of the United States, and is the second-leading
cause of cancer-related death [1]. Recent development
in the fields of diagnosis and follow-up of prostate
cancer using prostate-specific antigen (PSA) have contributed to early detection and accurate prediction of
prognosis. However, despite these advances, more
than 50% of patients still show evidence of advanced
disease at time of diagnosis, and serum levels of PSA
are not correlated with clinical course in some patients
with hormone-refractory prostate cancer [2]; hence,
there is a pressing need to develop a novel diagnostic
© 1999 Wiley-Liss, Inc.
and monitoring system in order to further improve the
prognosis of prostate cancer patients.
Cancer cells possess a high degree of proteolytic
activity, resulting in the acquisition of the ability to
degrade and subsequently invade surrounding normal tissues [3]. Several proteolytic enzyme systems are
reported to be involved in the degradation of the extracellular matrix and basement membrane, and
among them, the urokinase-type plasminogen activa*Correspondence to: Hideaki Miyake, now at the Department of
Cancer Endocrinology, British Columbia Cancer Agency, 600 West
10th Ave., Vancouver, British Columbia V5Z 4E6, Canada.
Received 5 August 1998; Accepted 30 October 1998
124
Miyake et al.
tor (uPA)-mediated plasminogen activation pathway
is one of the most important cascades for the invasion
of cancer cells [4]. uPA is produced and secreted by
various types of cancer cells, and binds with high affinity to its specific cell surface receptor (uPAR). uPA
exerts its effect by converting the proenzyme plasminogen into the widely acting serine protease plasmin,
which cleaves the extracellular components, including
fibronectin, laminin, and collagen. The binding of uPA
to uPAR increases its enzymatic activity and further
allows a focal and directional proteolysis of the extracellular matrix [5]. Thus, not only uPA but also uPAR
may play a crucial role in the invasion and metastasis
of cancer cells.
Using clinical tissue samples and tumor cell lines,
several investigators revealed that the level of uPA in
prostate cancer correlates with an aggressive and invasive phenotype [6–8]. In addition, a number of experimental findings clearly demonstrated the important role of the uPA/uPAR system in the malignant
progression of human and rodent prostate cancer
models [9–12]. Crowly et al. [9] showed that displacement of uPAR-bound uPA with an active-site mutant
uPA blocks spontaneous metastasis of a human prostate cancer cell line in nude mice. Achbarou et al. [10]
showed that introduction of the uPA gene into prostate cancer cells enhanced skeletal metastasis of the
cells. These findings suggest that uPA and uPAR may
serve as useful markers and prognostic factors for
prostate cancer progression.
Recently, elevated levels of uPA and uPAR in various body fluids of cancer patients, such as sera, ascites, and pleural effusions, were reported [13–15].
However, there has been no report regarding serum
levels of uPA and uPAR in human prostate cancer
patients. Therefore, in the present study, we measured
the serum levels of uPA and uPAR in patients with
prostate cancer, and analyzed the relationship between these levels and several clinicopathological factors.
MATERIALS AND METHODS
Patient Characteristics
Between January 1993–December 1997, serum
samples were obtained before any clinical treatment
from 72 patients with prostate cancer (age 47–89 years,
median 71) and 62 patients with BPH (age 53–84 years,
median 69). Diagnosis was confirmed histopathologically by transrectal needle biopsy under the guidance
of transrectal ultrasonography. Sera were also collected from 70 healthy males (age 51–82 years, median
67) who had no suspicious findings of prostate cancer
in tests including digital rectal examination and mea-
surement of serum PSA levels. Informed consent was
obtained from all patients and healthy controls for
measuring serum uPA and uPAR.
Patient characteristics are summarized in Table I.
Thirty-five patients received hormonal therapy owing
to bone metastases. Thirty-one patients underwent
retropubic radical prostatectomy (RRP), and among
them, 15 patients had pathologically confirmed organconfined disease (pT1N0M0 or pT2N0M0), and 16 patients had nonorgan-confined disease (pT3 艋 and/or
N+). The remaining 6 prostate cancer patients without
evidence of distant metastases did not receive radical
surgery and underwent hormonal therapy due to severe heart or liver disease. The stage was determined
according to the UICC TNM classification [16], and
tumor differentiation was determined by Gleason
score [17].
Measurement of Serum Levels of uPA and uPAR
The concentrations of uPA and uPAR were determined using quantitative sandwich EIA kits for human uPA and uPAR (American Diagnostica, Greenwich, CT), respectively. For each analysis, 100 ␮l of 1:5
diluted serum samples were added to microtiter plates
coated with a purified polyclonal antibody against human uPA or uPAR. Bound uPA or uPAR was detected
by an additional biotinylated anti-uPA or anti-uPAR
antibody, respectively. After addition of streptavidinconjugated horseradish peroxidase, peroxidasemediated conversion of 3,3⬘,5,5⬘-tetramethylbenzidine
was measured as an optical density at 450 nm with a
microculture plate reader (Becton Dickinson Labware,
Lincoln Park, NJ). All analyses and calibrations were
performed in duplicate. Each microtiter plate included
recombinant human uPA or uPAR standards for calibration. The blank value was subtracted from the duplicate readings for each standard and sample. A standard curve was created using Stat View 4.02 (Abacus
Concepts, Inc., Berkeley, CA) by plotting the logarithm of the mean absorbance of each sample vs. the
sample concentration.
The rank correlation coefficients were determined
between the serum uPA and PSA levels, and between
the serum uPAR and PSA levels according to the
Spearman rank test with Statgraphics (Statistical
Graphics, Rockville, MD).
Statistics
Differences in the serum levels of uPA and uPAR
between controls and prostate cancer patients were
calculated by the Mann-Whitney U-test. Differences in
elevation of serum uPA and uPAR levels were determined by chi-square test. The overall survival of pros-
Serum uPA and uPAR in Prostate Cancer
125
TABLE I. Serum uPA and uPAR Levels in Healthy Controls and Patients With BPH and Prostate Cancer*
uPA (ng/ml)
Number of
subjects (%)
Healthy controls
BPH
Prostate cancer
Overall
Clinical stage
T1
T2
T3
T4
Metastasisa
Negative
Positive
Lymph node metastasis
Negative
Positive
Bone metastasis
Negative
Positive
Gleason score
2–4
5–7
8–10
Mean ± SD (range)
uPAR (ng/ml)
P value
Mean ± SD (range)
P value
70 (100)
62 (100)
362 ± 90 (198–511)
389 ± 163 (201–883)
72 (100)
453 ± 188 (245–971)
5.5 ± 2.8 (1.5–11.4)
6 (8)
35 (49)
27 (38)
4 (5)
377 ± 172 (245–702)
411 ± 156 (261–883)
523 ± 199 (257–971)
451 ± 85 (401–636)
<0.05
3.9 ± 2.7 (1.6–6.2)
4.8 ± 2.7 (1.5–9.7)
6.9 ± 3.2 (1.8–11.4)
6.5 ± 2.4 (2.1–8.8)
25 (35)
47 (65)
391 ± 177 (257–935)
486 ± 194 (245–971)
<0.05
4.2 ± 2.6 (1.5–10.7)
6.2 ± 2.9 (1.6–11.4)
<0.01
54 (75)
18 (25)
449 ± 193 (245–949)
465 ± 180 (266–971)
NS
5.4 ± 2.8 (1.5–10.9)
5.8 ± 2.4 (1.6–11.4)
NS
37 (51)
35 (49)
400 ± 179 (245–935)
509 ± 191 (257–971)
<0.05
4.6 ± 2.2 (1.5–10.7)
6.4 ± 3.0 (1.7–11.4)
<0.01
20 (28)
23 (32)
29 (40)
431 ± 175 (245–889)
459 ± 185 (269–959)
463 ± 192 (277–971)
NS
5.1 ± 2.3 (1.5–10.1)
5.6 ± 2.7 (1.6–11.4)
5.7 ± 2.9 (1.6–11.0)
NS
NS
3.9 ± 1.2 (1.4–5.5)
4.2 ± 1.5 (1.7–7.2)
<0.05
NS
<0.005
<0.01
*NS, not significant.
a
Either lymph node metastasis or bone metastasis, or both.
tate cancer patients was examined by the KaplanMeier method, and differences were evaluated by logrank test. The prognostic significance of some factors
was assessed by the Cox proportional hazards regression model. A difference with P < 0.05 was considered
significant.
in prostate cancer patients with metastasis (bone and/
or lymph node metastasis) were significantly higher
than those in patients without metastasis (P < 0.05 and
P < 0.01, respectively). However, serum levels of uPA
and uPAR in prostate cancer patients were not related
to Gleason score.
RESULTS
Elevation of Serum uPA and uPAR
Serum uPA and uPAR Levels
In healthy controls, the mean serum levels of uPA
and uPAR were 362.4 ± 89.7 ng/ml (range, 198–511
ng/ml) and 3.9 ± 1.2 ng/ml (range, 1.4–5.5 ng/ml),
respectively, and the variations in levels of both uPA
and uPAR were not related to age (data not shown).
There were no significant differences in serum uPA or
uPAR levels between healthy controls and patients
with BPH. In contrast, serum levels of uPA and uPAR
in patients with prostate cancer were significantly
higher than those in patients with BPH (P < 0.05 and
P < 0.005, respectively) (Table I).
Serum uPA and uPAR levels in patients with T3 or
T4 prostate cancer were significantly higher than those
in patients with T1 or T2 prostate cancer (P < 0.05 and
P < 0.01, respectively). Serum levels of uPA and uPAR
The cutoff values for normal serum levels of uPA
and uPAR were determined by the mean level of
healthy controls plus 2 standard deviations; therefore,
the normal values of uPA and uPAR were less than
541.8 ng/ml and 6.3 ng/ml, respectively. According to
these criteria, the specificities of the elevation of serum
levels of uPA and uPAR in healthy controls were 100%
and 100%, respectively, and those in patients with
BPH were 90% and 95%, respectively (data not
shown). The elevation of serum levels of uPA and
uPAR in patients with prostate cancer and BPH is
shown in Table II. The elevation of serum levels of
uPA and uPAR in prostate cancer patients was significantly higher than in patients with BPH (P < 0.005 and
P < 0.001, respectively). In addition, the differences of
elevation of serum uPA and uPAR levels between
126
Miyake et al.
TABLE II. Elevation of Serum Levels of uPA and uPAR in Patients With BPH and Prostate Cancer*
Elevation (%)
Number of
subjects (%)
BPH
Prostate cancer
Overall
Clinical stage
T1
T2
T3
T4
Metastasisa
Negative
Positive
Gleason score
2–4
5–7
8–10
uPA
(%)
62 (100)
uPAR
(%)
P value
6 (10)
uPA or
uPAR (%) P value
P value
3 (5)
<0.005
8 (13)
<0.001
<0.001
72 (100)
25 (35)
29 (40)
39 (54)
6 (8)
35 (49)
27 (38)
4 (5)
1 (17)
7 (20)
16 (59)
1 (25)
<0.005
0 (0)
6 (17)
21 (78)
2 (50)
<0.001
1 (17)
12 (34)
24 (89)
2 (50)
<0.001
25 (35)
47 (65)
4 (16)
21 (45)
<0.05
4 (16)
25 (53)
<0.005
7 (28)
32 (68)
<0.005
20 (28)
23 (32)
29 (40)
5 (25)
8 (35)
12 (41)
NS
5 (25)
10 (43)
14 (48)
NS
8 (40)
13 (57)
18 (62)
NS
*NS, not significant.
a
Either lymph node metastasis or bone metastasis, or both.
TABLE III. Serum uPA and uPA Levels in Patients With BPH and Prostate Cancer Who Underwent
Radical Prostatectomy*
uPA (ng/ml)
BPH
Organ-confined
prostate cancera
Nonorgan-confined
prostate cancerb
Number
of
subjects
Mean
± SD
62
389 ± 163
15
401 ± 147
16
517 ± 166
P
value
NS
uPAR (ng/ml)
Mean
± SD
4.2 ± 1.5
P
value
NS
4.4 ± 2.5
<0.05
6.4 ± 2.7
Elevation (%)
uPA
(%)
6 (10)
P
value
NS
3 (20)
<0.05
4 (25)
uPAR
(%)
3 (5)
P
value
NS
2 (13)
NS
8 (50)
uPA or
uPAR (%)
8 (13)
P
value
NS
4 (27)
<0.05
10 (63)
<0.05
*NS, not significant.
a
pT1N0M0 or pT2N0M0.
b
pT3 艋 or N+.
prostate cancer patients with and without metastasis
were also significant (P < 0.05 and P < 0.005, respectively). However, there were no significant differences
in elevation of serum uPA and uPA levels between
patients with Gleason grade 2–4 prostate cancer and
patients with Gleason grade 5–7 or Gleason grade
8–10 prostate cancer.
Relationship Between Pathological Findings and
Serum Levels of uPA and uPAR
There were no significant differences in serum uPA
or uPAR levels between patients with BPH and organconfined prostate cancer (pT1N0M0 or pT2N0M0);
however, the differences in serum uPA and uPAR lev-
els between patients with organ-confined disease and
patients with nonorgan-confined disease (pT3 艋 or
N+) were significant (P < 0.05 and P < 0.05, respectively) (Table III).
There were no significant differences in elevation of
serum level of uPA among BPH, organ-confined disease, and nonorgan-confined disease; however, the
difference in the elevation of uPAR between organconfined disease and nonorgan-confined disease was
significant (P < 0.05) (Table III).
Relationship of Serum uPA and uPAR to PSA
The relationships between serum uPA and PSA levels and between serum uPAR and PSA levels in pros-
Serum uPA and uPAR in Prostate Cancer
Fig. I. Relationships between serum uPA, uPAR, and PSA. A:
Serum uPA level and PSA. B: Serum uPAR level and PSA.
tate cancer patients are shown in Figure 1A,B, respectively. There was no correlation between serum uPA
level and PSA (r = 0.08) or between serum uPAR and
PSA (r = 0.01).
Survival of Prostate Cancer Patients According to
Elevation of Serum uPA and uPAR
The overall survival rate of prostate cancer patients
with an elevated level of serum uPA was not significantly different from that of patients with a normal
level (Fig. 2A), and the difference in overall survival
rate between prostate cancer patients with an elevated
serum level of uPAR and patients with a normal level
was also not significant (Fig. 2B). However, the overall
127
Fig. 2. Overall survival rates of prostate cancer patients according to serum uPA and uPAR status. A: uPA. B: uPAR. C: Either
uPA or uPAR, or both. The overall survival rates of patients with
elevated serum levels of either uPA or uPAR, or of both, were
significantly lower than the overall survival rate of patients with
normal levels of both uPA and uPAR.
survival rate of prostate cancer patients with elevated
serum levels of either uPA or uPAR, or of both, was
significantly lower than the survival rate of patients
with normal levels of both uPA and uPAR (P < 0.05)
(Fig. 2C).
To compare the predictive value of serum uPA and
uPAR status in prognosis, univariate and multivariate
analyses with the Cox regression hazards model were
performed (Table IV); however, the elevation of serum
levels of either uPA or uPAR, or of both, was not an
independent prognostic predictor. The analyses further revealed that bone and/or lymph node metastasis
was strongly associated with overall survival (univariate analysis, P < 0.01; multivariate analysis, P < 0.05),
128
Miyake et al.
TABLE IV. Association of Various Factors With Overall Survival Determined by Cox Univariate and Multivariate
Proportional Hazards Model*
Univariate
Variables
Serum uPA and uPAR status (normal vs. elevated)a
Age (years) (<61 vs. ⱖ61)
Clinical stage (T1 vs. T2 vs. T3 vs. T4)
Gleason score (<8 vs. ⱖ8)
PSA level (<10 ng/ml vs. ⱖ10 ng/ml)
Metastasis (negative vs. positive)b
Multivariate
Hazard
ratio
95% CI
P value
Hazard
ratio
95% CI
P value
1.89
1.19
1.98
1.66
1.39
2.02
0.97–2.88
0.58–2.69
1.11–3.20
0.85–2.81
0.61–2.96
1.12–3.23
0.044
0.74
0.041
0.12
0.16
0.0079
0.64
1.34
2.14
0.61
1.89
3.56
0.21–1.82
0.55–3.11
0.88–2.21
0.21–1.70
0.70–1.91
1.19–8.67
0.091
0.30
0.16
0.081
0.15
0.019
*CI, confidence interval.
a
Elevation of serum levels of either uPA or uPAR, or both.
b
Either lymph node metastasis or bone metastasis, or both.
regardless of uPA and uPAR status, age, PSA level,
clinical stage, and Gleason score.
DISCUSSION
A number of clinical studies have demonstrated
that uPA and/or uPAR are overexpressed in several
types of human malignant tumors, including prostate
cancer, and that the expression level of the uPA system closely correlates with tumor progression
[6,8,18,19]. Several experimental findings also demonstrated that the uPA-uPAR system plays a crucial role
in invasion and metastasis of prostate cancer cells both
in vitro and in vivo [9–12]. Furthermore, recent studies
revealed that serum levels of uPA and uPAR appear to
be indicative of malignancy in gastric and ovarian cancer [13–15]. Therefore, in the present study, serum levels of uPA and uPAR were examined in healthy controls, and in BPH and prostate cancer patients, and an
investigation of whether they could be used as predictors of disease progression and prognosis in prostate
cancer patients was conducted.
In this series, we showed for the first time that both
serum uPA and uPAR levels in patients with prostate
cancer were significantly higher than levels in patients
with BPH or in healthy controls. In addition, the elevations of serum uPA and uPAR were much higher
in prostate cancer patients with metastases than in
those without metastases. Soff et al. [11] and Rabbani
et al. [12] demonstrated that prostate cancer metastases are suppressed by the inhibition of the uPA system, using human and rat prostate cancer cells, respectively. Considering these findings and our present results, we conclude that the uPA and uPAR system
contributes to prostate cancer development, and that
serum uPA and uPA levels can be used to predict
prostate cancer progression.
In order to accurately distinguish prostate cancer
patients with organ-confined disease from those with
nonorgan-confined disease preoperatively, several
methods have been introduced into clinical practice,
such as computerized tomography, magnetic resonance imaging, PSA density, and histological grading
of biopsy specimens [20]. However, even if these
methods are combined, it remains difficult to correctly
identify patients with nonorgan-confined disease. In
the present study, the elevation of serum levels of either or both uPA and uPAR in patients with nonorgan-confined disease was significantly higher than
that in patients with organ-confined disease. These
findings indicate that levels of serum uPA and uPAR
are useful markers for the detection of patients with
nonorgan-confined disease.
In this series, no significant correlation was observed between serum uPA and PSA levels, or between serum uPAR and PSA levels. Therefore, serum
uPA and uPAR levels can be regarded as clinical factors independent of serum PSA.
It is of particular interest whether the elevations of
serum uPA and/or uPAR concentrations are associated with the poor prognosis of prostate cancer patients. In this study, we showed that the overall survival rate of prostate cancer patients with either serum
uPA or uPAR elevation, or both serum uPA and uPAR
elevation, was significantly lower than that of patients
with normal levels of uPA and uPAR. These findings
suggest that measurement of serum uPA and uPAR
may provide additional information in determining
prognosis and patient treatment strategy, i.e., aggressive therapy should be performed in patients with elevated serum levels of uPA and/or uPAR, whereas
patients with normal levels of both uPA and uPAR
may not need to undergo intensive additional therapies if the initial treatment is successfully performed.
Serum uPA and uPAR in Prostate Cancer
In conclusion, our results suggest that uPA and/or
uPAR expression is associated with the progression of
prostate cancer, and that serum uPA and uPAR levels
indicate the degree of prostate cancer progression and
patient prognosis. Hence, measurement of serum uPA
and uPAR could serve as useful adjuncts to conventional diagnostic tools.
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