Elevation of Serum Levels of Urokinase-TypePlasminogen Activator and Its Receptor IsAssociated 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 acti-vator (uPA) and its receptor (uPAR) are overexpressed in serum as well as in tumor tissuesin patients with various types of cancer. In this study, we examined whether the serum levelsof uPA and uPAR could be used as predictors of the progression and prognosis of prostatecancer.METHODS. Serum levels of uPA and uPAR in 54 healthy controls, 62 patients with benignprostatic hypertrophy (BPH), and 72 patients with prostate cancer were measured by a sand-wich enzyme immunoassay.RESULTS. The mean serum levels of uPA and uPAR in patients with prostate cancer weresignificantly higher than those in healthy controls and patients with BPH. Furthermore, theserum uPA and uPAR levels in prostate cancer patients with metastasis were significantlyelevated compared with those in patients without metastasis. Among patients who under-went radical prostatectomy, the serum levels of uPA and uPAR in patients with pathologi-cally 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 uPAor uPAR, or of both, was significantly lower than that of patients with normal serum levelsof uPA and uPAR.CONCLUSIONS. The results of this study indicate that the elevation of serum levels of eitheruPA or uPAR, or of both, could be used as new predictors of progression and prognosis inpatients 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 inmen of the United States, and is the second-leadingcause of cancer-related death [1]. Recent developmentin the fields of diagnosis and follow-up of prostatecancer using prostate-specific antigen (PSA) have con-tributed to early detection and accurate prediction ofprognosis. However, despite these advances, morethan 50% of patients still show evidence of advanceddisease at time of diagnosis, and serum levels of PSAare not correlated with clinical course in some patientswith hormone-refractory prostate cancer [2]; hence,there is a pressing need to develop a novel diagnostic

and monitoring system in order to further improve theprognosis of prostate cancer patients.

Cancer cells possess a high degree of proteolyticactivity, resulting in the acquisition of the ability todegrade and subsequently invade surrounding nor-mal tissues [3]. Several proteolytic enzyme systems arereported to be involved in the degradation of the ex-tracellular matrix and basement membrane, andamong them, the urokinase-type plasminogen activa-

*Correspondence to: Hideaki Miyake, now at the Department ofCancer Endocrinology, British Columbia Cancer Agency, 600 West10th Ave., Vancouver, British Columbia V5Z 4E6, Canada.Received 5 August 1998; Accepted 30 October 1998

The Prostate 39:123–129 (1999)

© 1999 Wiley-Liss, Inc.

tor (uPA)-mediated plasminogen activation pathwayis one of the most important cascades for the invasionof cancer cells [4]. uPA is produced and secreted byvarious types of cancer cells, and binds with high af-finity to its specific cell surface receptor (uPAR). uPAexerts its effect by converting the proenzyme plasmin-ogen into the widely acting serine protease plasmin,which cleaves the extracellular components, includingfibronectin, laminin, and collagen. The binding of uPAto uPAR increases its enzymatic activity and furtherallows a focal and directional proteolysis of the extra-cellular matrix [5]. Thus, not only uPA but also uPARmay play a crucial role in the invasion and metastasisof cancer cells.

Using clinical tissue samples and tumor cell lines,several investigators revealed that the level of uPA inprostate cancer correlates with an aggressive and in-vasive phenotype [6–8]. In addition, a number of ex-perimental findings clearly demonstrated the impor-tant role of the uPA/uPAR system in the malignantprogression of human and rodent prostate cancermodels [9–12]. Crowly et al. [9] showed that displace-ment of uPAR-bound uPA with an active-site mutantuPA blocks spontaneous metastasis of a human pros-tate cancer cell line in nude mice. Achbarou et al. [10]showed that introduction of the uPA gene into pros-tate cancer cells enhanced skeletal metastasis of thecells. These findings suggest that uPA and uPAR mayserve as useful markers and prognostic factors forprostate cancer progression.

Recently, elevated levels of uPA and uPAR in vari-ous body fluids of cancer patients, such as sera, asci-tes, and pleural effusions, were reported [13–15].However, there has been no report regarding serumlevels of uPA and uPAR in human prostate cancerpatients. Therefore, in the present study, we measuredthe serum levels of uPA and uPAR in patients withprostate cancer, and analyzed the relationship be-tween these levels and several clinicopathological fac-tors.

MATERIALS AND METHODS

Patient Characteristics

Between January 1993–December 1997, serumsamples were obtained before any clinical treatmentfrom 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 histopathologi-cally by transrectal needle biopsy under the guidanceof transrectal ultrasonography. Sera were also col-lected from 70 healthy males (age 51–82 years, median67) who had no suspicious findings of prostate cancerin tests including digital rectal examination and mea-

surement of serum PSA levels. Informed consent wasobtained from all patients and healthy controls formeasuring serum uPA and uPAR.

Patient characteristics are summarized in Table I.Thirty-five patients received hormonal therapy owingto bone metastases. Thirty-one patients underwentretropubic radical prostatectomy (RRP), and amongthem, 15 patients had pathologically confirmed organ-confined disease (pT1N0M0 or pT2N0M0), and 16 pa-tients had nonorgan-confined disease (pT3 ø and/orN+). The remaining 6 prostate cancer patients withoutevidence of distant metastases did not receive radicalsurgery and underwent hormonal therapy due to se-vere heart or liver disease. The stage was determinedaccording to the UICC TNM classification [16], andtumor differentiation was determined by Gleasonscore [17].

Measurement of Serum Levels of uPA and uPAR

The concentrations of uPA and uPAR were deter-mined using quantitative sandwich EIA kits for hu-man uPA and uPAR (American Diagnostica, Green-wich, CT), respectively. For each analysis, 100 ml of 1:5diluted serum samples were added to microtiter platescoated with a purified polyclonal antibody against hu-man uPA or uPAR. Bound uPA or uPAR was detectedby an additional biotinylated anti-uPA or anti-uPARantibody, respectively. After addition of streptavidin-conjugated horseradish peroxidase, peroxidase-mediated conversion of 3,38,5,58-tetramethylbenzidinewas measured as an optical density at 450 nm with amicroculture plate reader (Becton Dickinson Labware,Lincoln Park, NJ). All analyses and calibrations wereperformed in duplicate. Each microtiter plate includedrecombinant human uPA or uPAR standards for cali-bration. The blank value was subtracted from the du-plicate readings for each standard and sample. A stan-dard curve was created using Stat View 4.02 (AbacusConcepts, Inc., Berkeley, CA) by plotting the loga-rithm of the mean absorbance of each sample vs. thesample concentration.

The rank correlation coefficients were determinedbetween the serum uPA and PSA levels, and betweenthe serum uPAR and PSA levels according to theSpearman rank test with Statgraphics (StatisticalGraphics, Rockville, MD).

Statistics

Differences in the serum levels of uPA and uPARbetween controls and prostate cancer patients werecalculated by the Mann-Whitney U-test. Differences inelevation of serum uPA and uPAR levels were deter-mined by chi-square test. The overall survival of pros-

124 Miyake et al.

tate cancer patients was examined by the Kaplan-Meier method, and differences were evaluated by log-rank test. The prognostic significance of some factorswas assessed by the Cox proportional hazards regres-sion model. A difference with P < 0.05 was consideredsignificant.

RESULTS

Serum uPA and uPAR Levels

In healthy controls, the mean serum levels of uPAand uPAR were 362.4 ± 89.7 ng/ml (range, 198–511ng/ml) and 3.9 ± 1.2 ng/ml (range, 1.4–5.5 ng/ml),respectively, and the variations in levels of both uPAand uPAR were not related to age (data not shown).There were no significant differences in serum uPA oruPAR levels between healthy controls and patientswith BPH. In contrast, serum levels of uPA and uPARin patients with prostate cancer were significantlyhigher than those in patients with BPH (P < 0.05 andP < 0.005, respectively) (Table I).

Serum uPA and uPAR levels in patients with T3 orT4 prostate cancer were significantly higher than thosein patients with T1 or T2 prostate cancer (P < 0.05 andP < 0.01, respectively). Serum levels of uPA and uPAR

in prostate cancer patients with metastasis (bone and/or lymph node metastasis) were significantly higherthan those in patients without metastasis (P < 0.05 andP < 0.01, respectively). However, serum levels of uPAand uPAR in prostate cancer patients were not relatedto Gleason score.

Elevation of Serum uPA and uPAR

The cutoff values for normal serum levels of uPAand uPAR were determined by the mean level ofhealthy controls plus 2 standard deviations; therefore,the normal values of uPA and uPAR were less than541.8 ng/ml and 6.3 ng/ml, respectively. According tothese criteria, the specificities of the elevation of serumlevels of uPA and uPAR in healthy controls were 100%and 100%, respectively, and those in patients withBPH were 90% and 95%, respectively (data notshown). The elevation of serum levels of uPA anduPAR in patients with prostate cancer and BPH isshown in Table II. The elevation of serum levels ofuPA and uPAR in prostate cancer patients was signifi-cantly higher than in patients with BPH (P < 0.005 andP < 0.001, respectively). In addition, the differences ofelevation of serum uPA and uPAR levels between

TABLE I. Serum uPA and uPAR Levels in Healthy Controls and Patients With BPH and Prostate Cancer*

Number ofsubjects (%)

uPA (ng/ml) uPAR (ng/ml)

Mean ± SD (range) P value Mean ± SD (range) P value

Healthy controls 70 (100) 362 ± 90 (198–511) NS 3.9 ± 1.2 (1.4–5.5) NSBPH 62 (100) 389 ± 163 (201–883) 4.2 ± 1.5 (1.7–7.2)Prostate cancer <0.05 <0.005

Overall 72 (100) 453 ± 188 (245–971) 5.5 ± 2.8 (1.5–11.4)Clinical stage

T1 6 (8) 377 ± 172 (245–702) 3.9 ± 2.7 (1.6–6.2)T2 35 (49) 411 ± 156 (261–883) <0.05 4.8 ± 2.7 (1.5–9.7) <0.01T3 27 (38) 523 ± 199 (257–971) 6.9 ± 3.2 (1.8–11.4)T4 4 (5) 451 ± 85 (401–636) 6.5 ± 2.4 (2.1–8.8)

Metastasisa

Negative 25 (35) 391 ± 177 (257–935) 4.2 ± 2.6 (1.5–10.7)Positive 47 (65) 486 ± 194 (245–971) <0.05 6.2 ± 2.9 (1.6–11.4) <0.01

Lymph node metastasisNegative 54 (75) 449 ± 193 (245–949) 5.4 ± 2.8 (1.5–10.9)Positive 18 (25) 465 ± 180 (266–971) NS 5.8 ± 2.4 (1.6–11.4) NS

Bone metastasisNegative 37 (51) 400 ± 179 (245–935) 4.6 ± 2.2 (1.5–10.7)Positive 35 (49) 509 ± 191 (257–971) <0.05 6.4 ± 3.0 (1.7–11.4) <0.01

Gleason score2–4 20 (28) 431 ± 175 (245–889) 5.1 ± 2.3 (1.5–10.1)5–7 23 (32) 459 ± 185 (269–959) NS 5.6 ± 2.7 (1.6–11.4) NS8–10 29 (40) 463 ± 192 (277–971) 5.7 ± 2.9 (1.6–11.0)

*NS, not significant.aEither lymph node metastasis or bone metastasis, or both.

Serum uPA and uPAR in Prostate Cancer 125

prostate cancer patients with and without metastasiswere also significant (P < 0.05 and P < 0.005, respec-tively). However, there were no significant differencesin elevation of serum uPA and uPA levels betweenpatients with Gleason grade 2–4 prostate cancer andpatients with Gleason grade 5–7 or Gleason grade8–10 prostate cancer.

Relationship Between Pathological Findings andSerum Levels of uPA and uPAR

There were no significant differences in serum uPAor uPAR levels between patients with BPH and organ-confined prostate cancer (pT1N0M0 or pT2N0M0);however, the differences in serum uPA and uPAR lev-

els between patients with organ-confined disease andpatients with nonorgan-confined disease (pT3 ø orN+) were significant (P < 0.05 and P < 0.05, respec-tively) (Table III).

There were no significant differences in elevation ofserum level of uPA among BPH, organ-confined dis-ease, and nonorgan-confined disease; however, thedifference in the elevation of uPAR between organ-confined disease and nonorgan-confined disease wassignificant (P < 0.05) (Table III).

Relationship of Serum uPA and uPAR to PSA

The relationships between serum uPA and PSA lev-els and between serum uPAR and PSA levels in pros-

TABLE III. Serum uPA and uPA Levels in Patients With BPH and Prostate Cancer Who UnderwentRadical Prostatectomy*

Numberof

subjects

uPA (ng/ml) uPAR (ng/ml) Elevation (%)

Mean± SD

Pvalue

Mean± SD

Pvalue

uPA(%)

Pvalue

uPAR(%)

Pvalue

uPA oruPAR (%)

Pvalue

BPH 62 389 ± 163NS

4.2 ± 1.5NS

6 (10)NS

3 (5)NS

8 (13)NSOrgan-confined

prostate cancera 15 401 ± 147 4.4 ± 2.5 3 (20) 2 (13) 4 (27)Nonorgan-confined

prostate cancerb 16 517 ± 166<0.05

6.4 ± 2.7<0.05

4 (25)NS

8 (50)<0.05

10 (63)<0.05

*NS, not significant.apT1N0M0 or pT2N0M0.bpT3 ø or N+.

TABLE II. Elevation of Serum Levels of uPA and uPAR in Patients With BPH and Prostate Cancer*

Number ofsubjects (%)

Elevation (%)

uPA(%) P value

uPAR(%) P value

uPA oruPAR (%) P value

BPH 62 (100) 6 (10) 3 (5) 8 (13)Prostate cancer <0.005 <0.001 <0.001

Overall 72 (100) 25 (35) 29 (40) 39 (54)Clinical stage

T1 6 (8) 1 (17) 0 (0) 1 (17)T2 35 (49) 7 (20) <0.005 6 (17) <0.001 12 (34) <0.001T3 27 (38) 16 (59) 21 (78) 24 (89)T4 4 (5) 1 (25) 2 (50) 2 (50)

Metastasisa

Negative 25 (35) 4 (16) 4 (16) 7 (28)Positive 47 (65) 21 (45)

<0.0525 (53)

<0.00532 (68)

<0.005

Gleason score2–4 20 (28) 5 (25) 5 (25) 8 (40)5–7 23 (32) 8 (35) NS 10 (43) NS 13 (57) NS8–10 29 (40) 12 (41) 14 (48) 18 (62)

*NS, not significant.aEither lymph node metastasis or bone metastasis, or both.

126 Miyake et al.

tate cancer patients are shown in Figure 1A,B, respec-tively. There was no correlation between serum uPAlevel and PSA (r = 0.08) or between serum uPAR andPSA (r = 0.01).

Survival of Prostate Cancer Patients According toElevation of Serum uPA and uPAR

The overall survival rate of prostate cancer patientswith an elevated level of serum uPA was not signifi-cantly different from that of patients with a normallevel (Fig. 2A), and the difference in overall survivalrate between prostate cancer patients with an elevatedserum level of uPAR and patients with a normal levelwas also not significant (Fig. 2B). However, the overall

survival rate of prostate cancer patients with elevatedserum levels of either uPA or uPAR, or of both, wassignificantly lower than the survival rate of patientswith normal levels of both uPA and uPAR (P < 0.05)(Fig. 2C).

To compare the predictive value of serum uPA anduPAR status in prognosis, univariate and multivariateanalyses with the Cox regression hazards model wereperformed (Table IV); however, the elevation of serumlevels of either uPA or uPAR, or of both, was not anindependent prognostic predictor. The analyses fur-ther revealed that bone and/or lymph node metastasiswas strongly associated with overall survival (univari-ate analysis, P < 0.01; multivariate analysis, P < 0.05),

Fig. I. Relationships between serum uPA, uPAR, and PSA. A:Serum uPA level and PSA. B: Serum uPAR level and PSA.

Fig. 2. Overall survival rates of prostate cancer patients accord-ing to serum uPA and uPAR status. A: uPA. B: uPAR. C: EitheruPA or uPAR, or both. The overall survival rates of patients withelevated serum levels of either uPA or uPAR, or of both, weresignificantly lower than the overall survival rate of patients withnormal levels of both uPA and uPAR.

Serum uPA and uPAR in Prostate Cancer 127

regardless of uPA and uPAR status, age, PSA level,clinical stage, and Gleason score.

DISCUSSION

A number of clinical studies have demonstratedthat uPA and/or uPAR are overexpressed in severaltypes of human malignant tumors, including prostatecancer, and that the expression level of the uPA sys-tem closely correlates with tumor progression[6,8,18,19]. Several experimental findings also demon-strated that the uPA-uPAR system plays a crucial rolein invasion and metastasis of prostate cancer cells bothin vitro and in vivo [9–12]. Furthermore, recent studiesrevealed that serum levels of uPA and uPAR appear tobe indicative of malignancy in gastric and ovarian can-cer [13–15]. Therefore, in the present study, serum lev-els of uPA and uPAR were examined in healthy con-trols, and in BPH and prostate cancer patients, and aninvestigation of whether they could be used as predic-tors of disease progression and prognosis in prostatecancer patients was conducted.

In this series, we showed for the first time that bothserum uPA and uPAR levels in patients with prostatecancer were significantly higher than levels in patientswith BPH or in healthy controls. In addition, the el-evations of serum uPA and uPAR were much higherin prostate cancer patients with metastases than inthose without metastases. Soff et al. [11] and Rabbaniet al. [12] demonstrated that prostate cancer metasta-ses are suppressed by the inhibition of the uPA sys-tem, using human and rat prostate cancer cells, respec-tively. Considering these findings and our present re-sults, we conclude that the uPA and uPAR systemcontributes to prostate cancer development, and thatserum uPA and uPA levels can be used to predictprostate cancer progression.

In order to accurately distinguish prostate cancerpatients with organ-confined disease from those withnonorgan-confined disease preoperatively, severalmethods have been introduced into clinical practice,such as computerized tomography, magnetic reso-nance imaging, PSA density, and histological gradingof biopsy specimens [20]. However, even if thesemethods are combined, it remains difficult to correctlyidentify patients with nonorgan-confined disease. Inthe present study, the elevation of serum levels of ei-ther or both uPA and uPAR in patients with nonor-gan-confined disease was significantly higher thanthat in patients with organ-confined disease. Thesefindings indicate that levels of serum uPA and uPARare useful markers for the detection of patients withnonorgan-confined disease.

In this series, no significant correlation was ob-served between serum uPA and PSA levels, or be-tween serum uPAR and PSA levels. Therefore, serumuPA and uPAR levels can be regarded as clinical fac-tors independent of serum PSA.

It is of particular interest whether the elevations ofserum uPA and/or uPAR concentrations are associ-ated with the poor prognosis of prostate cancer pa-tients. In this study, we showed that the overall sur-vival rate of prostate cancer patients with either serumuPA or uPAR elevation, or both serum uPA and uPARelevation, was significantly lower than that of patientswith normal levels of uPA and uPAR. These findingssuggest that measurement of serum uPA and uPARmay provide additional information in determiningprognosis and patient treatment strategy, i.e., aggres-sive therapy should be performed in patients with el-evated serum levels of uPA and/or uPAR, whereaspatients with normal levels of both uPA and uPARmay not need to undergo intensive additional thera-pies if the initial treatment is successfully performed.

TABLE IV. Association of Various Factors With Overall Survival Determined by Cox Univariate and MultivariateProportional Hazards Model*

Variables

Univariate Multivariate

Hazardratio 95% CI P value

Hazardratio 95% CI P value

Serum uPA and uPAR status (normal vs. elevated)a 1.89 0.97–2.88 0.044 0.64 0.21–1.82 0.091Age (years) (<61 vs. $61) 1.19 0.58–2.69 0.74 1.34 0.55–3.11 0.30Clinical stage (T1 vs. T2 vs. T3 vs. T4) 1.98 1.11–3.20 0.041 2.14 0.88–2.21 0.16Gleason score (<8 vs. $8) 1.66 0.85–2.81 0.12 0.61 0.21–1.70 0.081PSA level (<10 ng/ml vs. $10 ng/ml) 1.39 0.61–2.96 0.16 1.89 0.70–1.91 0.15Metastasis (negative vs. positive)b 2.02 1.12–3.23 0.0079 3.56 1.19–8.67 0.019

*CI, confidence interval.aElevation of serum levels of either uPA or uPAR, or both.bEither lymph node metastasis or bone metastasis, or both.

128 Miyake et al.

In conclusion, our results suggest that uPA and/oruPAR expression is associated with the progression ofprostate cancer, and that serum uPA and uPAR levelsindicate the degree of prostate cancer progression andpatient prognosis. Hence, measurement of serum uPAand uPAR could serve as useful adjuncts to conven-tional diagnostic tools.

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