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Association of the Circulating Levels of the Urokinase System of Plasminogen Activation With the Presence of Prostate Cancer and Invasion, Progression, and Metastasis

Shahrokh F. Shariat, Claus G. Roehrborn, John D. McConnell, Sangtae Park, Nina Alam, Thomas M. Wheeler, Kevin M. Slawin

From the Departments of Urology and Pathology, University of Texas Southwestern Medical Center, Dallas; and Baylor Prostate Center, Scott Department of Urology and Department of Pathology, Baylor College of Medicine, Houston, TX

Address reprint requests to Shahrokh F. Shariat, MD, Department of Urology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9110; e-mail: Shahrokh.Shariat{at}UTSouthwestern.edu

	ABSTRACT

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Purpose: To assess whether preoperative plasma levels of urokinase-type plasminogen activator (uPA) and its soluble receptor (uPAR) would predict cancer of the prostate (CaP) presence, stage, and prognosis.

Patients and Methods: Plasma levels of uPA and uPAR were measured in patients who underwent radical prostatectomy for clinically localized CaP (preoperative, n = 429; postoperative, n = 76), 44 healthy men, 19 patients with metastases to regional lymph nodes, and 10 patients with bone metastases.

Results: uPA and uPAR levels were significantly elevated in patients with CaP compared with healthy men and significantly declined after prostate removal. In CaP patients, uPA and uPAR levels both increased significantly from patients with nonmetastatic CaP to patients with lymph node metastases to patients with skeletal metastases. On univariate analysis, preoperative uPA and uPAR levels were significantly elevated in patients with extracapsular extension, seminal vesicle involvement, higher prostatectomy Gleason sum, lymph node invasion, lymphovascular invasion, perineural invasion, and higher tumor volume. Higher preoperative uPAR was associated with biochemical progression in univariate analysis. Conversely, higher preoperative uPA was independently associated with biochemical progression in preoperative or postoperative multivariate models. In patients with biochemical progression, preoperative uPA and uPAR were both significantly associated with shorter postprogression total serum prostate-specific antigen doubling times, failure to respond to salvage local radiation therapy, and/or development of distant metastasis.

Conclusion: Elevation of plasma uPA and uPAR levels in CaP patients seems to be partly caused by local release from the prostate. Plasma levels of uPA and uPAR are associated with features of biologically aggressive CaP, disease progression after radical prostatectomy, and metastasis.

	INTRODUCTION

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The urokinase plasminogen activation (uPA) system plays a key role in degrading the extracellular matrix and basement membrane, thereby promoting metastasis and angiogenesis.^1-3 The inactive precursor of the serine protease, uPA, is activated by binding a specific membrane-bound or soluble cell surface receptor (urokinase-type plasminogen activator receptor [uPAR]), which accelerates the conversion of plasminogen into plasmin. Plasmin, in turn, degrades a wide spectrum of extracellular matrix proteins and basement membrane components through activation of a cascade of proteases, including metalloproteinases. uPAR plays a key role not only in localizing uPA activity, but also in mediating various signaling events essential for the differentiation and migration of cells within the tumor environment.^4,5

In recent years, growing evidence has demonstrated that the components of the uPA axis are also involved in other processes independent of plasmin formation such as cell proliferation, chemotaxis, cell adhesion, and angiogenesis.^1-3 Increased local expression of components of the uPA system has been associated with pathologic features and disease prognosis for patients with various cancers.⁶ Tissue levels of uPA and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) were the first biologic markers to have been validated in a prospective randomized trial⁷ and a pooled analysis of 8,377 breast cancer patients.⁸ Specifically, it has been shown that node-negative breast cancer patients with low tissue levels of uPA concentrations are at low risk of disease relapse and therefore are unlikely to benefit from adjuvant chemotherapy, whereas those with high tissue levels of uPA and/or PAI-1 are more likely to benefit from adjuvant cyclophosphamide, methotrexate, and fluorouracil.⁷ Moreover, elevated circulating levels of uPA and uPAR have been associated with poor prognosis in patients with different cancers.^9-12

In prostate cancer (CaP), increased levels of uPA and uPAR have been shown to be associated with tumor invasion^13-15 and osteoblastic metastases.¹⁶ Immunohistochemical studies have shown an incremental increase in uPA expression from benign epithelium to primary organ-confined CaP, to CaP extending beyond the prostatic capsule, and to skeletal metastases.^17-20 Elevated circulating levels of uPA and/or uPAR have been associated with advanced CaP stage and bone metastases.^21-23 However, the prognostic value of circulating levels of uPA and uPAR in patients diagnosed with clinically localized CaP has not yet been studied. In addition, the origin of the components of the uPA system of plasminogen activation in CaP remains speculative.

We hypothesized that men with apparently clinically localized CaP harboring occult metastases would also have elevated plasma levels of components of the uPA system of plasminogen activation that would be associated with a higher risk of biochemical progression despite effective local control of disease. Therefore, to determine the relationship of the major components of the uPA system with established markers of CaP presence, invasion, metastasis, and progression, we studied pre- and postoperative plasma levels of uPA and uPAR in patients with clinically localized CaP who underwent radical prostatectomy, patients with CaP metastases to regional lymph nodes, patients with newly diagnosed CaP metastases to bone, and healthy men. The availability of pre- and postoperative plasma specimens provided a unique opportunity to study the origin of circulating components of the uPA system in CaP patients.

	PATIENTS AND METHODS

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Patient Population
All studies were undertaken with the approval and oversight of the institutional review board for the protection of human patients at each institution. We measured plasma uPA and uPAR levels in 44 healthy patients without cancer, 19 patients with CaP metastatic to regional lymph nodes, and 10 patients with bone scan–proven, metastatic CaP. These patients were recruited in a nonconsecutive manner between January 12, 1994 and May 5, 1998. The patients with metastatic lymph node or bone disease were not treated with either hormonal therapy or radiation therapy before plasma collection. The healthy noncancer group had no previous history of any cancer or chronic disease, had a normal digital rectal examination, and had total serum prostate-specific antigen (T-PSA) levels of less than 2.0 ng/mL.

In addition, we measured preoperative plasma levels of uPA and uPAR in 429 patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma at The University of Texas Southwestern Medical Center (Dallas, TX) and Baylor College of Medicine (Houston, TX) during the period from July 12, 1994 through March 29, 2004. We also measured postoperative plasma levels of uPA and uPAR 6 to 8 weeks after radical prostatectomy in a convenience sample of 76 of the 429 patients who had undetectable postoperative T-PSA levels. No patient was treated preoperatively with either hormonal or radiation therapy, and none had secondary cancers. The clinical stage was assigned by the operative surgeon according to the 1992 TNM system. The mean patient age in this study was 60.8 ± 7.2 years (median, 61.3 years; range, 39.4 to 75.5 years). T-PSA was measured by the Hybritech Tandem-R assay (Hybritech Inc, San Diego, CA). Staff pathologists from our institution, who were blinded to clinical outcome, examined all prostatectomy specimens pathologically in accordance with the guidelines of the College of American Pathologists.²⁴

uPA, uPAR, and Plasminogen Activator Inhibitor Type 2 Measurements
Preoperative serum and plasma samples were collected at least 4 weeks after transrectal guided needle biopsy of the prostate, typically on the morning of the day of surgery after an overnight fast. Postoperative plasma samples were collected between 6 and 8 weeks after surgery. Blood was collected into Vacutainer CPT tubes (Becton Dickinson, Franklin Lakes, NJ) containing sodium citrate anticoagulant and centrifuged at room temperature for 20 minutes at 1,500 x g. The top layer, corresponding to diluted plasma, was decanted using sterile transfer pipettes and immediately frozen and stored at –80°C in polypropylene cryopreservation vials (Nalge Nunc, Rochester, NY). For quantitative measurements of serum and plasma uPA, uPAR, and plasminogen activator inhibitor type 2 (PAI-2) levels, we used specific quantitative sandwich enzyme immunoassays (American Diagnostica, Greenwich, CT). Every sample was run in duplicate, and the mean was calculated for data analysis. Differences between the two measurements were minimal, as shown by the intra-assay precision coefficient of variation of only 7.5% ± 3.0% for uPA and 8.5% ± 6.7% for uPAR. Plasma plasminogen activator inhibitor type 2 levels were undetectable in 81 of the first 120 prostatectomy patients and, therefore, were not included in the outcome analyses.

Postoperative Follow-Up
Patients generally were scheduled to have a digital rectal examination and serum T-PSA evaluation postoperatively every 3 months for the first year, semiannually from the second through the fifth years, and annually thereafter. Biochemical progression was defined as a sustained elevation, on two or more occasions, of T-PSA more than 0.2 ng/mL and was assigned to the date of the first value more than 0.2 ng/mL. Patients who received adjuvant radiation therapy before biochemical progression because of clinical or pathologic characteristics were considered to have disease progression from the date of the first T-PSA value more than 0.2 ng/mL. Surgery was halted before prostate removal in two of 14 patients with lymph node–positive disease at the time of radical prostatectomy. These two patients were categorized among those with biochemical progression from the day after surgery. For patients who had biochemical progression, postprogression T-PSA doubling time was calculated using the following formula: T-PSA doubling time = ln(2) x T/[log(final T-PSA) – log(initial T-PSA)].²⁵ All patients had to have at least three T-PSA measurements available after biochemical progression. T-PSA doubling time calculations could not be performed in nine patients because of start of hormonal therapy for persistent T-PSA elevation after surgery and/or metastases.

Statistical Analysis
Differences in uPA and uPAR levels between clinical and pathologic features were tested using the Mann-Whitney U and Kruskal-Wallis tests. Spearman rank correlation coefficient was used to compare ordinal and continuous variables. Logistic regression methodology was used for multivariate analysis of binary outcome variables. The Kaplan-Meier method was used to calculate survival functions, and differences were assessed with the log-rank statistic. Multivariate survival analyses were performed using the Cox proportional hazards regression model. Preoperative levels of T-PSA, uPA, and uPAR had skewed distributions and, therefore, were modeled with a log transformation. Differences in uPA and uPAR levels between pre- and postoperative samples were tested using the Wilcoxon signed rank test. Statistical significance in this study was set as P .05. All reported P values are two sided. All analyses were performed with SPSS statistical package version 13.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Difference in Plasma Levels of uPA and uPAR Between Healthy Men, Patients With Clinically Localized CaP, and Patients With Metastatic CaP
Plasma levels of uPA and uPAR in the different men are listed in Table 1 and shown in Figures 1A and 1B. Plasma uPA and uPAR levels were significantly higher in patients with bone metastases compared with all other groups (all P .044). Plasma uPA and uPAR levels were significantly higher in patients with lymph node metastases compared with prostatectomy patients without lymph node metastases and healthy controls (both P < .001). Plasma uPA and uPAR levels were significantly higher in prostatectomy patients without lymph node metastases compared with healthy controls (P < .040). There were no statistical differences in age between groups.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Plots of the median, 10th, 25th, 75th, and 90th percentiles of (A) preoperative urokinase-type plasminogen activator (uPA) levels and (B) preoperative uPA receptor (uPAR) levels in healthy men, radical prostatectomy patients stratified by pathologic stage, and patients with prostate cancer metastatic to lymph nodes or to bones as vertical boxes with error bars.

Association of Preoperative Plasma Levels of uPA and uPA With Biochemical CaP Progression
Overall, 19.3% of patients (83 of 429 patients) experienced biochemical progression with a median postoperative follow-up time of 37.0 months (range, 0.9 to 103.8 months). The estimated biochemical progression-free survival rates (± SE) were 78.1% ± 2.4% at 3 years after surgery and 75.2% ± 2.6% at 5 years after surgery. uPA and uPAR were analyzed as categoric variables on the basis of their tertile distribution in the prostatectomy patients. The distributions of both uPA and uPAR in patients who experienced biochemical progression were skewed towards the highest tertile compared with patients who did not experience biochemical progression (Figs 2A and 2B).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimates of biochemical progression-free survival probability for the 429 patients treated with radical prostatectomy for clinically localized prostate cancer stratified into (A) preoperative urokinase-type plasminogen activator (uPA) tertiles and (B) preoperative uPA receptor (uPAR) tertiles.

Differences Between Pre- and Postprostatectomy Plasma Levels of uPA and uPAR
We measured plasma uPA and uPAR levels in 76 patients before radical prostatectomy and 6 to 8 weeks after radical prostatectomy. Postoperative uPA and uPAR levels (median, 0.24 ng/mL; range, 0.10 to 0.72 ng/mL; and median, 1.5 ng/mL; range, 0.8 to 2.8 ng/mL, respectively) were lower (P < .001 and P = .037, respectively) than preoperative levels (median, 0.41 ng/mL; range, 0.10 to 0.80 ng/mL; and median, 1.7 ng/mL; range, 0.3 to 3.1 ng/mL, respectively).

	DISCUSSION

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Circulating levels of uPA and uPAR were higher in patients with CaP compared with healthy controls and decreased significantly after radical prostatectomy. In patients with CaP, plasma levels of uPA and uPAR were both higher in patients with CaP metastatic to bones than in patients with metastases to regional lymph nodes, who in turn had higher levels than patients with nonmetastatic CaP. Among patients with clinically localized CaP who underwent radical prostatectomy, preoperative plasma levels of uPA and uPAR were both significantly elevated in patients with features of biologically aggressive disease such as extracapsular extension, seminal vesicle involvement, higher prostatectomy Gleason sum, lymph node metastases, lymphovascular invasion, and perineural invasion. Preoperative uPAR level was associated with biochemical progression after radical prostatectomy in univariate but not multivariate analyses. In contrast, in both pre- and postoperative multivariate analyses, higher preoperative uPA level was associated with biochemical progression after surgery. Finally, in patients who experienced disease progression, preoperative plasma levels of uPA and uPAR were significantly higher in patients with features of aggressive progression compared with patients with features of nonaggressive progression.

In concordance with one previous study,²³ we found that circulating levels of uPA and uPAR were both higher in CaP patients compared with healthy men without cancer. However, because of a large overlap in uPA and uPAR levels between the groups, use of these markers for early diagnosis of CaP is questionable. The exact source and biologic role of the elevated levels of circulating uPA and uPAR in CaP patients is not clearly defined. Holst-Hansen et al²⁶ recently demonstrated that uPAR is directly released by breast cancer cells in a cell-dependent manner with a constant and direct correlation between cell number and amount of uPAR released. In addition, they showed that tumor cells in breast cancer xenograft models release uPAR into blood and that the concentration of plasma uPAR is highly correlated with tumor volume. These findings, together with the association of circulating uPA and uPAR levels with prostatic tumor burden and their significant decrease after prostate removal, suggest that direct local production by malignant cells significantly contributes to the increased circulating levels of these markers in patients with CaP. This increased shedding of uPA and uPAR in cancer could be caused by release from the surface of tumor cells and/or stromal cells in the cancer tissue as a result of increased intratumoral proteolysis. However, the release of circulating uPA and uPAR from the tumor to the blood may not be proportional to the amount of uPA and uPAR present in the tumor tissue. Indeed, Riisbro et al²⁷ did not find any correlation between uPAR levels in serum and tumor cytosols of breast cancer patients, suggesting that the increased circulating levels found in breast cancer patients could not have been solely the result of an increased amount of uPAR being shed from the primary tumor tissue. In multivariate analyses, these authors found that plasma levels of uPAR were associated with relapse or early death, whereas uPAR levels in tumor cytosol were not. In agreement with these findings, a growing body of evidence supports the theory or suggests that some of the increase in blood uPA and uPAR levels could occur because of a systematic reaction to the malignant cells, including activation of blood monocytes and neutrophils.

We found that plasma levels of uPA and uPAR were elevated in patients who had features of biologically aggressive CaP such as higher biopsy Gleason sum, extraprostatic extension, seminal vesicle involvement, higher prostatectomy Gleason sum, lymph node invasion, lymphovascular invasion, perineural invasion, and higher prostatectomy tumor volume. More importantly, preoperative uPA was an independent predictor of biochemical disease progression after adjustments for the effects of pre- and postoperative standard features. In contrast, preoperative plasma uPAR was associated with biochemical progression only in univariate analysis. However, only 19% of our patient cohort experienced biochemical disease progression after a median follow-up time of approximately 3 years. In addition, most of the patients in our study had favorable clinicopathologic features. Thus, the lack of independent association of preoperative uPAR with biochemical progression after surgery may be a result of a lack of association with local and/or biologically more indolent disease. In support of this hypothesis, patients with features of aggressive progression had higher levels of uPAR than patients with features of nonaggressive progression. Nevertheless, larger studies with more events and longer follow-up times are required for a more definitive statement regarding the association of preoperative uPA and uPAR levels with CaP progression and, more importantly, profound clinical end points such as metastases and survival.

In conclusion, plasma levels of uPA and uPAR were markedly elevated in men with CaP metastatic to bone. In addition, they were significantly higher in patients with clinically localized and metastatic CaP than in healthy men. Furthermore, we found that these higher circulating levels of uPA and uPAR probably were at least in part prostatic in origin because they decreased significantly after the prostate was removed. In men without clinical evidence of metastases, preoperative plasma uPA was a strong predictor of biochemical progression after surgery. Preoperative uPA and uPAR levels were both associated with features of aggressive CaP progression, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy. Larger, prospective studies are required to validate uPA and uPAR as markers of the metastatic CaP phenotype and to construct potentially better preoperative predictive models of early metastases and disease progression after definitive local therapy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Shahrokh F. Shariat, Kevin M. Slawin

Financial support: Shahrokh F. Shariat, Claus G. Roehrborn, Kevin M. Slawin

Administrative support: Claus G. Roehrborn, John D. McConnell, Thomas M. Wheeler, Kevin M. Slawin

Provision of study materials or patients: Shahrokh F. Shariat, Claus G.Roehrborn, John D. McConnell, Nina Alam, Thomas M. Wheeler, Kevin M. Slawin

Collection and assembly of data: Shahrokh F. Shariat, Sangtae Park, Nina Alam, Thomas M. Wheeler

Data analysis and interpretation: Shahrokh F. Shariat, Kevin M. Slawin

Manuscript writing: Shahrokh F. Shariat

Final approval of manuscript: Shahrokh F. Shariat, Claus G. Roehrborn, John D. McConnell, Sangtae Park, Nina Alam, Thomas M. Wheeler, Kevin M. Slawin

	Appendix

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Impact of collection formats on uPA, uPAR, and PAI-1 levels.
In a preliminary study, we assessed the effect of different collection formats on uPA, uPAR, and PAI-1 levels. We obtained three synchronously drawn blood specimens from 10 randomly selected healthy controls. Plasma was separated using VacutainerK₃EDTA 5-mL tubes containing 0.057 mL of 15% K₃ EDTA solution (Becton Dickinson, Franklin Lakes, NJ) or VacutainerCPT 8-mL tubes containing sodium citrate (Becton Dickinson). Serum was separated using Vacutainer Brand SST Serum Separator tubes (Becton Dickinson). Mean values of uPA, uPAR, and PAI-1 levels measured in citrate plasma from VacutainerCPT tubes were 28%, 33%, and 23% lower than the values measured in VacutainerK₃EDTA plasma, respectively, and 36%, 39%, and 41% lower than the values measured in serum, respectively. The lower uPA, uPAR, and PAI-1 values obtained with the citrate plasma were attributable to dilution of the top plasma layer primarily by 1.0 mL of 0.1 M sodium citrate anticoagulant. Although absolute uPA, uPAR, and PAI-1 levels measured in serum and in plasma using different collection formats were significantly different (all P < .001), all three collection formats were highly correlated with each other (uPA, rho 0.73; uPAR, rho 0.67; and PAI-1, rho 0.78; all P < .001). uPA and uPAR are involved in platelet formation and senescence (Stephens RW, Pedersen AN, Nielsen HJ, et al. Clin Chem 43:1868-1876, 1997; Wohn KD, Kanse SM, Deutsch V, et al. Thromb Haemost 77:540-547, 1997). Although serum measurements of uPA have been reported to be variable and often highly nonspecific, citrate and EDTA plasma resulted in fewer nonspecific signals (Riisbro R, Christensen IJ, Piironen T, et al. Clin Cancer Res 8:1132-1141, 2002). Therefore, to avoid potential interferences, we used plasma from VacutainerCPT sodium citrate tubes for uPA, uPAR, and PAI-1 measurements for our study.

	NOTES

 
Supported by the Austrian Program for Advanced Research and Technology.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Andreasen PA, Kjoller L, Christensen L, et al: The urokinase-type plasminogen activator system in cancer metastasis: A review. Int J Cancer 72:1-22, 1997[CrossRef][Medline]

2. Chapman HA: Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr Opin Cell Biol 9:714-724, 1997[CrossRef][Medline]

3. Rabbani SA, Mazar AP: The role of the plasminogen activation system in angiogenesis and metastasis. Surg Oncol Clin N Am 10:393-415, 2001[Medline]

4. Xing RH, Rabbani SA: Overexpression of urokinase receptor in breast cancer cells results in increased tumor invasion, growth and metastasis. Int J Cancer 67:423-429, 1996[CrossRef][Medline]

5. Busso N, Masur SK, Lazega D, et al: Induction of cell migration by pro-urokinase binding to its receptor: Possible mechanism for signal transduction in human epithelial cells. J Cell Biol 126:259-270, 1994[Abstract/Free Full Text]

6. Duffy MJ: Urokinase-type plasminogen activator: A potent marker of metastatic potential in human cancers. Biochem Soc Trans 30:207-210, 2002[CrossRef][Medline]

7. Janicke F, Prechtl A, Thomssen C, et al: Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 93:913-920, 2001[Abstract/Free Full Text]

8. Look MP: Pooled analysis of uPA and PAI-1 for prognosis in primary breast cancer patients: EORTC Receptor and Biomarker Study Group. Int J Biol Markers 15:70-72, 2000[Medline]

9. Sier CF, Stephens R, Bizik J, et al: The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res 58:1843-1849, 1998[Abstract/Free Full Text]

10. Fernebro E, Madsen RR, Ferno M, et al: Prognostic importance of the soluble plasminogen activator receptor, suPAR, in plasma from rectal cancer patients. Eur J Cancer 37:486-491, 2001[CrossRef][Medline]

11. Stephens RW, Nielsen HJ, Christensen IJ, et al: Plasma urokinase receptor levels in patients with colorectal cancer: Relationship to prognosis. J Natl Cancer Inst 91:869-874, 1999[Abstract/Free Full Text]

12. Shariat SF, Monoski MA, Andrews B, et al: Association of plasma urokinase-type plasminogen activator and its receptor with clinical outcome in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder. Urology 61:1053-1058, 2003[CrossRef][Medline]

13. Gaylis FD, Keer HN, Wilson MJ, et al: Plasminogen activators in human prostate cancer cell lines and tumors: Correlation with the aggressive phenotype. J Urol 142:193-198, 1989[Medline]

14. Keer HN, Gaylis FD, Kozlowski JM, et al: Heterogeneity in plasminogen activator (PA) levels in human prostate cancer cell lines: Increased PA activity correlates with biologically aggressive behavior. Prostate 18:201-214, 1991[Medline]

15. Hoosein NM, Boyd DD, Hollas WJ, et al: Involvement of urokinase and its receptor in the invasiveness of human prostatic carcinoma cell lines. Cancer Commun 3:255-264, 1991[Medline]

16. Achbarou A, Kaiser S, Tremblay G, et al: Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res 54:2372-2377, 1994[Abstract/Free Full Text]

17. Kirchheimer JC, Pfluger H, Ritschl P, et al: Plasminogen activator activity in bone metastases of prostatic carcinomas as compared to primary tumors. Invasion Metastasis 5:344-355, 1985[Medline]

18. Kirchheimer J, Koller A, Binder BR: Isolation and characterization of plasminogen activators from hyperplastic and malignant prostate tissue. Biochim Biophys Acta 797:256-265, 1984[Medline]

19. Camiolo SM, Markus G, Englander LS, et al: Plasminogen activator content and secretion in explants of neoplastic and benign human prostate tissues. Cancer Res 44:311-318, 1984[Abstract/Free Full Text]

20. Van Veldhuizen PJ, Sadasivan R, Cherian R, et al: Urokinase-type plasminogen activator expression in human prostate carcinomas. Am J Med Sci 312:8-11, 1996[CrossRef][Medline]

21. Hienert G, Kirchheimer JC, Christ G, et al: Plasma urokinase-type plasminogen activator correlates to bone scintigraphy in prostatic carcinoma. Eur Urol 15:256-258, 1988[Medline]

22. Hienert G, Kirchheimer JC, Pfluger H, et al: Urokinase-type plasminogen activator as a marker for the formation of distant metastases in prostatic carcinomas. J Urol 140:1466-1469, 1988[Medline]

23. Miyake H, Hara I, Yamanaka K, et al: Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate 39:123-129, 1999[CrossRef][Medline]

24. Henson DE, Hutter RV, Farrow G: Practice protocol for the examination of specimens removed from patients with carcinoma of the prostate gland: A publication of the Cancer Committee, College of American Pathologists, Task Force on the Examination of Specimens Removed From Patients With Prostate Cancer. Arch Pathol Lab Med 118:779-783, 1994[Medline]

25. Schmid HP, McNeal JE, Stamey TA: Observations on the doubling time of prostate cancer: The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 71:2031-2040, 1993[CrossRef][Medline]

26. Holst-Hansen C, Hamers MJ, Johannessen BE, et al: Soluble urokinase receptor released from human carcinoma cells: A plasma parameter for xenograft tumour studies. Br J Cancer 81:203-211, 1999[CrossRef][Medline]

27. Riisbro R, Christensen IJ, Piironen T, et al: Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin Cancer Res 8:1132-1141, 2002[Abstract/Free Full Text]

Submitted January 11, 2006; accepted July 31, 2006.

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