Skip to main content

Advertisement

SpringerLink
Log in

uPA/PAI-1 ratios distinguish benign prostatic hyperplasia and prostate cancer

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Urokinase plasminogen activator (uPA) and its inhibitor type 1 (PAI-1) are associated with tumour metabolism and are widely considered to be informative for the identification of cancer. We have analysed prostate tissue resections from patients with prostate cancer (PCa) and with benign prostatic hyperplasia (BPH) for protein levels of uPA and PAI-1, and searched for distinctions between these two clinical manifestations.

Methods

Prostate tissue was deep frozen in liquid N2 and homogenized in a stainless steel punch homogenizer. The tissue powder was extracted with a pH 8.5 TRIS/Triton X-100 buffer, and the extract analysed by FEMTELLE assay to generate uPA and PAI-1 readings in ng/mg protein. The uPA/PAI-1 ratio was calculated for each sample, and the mean ratios for the two diagnostic groups were compared.

Results

The concentration of uPA (mean ± SD) was found to be 0.19 ± 0.04 ng/mg protein (range 0.05–0.72 ng/mg) and 0.15 ± 0.02 ng/mg protein (range 0.03–0.78 ng/mg) in PCa and BPH samples, respectively. The concentration of PAI-1 was found to be 4.93 ± 0.90 ng/mg (range 1.10–11.80 ng/mg) and 5.87 ± 0.70 ng/mg (range 0.2–25.0 ng/mg) in PCa and BPH samples, respectively. A consistent finding being that PAI-1 concentrations exceed uPA concentrations by far giving rise to characteristic uPA/PAI-1 ratios. In BPH samples, there was a trend of PAI-1 to increase with uPA content, while in PCa samples, PAI-1 remained fairly constant. The mean uPA/PAI-1 ratio in PCa samples was found to be 0.06 ± 0.01 and was significantly higher than in BPH samples where the mean uPA/PAI-1 ratio was 0.03 ± 0.003 (p = 0.0028). R 2 = 0.1389.

Conclusion

Using a contingent of 62 patients of which 46 were BPH and 16 were PCa, we report definitive concentrations of uPA and PAI-1 in tumour tissue extracts and show that the uPA/PAI-1 ratio emerges as a candidate marker to distinguish between BPH and PCa.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abe J, Urano T, Konno H, Erhan Y, Tanaka T, Nishino N et al (1999) Larger and more invasive colorectal carcinoma contains larger amounts of plasminogen activator inhibitor type 1 and its relative ratio over urokinase receptor correlates well with tumor size. Cancer 86(12):2602–2611

    Article  PubMed  CAS  Google Scholar 

  • Andreasen PA, Kjøller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72(1):1–22 Review

    Article  PubMed  CAS  Google Scholar 

  • Angenete E, Langenskiöld M, Palmgren I, Falk P, Oresland T, Ivarsson ML (2009) uPA and PAI-1 in rectal cancer—relationship to radiotherapy and clinical outcome. J Surg Res 153(1):46–53

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Gharib TG, Huang CC, Taylor JM, Misek DE, Kardia SL et al (2002) Discordant protein and mRNA expression in lung adenocarcinomas. Mol Cell Proteomics 1(4):304–313

    Article  PubMed  CAS  Google Scholar 

  • Clark AJ, Ishii S, Richert N, Merlino GT, Pastan I (1985) Epidermal growth factor regulates the expression of its own receptor. Proc Natl Acad Sci USA 82(24):8374–8378

    Article  PubMed  CAS  Google Scholar 

  • Czekay RP et al (2011) PAI-1: an integrator of cell signaling and migration. Int J Cell Biol 2011: Article ID 562481. doi:1155/2011/562481

  • Danø K, Andreasen PA, Grøndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L (1985) Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44:139–266 Review

    Article  PubMed  Google Scholar 

  • de Veas RG, Schweigerer L, Medina MA (1998) Modulation of the proteolytic balance plasminogen activator/plasminogen activator inhibitor by enhanced N-myc oncogene expression or application of genistein. Eur J Cancer 34(11):1736–1740

    Article  Google Scholar 

  • Dong Z, Saliganan AD, Meng H, Nabha SM, Sabbota AL, Sheng S et al (2008) Prostate cancer cell-derived urokinase-type plasminogen activator contributes to intraosseous tumor growth and bone turnover. Neoplasia 10(5):439–449

    PubMed  CAS  Google Scholar 

  • Duffy MJ (2002) Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clin Chem 48(8):1194–1197 Review

    PubMed  CAS  Google Scholar 

  • Duffy MJ, McGowan PM, Gallagher WM (2008) Cancer invasion and metastasis: changing views. J Pathol 214(3):283–293 Review

    Article  PubMed  CAS  Google Scholar 

  • Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174

    Article  PubMed  CAS  Google Scholar 

  • Gupta A, Lotan Y, Ashfaq R, Roehrborn CG, Raj GV, Aragaki CC et al (2009) Predictive value of the differential expression of the urokinase plasminogen activation axis in radical prostatectomy patients. Eur Urol 55(5):1124–1133

    Article  PubMed  CAS  Google Scholar 

  • Gygi SP, Rochon Y, Franza BR, Aebersold R (1999) Correlation between protein and mRNA abundance in yeast. Mol Cell Biol 19(3):1720–1730

    PubMed  CAS  Google Scholar 

  • Harbeck N, Thomssen C, Berger U, Ulm K, Kates RE, Höfler H et al (1999) Invasion marker PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following first relapse. Breast Cancer Res Treat 54(2):147–157

    Article  PubMed  CAS  Google Scholar 

  • Harbeck N, Kates RE, Look MP, Meijer-Van Gelder ME, Klijn JG, Krüger A et al (2002) Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424). Cancer Res 62(16):4617–4622

    PubMed  CAS  Google Scholar 

  • Jänicke F, Pache L, Schmitt M, Ulm K, Thomssen C, Prechtl A et al (1994) Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1. Cancer Res 54(10):2527–2530

    PubMed  Google Scholar 

  • Jänicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M et al (2001) German N0 Study Group. 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(12):913–920

    Article  PubMed  Google Scholar 

  • Kantelhardt EJ, Hanf V, Weiss F, Ehrke C, Lantzsch T, Uleer C et al (2010) PiA Studie - Prognose im Alltag bei Patientinnen mit neu diagnostiziertem operablem Mammakarzinom. Risikoabschätzung anhand der Prognosemarker uPA/PAI-1 Senologie 2:133

    Google Scholar 

  • Kantelhardt EJ, Vetter M, Schmidt M, Veyret C, Augustin D, Hanf V et al (2011) Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: phase III NNBC3-Europe trial (AGO, GBG, EORTC-PBG) comparing 6 × FEC versus 3 × FEC/3 × Docetaxel. BMC Cancer 11:140

    Article  PubMed  CAS  Google Scholar 

  • Loskutoff DJ (1988) Type 1 plasminogen activator inhibitor. In: Coller BS (ed) Progress in hemostasis and thrombosis. WB Saunders, Philadelphia, pp 87–115

    Google Scholar 

  • Nekarda H, Schmitt M, Ulm K, Wenninger A, Vogelsang H, Becker K et al (1994) Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res 54(11):2900–2907

    PubMed  CAS  Google Scholar 

  • Nomiya T, Nemoto K, Miyachi H, Fujimoto K, Takahashi C, Takeda K et al (2002) Significance of plasminogen-activation system in the formation of macroscopic types and invasion in esophageal carcinoma. Anticancer Res 22(5):2913–2916

    PubMed  CAS  Google Scholar 

  • Oren M (1999) Regulation of the p53 tumor suppressor protein. J Biol Chem 274(51):36031–36034 Review

    Article  PubMed  CAS  Google Scholar 

  • Pappot H, Pedersen AN, Brünner N, Christensen IJ (2006) The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma: relation to prognosis. Lung Cancer 51(2):193–200

    Article  PubMed  Google Scholar 

  • Schmitt M, Mengele K, Napieralski R, Magdolen V, Reuning U, Gkazepis A et al (2010) Clinical utility of level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn 10(8):1051–1067 Review

    Article  PubMed  CAS  Google Scholar 

  • Schmitt M, Harbeck N, Brünner N, Jänicke F, Meisner C, Mühlenweg B et al (2011) Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn 11(6):617–634 Review

    Article  PubMed  CAS  Google Scholar 

  • Shariat SF, Park S, Trinh QD, Roehrborn CG, Slawin KM, Karakiewicz PI (2007) Plasminogen activation inhibitor-1 improves the predictive accuracy of prostate cancer nomograms. J Urol 178(4 Pt 1):1229–1236 discussion 1236–1237

    Article  PubMed  CAS  Google Scholar 

  • Taubert H, Würl P, Greither T, Kappler M, Bache M, Lautenschläger C et al (2010) Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients. Br J Cancer 102(4):731–737

    Article  PubMed  CAS  Google Scholar 

  • Tsurusaki T, Koji T, Sakai H, Kanetake H, Saito Y (1998) Expression profile of prostate-specific antigen messenger RNA assessed by in situ hybridization is a novel prognostic marker for patients with untreated prostate cancer. Clin Cancer Res 4(9):2187–2194

    PubMed  CAS  Google Scholar 

  • Usher PA, Thomsen OF, Iversen P, Johnsen M, Brünner N, Høyer-Hansen G et al (2005) Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue. Int J Cancer 113(6):870–880

    Article  PubMed  CAS  Google Scholar 

  • Vetter M, Kantelhardt EJ, Annecke K, Dittmer J, Paepke D, Prechtl A et al (2007) Invasionsfaktoren uPA/PAI-1 im Tumorgewebe bei Patientinnen mit primärem Mammakarzinom: Von Forschungsergebnissen zur klinischen Anwendung am Beispiel der NNBC 3-Europe-Studie. Geburtsh Frauenheilk 67:1144–1152

    Article  CAS  Google Scholar 

  • Witzel ID, Milde-Langosch K, Wirtz RM, Roth C, Ihnen M, Mahner S et al (2010) Comparison of microarray-based RNA expression with ELISA-based protein determination of HER2, uPA and PAI-1 in tumour tissue of patients with breast cancer and relation to outcome. J Cancer Res Clin Oncol 136(11):1709–1718

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Drs. K. du Toit, J. Basson, H. van Heerden, S. Wessels and C. van der Walt of the Urology Department for prostate resections and Dr. M. Vetter for advice on the utilization of the FEMTELLE assay. Financial support was received from the University of Stellenbosch Faculty of Medicine and Health Sciences, and the Cancer Association of South Africa (CANSA) to LB. Material and travel support from AMERICAN DIAGNOSTICA (Pfungstadt, Germany) is also gratefully acknowledged.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Imaging and Clinical Oncology¸ Faculty of Medicine and Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg, 7505, South Africa

    Lothar Böhm, Antonio Serafin & John Akudugu

  2. Department of Urology, Faculty of Medicine and Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg, 7505, South Africa

    Pedro Fernandez & Andre van der Merwe

  3. Gatesville Medical Centre, Yusuf Gool Boulevard, Athlone, 7764, South Africa

    Naseem A. Aziz

Authors
  1. Lothar Böhm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Serafin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Akudugu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pedro Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andre van der Merwe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naseem A. Aziz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lothar Böhm.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Böhm, L., Serafin, A., Akudugu, J. et al. uPA/PAI-1 ratios distinguish benign prostatic hyperplasia and prostate cancer. J Cancer Res Clin Oncol 139, 1221–1228 (2013). https://doi.org/10.1007/s00432-013-1428-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-013-1428-y

Keywords

Search

Navigation