Advertisement

World Journal of Surgery

, Volume 31, Issue 3, pp 493–502 | Cite as

High Expression of Plasminogen Activator Inhibitor-2 (PAI-2) is a Predictor of Improved Survival in Patients with Pancreatic Adenocarcinoma

  • Ross SmithEmail author
  • AiQun Xue
  • Anthony Gill
  • Christopher Scarlett
  • Alexander Saxby
  • Adele Clarkson
  • Thomas Hugh
Article

Abstract

Objective

Recent findings suggest that the urokinase-type plasminogen activator (uPA), its receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and -2 (PAI-2) play key roles in cancer invasion.

Summary Background Data

The prognostic value of components of this system is well established in breast cancer. However, little is known of its involvement in pancreatic cancer (PC).

Methods

Quantitative real-time polymerase chain reaction (Q-RT-PCR) was used on tissue-banked specimens and immunohistochemistry (IHC) on paraffin specimens was used to measure expression of uPA, uPAR, PAI-1, and PAI-2 proteins in 46 PC and 12 cystadenoma specimens. Results were related to survival using Cox’s proportional hazards testing.

Results

Increased expression of uPA, uPAR, and PAI-1 in PC tissue were independently associated with a higher Union Internationale Contre le Cancer [International Union Against Cancer (UICC)] tumor stage (P < 0.001) and were intercorrelated (P < 0.001). Overexpression of uPAR indicated reduced survival (P = 0.03). Conversely, PAI-2 messenger ribonucleic acid (mRNA) overexpression, which occurred in 21 of 46 tumors, negatively correlated with tumor size (P = 0.008) and survival (P < 0.007) but not with uPA, uPAR, or tumor stage. There was good agreement between PAI-2 mRNA value and IHC score (P < 0.001). Using Cox’s stepwise analysis, PAI-2 mRNA value (HR = 0.24; P = 0.001) and UICC tumor stage (HR = 2.014; P = 0.001) independently predicted survival. An IHC score for PAI-2 of 3+ or 4+ also independently predicted improved survival (HR = 2.72; P = 0.025).

Conclusions

The uPA/uPAR/PAI-1 system is activated in advanced pancreatic cancer and may account for the tumor’s aggressive behavior, whereas PAI-2 expression appears to be independent of uPA/uPAR/PAI-1 and is associated with improved prognosis. Because of its intercorrelation with mRNA expression, PAI-2 IHC may be used as an indicator of survival.

Keywords

Pancreatic Cancer Japan Pancreas Society Tumor Tissue Level UICC Tumor Stage Neural Plexus Invasion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank Dr. Jaswinder S. Samra for kindly providing pancreatic samples, and Prof. Barry Allen for his insightful discussions concerning PAI-2. This study was supported by the Cancer Surgery Research Foundation (CanSur) and G.J. Tattersall’s Pty Ltd.

References

  1. 1.
    Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8–29PubMedCrossRefGoogle Scholar
  2. 2.
    Parker SL, Tong T, Bolden S, et al. Cancer statistics, 1997. CA Cancer J Clin 1997;47:5–27PubMedGoogle Scholar
  3. 3.
    Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 1997;225:621–633PubMedCrossRefGoogle Scholar
  4. 4.
    Kern S, Hruban R, Hollingsworth MA, et al. A white paper: the product of a pancreas cancer think tank. Cancer Res 2001;61:4923–4932PubMedGoogle Scholar
  5. 5.
    Seo Y, Baba H, Fukuda T, et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000;88:2239–2245PubMedCrossRefGoogle Scholar
  6. 6.
    Ellenrieder V, Adler G, Gress TM. Invasion and metastasis in pancreatic cancer. Ann Oncol 1999;10 (Suppl 4):46–50PubMedCrossRefGoogle Scholar
  7. 7.
    Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993;73:161–195PubMedGoogle Scholar
  8. 8.
    Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993;73:161–195PubMedGoogle Scholar
  9. 9.
    Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol 2000;10:415–433PubMedCrossRefGoogle Scholar
  10. 10.
    Blasi F, Vassalli JD, Dano K. Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors. J Cell Biol 1987;104:801–804PubMedCrossRefGoogle Scholar
  11. 11.
    Kwaan HC. The plasminogen-plasmin system in malignancy. Cancer Metastasis Rev 1992;11:291–311PubMedCrossRefGoogle Scholar
  12. 12.
    Liotta LA, Goldfarb RH, Brundage R, et al. Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. Cancer Res 1981;41:4629–4636PubMedGoogle Scholar
  13. 13.
    Murphy G, Atkinson S, Ward R, et al. The role of plasminogen activators in the regulation of connective tissue metalloproteinases. Ann N Y Acad Sci 1992;667:1–12PubMedCrossRefGoogle Scholar
  14. 14.
    Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004;10:39–49PubMedCrossRefGoogle Scholar
  15. 15.
    Borgfeldt C, Bendahl PO, Gustavsson B, et al. High tumor tissue concentration of urokinase plasminogen activator receptor is associated with good prognosis in patients with ovarian cancer. Int J Cancer 2003;107:658–665PubMedCrossRefGoogle Scholar
  16. 16.
    Foekens JA, Peters HA, Look MP, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000;60:636–643PubMedGoogle Scholar
  17. 17.
    Look MP, van Putten WL, Duffy MJ, et al. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 2002;94:116–128PubMedGoogle Scholar
  18. 18.
    Nordengren J, Fredstorp LM, Bendahl PO, et al. High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer. Int J Cancer 2002;97:379–385PubMedCrossRefGoogle Scholar
  19. 19.
    Salden M, Splinter TA, Peters HA, et al. The urokinase-type plasminogen activator system in resected non-small-cell lung cancer. Rotterdam Oncology Thoracic Study Group. Ann Oncol 2000;11:327–332PubMedCrossRefGoogle Scholar
  20. 20.
    Sheng S. The urokinase-type plasminogen activator system in prostate cancer metastasis. Cancer Metastasis Rev 2001;20:287–296PubMedCrossRefGoogle Scholar
  21. 21.
    Yang JL, Seetoo D, Wang Y, et al. Urokinase-type plasminogen activator and its receptor in colorectal cancer: independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. Int J Cancer 2000;89:431–439PubMedCrossRefGoogle Scholar
  22. 22.
    Cufer T, Borstnar S, Vrhovec I. Prognostic and predictive value of the urokinase-type plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in operable breast cancer. Int J Biol Markers 2003;18:106–115PubMedGoogle Scholar
  23. 23.
    Fredstorp-Lidebring M, Bendahl PO, Brunner N, et al. Urokinase plasminogen activator and its inhibitor, PAI-1, in association with progression-free survival in early stage endometrial cancer. Eur J Cancer 2001;37:2339–2348PubMedCrossRefGoogle Scholar
  24. 24.
    Borgfeldt C, Bendahl PO, Gustavsson B, et al. High tumor tissue concentration of urokinase plasminogen activator receptor is associated with good prognosis in patients with ovarian cancer. Int J Cancer 2003;107:658–665PubMedCrossRefGoogle Scholar
  25. 25.
    Cufer T, Borstnar S, Vrhovec I. Prognostic and predictive value of the urokinase-type plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in operable breast cancer. Int J Biol Markers 2003;18:106–115PubMedGoogle Scholar
  26. 26.
    Nagayama M, Sato A, Hayakawa H, et al. Plasminogen activators and their inhibitors in non-small cell lung cancer. Low content of type 2 plasminogen activator inhibitor associated with tumor dissemination. Cancer 1994;73:1398–1405PubMedCrossRefGoogle Scholar
  27. 27.
    Chambers SK, Gertz RE Jr, Ivins CM, et al. The significance of urokinase- type plasminogen activator, its inhibitors, and its receptor in ascites of patients with epithelial ovarian cancer. Cancer 1995;75:1627–1633PubMedCrossRefGoogle Scholar
  28. 28.
    Verspaget HW, Sier CF, Ganesh S, et al. Prognostic value of plasminogen activators and their inhibitors in colorectal cancer. Eur J Cancer 1995;31A:1105–1109PubMedCrossRefGoogle Scholar
  29. 29.
    Takeuchi Y, Nakao A, Harada A, et al. Expression of plasminogen activators and their inhibitors in human pancreatic carcinoma: immunohistochemical study. Am J Gastroenterol 1993;88:1928–1933PubMedGoogle Scholar
  30. 30.
    Cantero D, Friess H, Deflorin J, et al. Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer 1997;75:388–395PubMedGoogle Scholar
  31. 31.
    Harvey SR, Hurd TC, Markus G, et al. Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer. Clin Cancer Res 2003;9:4935–4943PubMedGoogle Scholar
  32. 32.
    Nielsen A, Scarlett CJ, Samra JS, et al. Significant overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma using real-time quantitative reverse transcription polymerase chain reaction. J Gastroenterol Hepatol 2005;20:256–263PubMedCrossRefGoogle Scholar
  33. 33.
    Nielsen A, Scarlett CJ, Samra JS, et al. Significant overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma using real-time quantitative reverse transcription polymerase chain reaction. J Gastroenterol Hepatol 2005;20:256–263PubMedCrossRefGoogle Scholar
  34. 34.
    Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, 5th ed. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 1997;80:1803–1804PubMedCrossRefGoogle Scholar
  35. 35.
    Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 2000;132:365–386PubMedGoogle Scholar
  36. 36.
    Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001;29:e45PubMedCrossRefGoogle Scholar
  37. 37.
    Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001;29:e45PubMedCrossRefGoogle Scholar
  38. 38.
    Cufer T, Borstnar S, Vrhovec I. Prognostic and predictive value of the urokinase-type plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in operable breast cancer. Int J Biol Markers 2003;18:106–115PubMedGoogle Scholar
  39. 39.
    Nagayama M, Sato A, Hayakawa H, et al. Plasminogen activators and their inhibitors in non-small cell lung cancer. Low content of type 2 plasminogen activator inhibitor associated with tumor dissemination. Cancer 1994;73:1398–1405PubMedCrossRefGoogle Scholar
  40. 40.
    Verspaget HW, Sier CF, Ganesh S, et al. Prognostic value of plasminogen activators and their inhibitors in colorectal cancer. Eur J Cancer 1995;31A:1105–1109PubMedCrossRefGoogle Scholar
  41. 41.
    Nordengren J, Fredstorp LM, Bendahl PO, et al. High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer. Int J Cancer 2002;97:379–385PubMedCrossRefGoogle Scholar
  42. 42.
    Schneider J, Pollan M, Tejerina A, et al. Accumulation of uPA-PAI-1 complexes inside the tumor cells is associated with axillary nodal invasion in progesterone-receptor-positive early breast cancer. Br J Cancer 2003;88:96–101PubMedCrossRefGoogle Scholar
  43. 43.
    Eren M, Painter CA, Gleaves LA, et al. Tissue- and agonist-specific regulation of human and murine plasminogen activator inhibitor-1 promoters in transgenic mice. J Thromb Haemost 2003;1:2389–2396PubMedCrossRefGoogle Scholar
  44. 44.
    Friess H, Cantero D, Graber H, et al. Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis. Gastroenterology 1997;113:904–913PubMedCrossRefGoogle Scholar
  45. 45.
    Allen BJ, Raja C, Rizvi S, et al. Targeted alpha therapy for cancer. Phys Med Biol 2004;49:3703–3712PubMedCrossRefGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2007

Authors and Affiliations

  • Ross Smith
    • 1
    Email author
  • AiQun Xue
    • 1
  • Anthony Gill
    • 2
  • Christopher Scarlett
    • 1
  • Alexander Saxby
    • 1
  • Adele Clarkson
    • 2
  • Thomas Hugh
    • 1
  1. 1.Department of SurgeryUniversity of Sydney, Royal North Shore HospitalSt. LeonardsAustralia
  2. 2.Department of Anatomical PathologyRoyal North Shore HospitalSt. LeonardsAustralia

Personalised recommendations