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Tissue-type plasminogen activator activity in morphologically normal tissues adjacent to gastrointestinal carcinomas is associated with the degree of tumor progression

Abstract

Purpose: To investigate whether the level of plasminogen activator (PA) activity assayed in gastrointestinal carcinomas and the “morphologically normal tissues” adjacent to them is associated with the degree of tumor progression. Methods: Tumor and “normal tissues” were obtained from gastrointestinal surgical samples to assess urokinase-type (u-PA) and tissue-type plasminogen activator (t-PA) activities by radial caseinolytic assay and the expression of PA inhibitor-1 (PAI-1) by ELISA. We compared the PA system between the tumor and “normal tissues” and we investigated the existence of correlations between: (a) PA production in the tumor and “normal tissues”, (b) different components of the PA system, and (c) PA system and the degree of tumor progression. Results: (1) Total PA activity, u-PA activity and PAI-1 expression are significantly higher in tumor than in “normal tissues”, whereas t-PA activity does not differ between them. (2) Total PA activity mainly correlates with u-PA activity in tumor tissues and similarly with u-PA and t-PA activities in “normal tissues”. (3) There is a significant association between t-PA activity in tumor and “normal tissues” and the degree of tumor progression. Conclusions: “Morphologically normal tissues” adjacent to carcinomas present abnormal t-PA activity that is associated with the degree of tumor progression. Assaying of this activity could be useful as a predictive parameter.

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References

  1. Abe J, Urano T, Konno H, Erhan Y, Tanaka T, Nishino N, Takada A, Nakamura S (1999) Larger and more invasive colorectal carcinoma contains larger amounts of plasminogen activator inhibitor type1 and its relative ratio over urokinase receptor correlates well with tumor size. Cancer 86:2602–2611

  2. Andreasen PA, Engelund R, Petersen HH (2000) The plasminogen activation system in tumor growth, invasion and metastasis. CMLS Cell Mol Life Sci 57:25–40

  3. Baker EA, Leaper DJ (2003) The plasminogen activator and matrix metalloproteinase systems in colorectal cancer: relationship to tumour pathology. Eur J Cancer 39:981–988

  4. Berger DH (2002) Plasmin/plasminogen system in colorectal cancer. World J Surg 26:767–771

  5. Berger DH, O’Mahony CA, Sheng H, Shao J, Albo D, DuBois RN, Beauchamp RD (2003) Intestinal transformation results in transforming growth factor-beta-dependent alteration in tumor cell-cell matrix interactions. Surgery 133:568–579

  6. Boccaccio C, Sabatino G, Medico E, Girolami F, Follenzi A, Reato G, Sottile A, Naldini L, Comoglio PM (2005) The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 434:396–400

  7. Cho JY, Chung HC, Noh SH, Roh JK, Min JS, Kim BS (1997) High level of Urokinase-type plasminogen activator is a new prognostic marker in patients with gastric carcinoma. Cancer 79:878–883

  8. Diaz VM, Hurtado M, Thomson TM, Reventos J, Paciucci R (2004) Specific interaction of tissue-type plasminogen activator (t-PA) with annexin II on the membrane of pancreatic cancer cells activates plasminogen and promotes invasion in vitro. Gut 53:993–1000

  9. Duffy MJ, Duggan C (2004) The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer. Clin Biochem 37:541–548

  10. Evans DM, Sloan Stakleff KD (2004) Control of pulmonary metastases of rat mammary cancer by inhibition of uPA and COX-2, singly and in combination. Clin Exp Metastasis 21:339–346

  11. Frandsen TL, Holst-Hansen C, Nielsen BS, Christensen IJ, Nyengaard JR, Carmeliet P, Brunner N (2001) Direct evidence of the importance of stromal urokinase plasminogen activator (uPA) in the growth of an experimental human breast cancer using a combined uPA gene-disrupted and immunodeficient xenograft model. Cancer Res 61:532–537

  12. Fox SB, Taylor M, Grondahl-Hansen J, Kakolyris S, Gatter KC, Harris AL (2001) Plasminogen activator inhibitor-1 as a measure of vascular remodelling in breast cancer. J Pathol 195:236–243

  13. Fujii T, Obara T, Tanno S, Ura H, Kohgo Y (1999) Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 as a prognostic factor in human colorectal carcinomas. Hepatogastroenterology 46:2299–2308

  14. Ganesh S, Sier CFM, Griffioen G, Vloedgraven HJM, de Boer A, Welvaart K, van de Velde CJH, van Krieken JHJM, Verheijen JH, Lamers CBHW, Verspaget HW (1994) Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 54:4065–4071

  15. Ganesh S, Sier CFM, Heerding MM, van Krieken JH, Griffioen G, Weelvaart K, van de Velde CJ, Verheijen JH, Lamers CB, Verspaget HW (1996) Prognostic value of the plasminogen activation system in patients with gastric carcinoma. Cancer 77:1035–1043

  16. Ganesh S, Sier CFM, Heerding MM, van Krieken JH, Griffioen G, Welvaart K, van de Valde CJ, Verheijen JH, Lamers CB, Verspaget HW (1997) Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes’ stage B and C colorectal cancer. Br J Cancer 75:1793–1801

  17. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG (eds) (2002) American Joint Committee on Cancer Staging Manual, 6th edn. Berlin, Springer-Verlag

  18. Grondahl-Hansen J, Ralfkiaer E, Kirkeby LT, Kristensen P, Lund LR, Dano K (1991) Localisation of urokinase-type plasminogen activator in stromal cells in adenocarcinomas of the colon in humans. Am J Pathol 138:111–117

  19. Heiss MM, Allgayer H, Gruetzner KU, Babic R, Jauch KW, Schildberg FW (1997) Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer. Ann Surg 226:736–744

  20. Herszenyi L, Plebani M, Carraro P, De Paoli M, Roveroni G, Cardin R, Foschia F, Tulassay Z, Naccarato R, Farinati F (2000) Proteases in gastrointestinal neoplastic diseases. Clin Chim Acta 291:171–187

  21. Illemann M, Hansen U, Nielsen HJ, Andreasen PA, Hoyer-Hansen G, Dano K, Nielsen BS (2004) Leading-edge myofibroblasts in human colon cancer express plasminogen activator inhibitor-1. Am J Clin Pathol 122:256–265

  22. Iwamoto J, Takahashi K, Mizokami Y, Otsubo T, Miura S, Narasaka T, Takeyama H, Omata T, Shimokoube K, Matsuoka T (2003) Expression of urokinase-type plasminogen activator and its receptor in gastric fibroblasts and effects of nonsteroidal antiinflammatory drugs and prostaglandin. Dig Dis Sci 48:2247–2256

  23. Kaneko T, Konno H, Baba M, Tanaka T, Nakamura S (2003) Urokinase-type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer. Cancer Sci 94:43–49

  24. Khan KMF, Howe LR, Falcone DJ (2004) Extracellular matrix-induced cyclooxygenase-2 regulates macrophage proteinase expression. J Biol Chem 279:22039–22046

  25. Kloblinski JE, Ahram M, Sloane BF (2000) Unraveling the role of proteases in cancer. Clin Chim Acta 291:113–135

  26. Konno H, Baba M, Shoji T, Ohta M, Suzuki S, Nakamura S (2002) Cyclooxygenase-2 expression correlates with uPAR levels and is responsible for poor prognosis of colorectal cancer. Clin Exp Metastasis 19:527–534

  27. Li G, Yang T, Yan J (2002) Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells. Biochem Biophys Res Commun 299:886–890

  28. Lipkin M (1974) Phase 1 and phase 2 proliferative lesions of colonic epithelial cells in diseases leading to colonic cancer. Cancer 34:878–888

  29. Lowry OH, Rosebrough NJ, Farr AL, Randall PJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275

  30. Murata S, Eguchi Y, Terata N, Tani T, Kodama M (1998) Expression of HLA-DR and urokinase- type plasminogen activator in stage IV gastric cancer. Gastric Cancer 1:71–77

  31. Nekarda H, Schmitt M, Ulm K, Wenninger A, Vogesang H, Becker K, Roder JD, Fink U, Siewert JR (1994) Prognostic impact of urokinase plasminogen activator and its inhibitor PAI-1 in completed resected gastric cancer. Cancer Res 54:2900–2907

  32. Nishikawa M, Stapleton PP, Freeman TA, Gaughan JP, Matsuda T, Daly JM (2004) NS-398 inhibits tumor growth and liver metastasis of colon cancer through induction of apoptosis and suppression of the plasminogen activation system in a mouse model. J Am Coll Surg 199:428–435

  33. Noel A, Maillard C, Rocks N, Jost M, Chabottaux V, Sounni NE, Maquoi E, Cataldo D, Foidart JM (2004) Membrane associated proteases and their inhibitors in tumour angiogenesis. J Clin Pathol 57:577–584

  34. Okusa Y, Ichikura T, Mochizuki H (1999) Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma. Cancer 85:1033–1037

  35. Papadopoulou S, Scorilas A, Yotis J, Arnogianaki N, Plataniotis G, Agnanti N, Talieri M (2002) Significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) expression in human colorectal carcinomas. Tumour Biol 23:170–178

  36. Pelletier JP, Mineau F, Fernandes J, Kiansa K, Ranger P, Martel-Pelletier J (1997) Two NSAIDs, nimesulide and naproxen, can reduce the synthesis of urokinase and IL-6 while increasing PAI-1, in human OA synovial fibroblasts. Clin Exp Rheumatol 15:393–398

  37. Pereyra-Alfonso S, Scicolone G, Fiszer de Plazas S, Pecci Saavedra J, Flores V (1995) Current Triton X-100 treatments do not allow a complete plasminogen activator extraction from developing nervous tissue. Neurochem Res 2:137–142

  38. Raigoso P, Junco A, Andicoechea A, Gonzalez A, Garcia-Muniz JL, Allende MT, Garcia-Moran M, Vizoso F (2000) Tissue-type plaminogen activator (tPA) content in colorectal cancer and in surrounding mucosa: relationship with clinicopathologic parameters and prognostic significance. Int J Biol Markers 15:44–50

  39. Sadowski T, Steinmeyer J (2002) Differential effects of nonsteroidal antiinflammatory drugs on the IL-1 altered expression of plasminogen activators and plasminogen activator inhibitor-1 by articular chondrocytes. Inflamm Res 51:427–433

  40. Sanz L, Vizoso F, Verez P, Allende MT, Corte MG, Abdel-Lah O, Martin A, Garcia-Muniz JL (2002) Prognostic significance of tissue-type plasminogen activator (tPA) content in gastric cancer and surrounding mucosa. Int J Biol Markers 17:169–176

  41. Seiler N, Schneider Y, Gosse F, Schleiffer R, Raul F (2004) Polyploidisation of metastatic colon carcinoma cells by microtubule and tubuline interacting drugs: effects on proteolytic activity and invasiveness. Int J Oncol 25:1039–1048

  42. Sier CFM, Verspaget HW, Griffioen G, Ganesh S, Vloedgraven HJM, Lamers CBHW (1993) Plasminogen activators in normal tissue and carcinomas of the human oesophagus and stomach. Gut 34:80–85

  43. Singh B, Berry JA, Shoher A, Ramakrishnan V, Lucci A (2005) COX-2 overexpression increases motility and invasion of breast cancer cells. Int J Oncol 26:1393–1399

  44. Skelly MM, Troy A, Duffy MJ, Mulcahy HE, Duggan C, Connell TG, O’Donoghue DP, Sheahan K (1997) Urokinase-type plasminogen activator in colorectal cancer: relationship with clinicopathological features and patient outcome. Clin Cancer Res 3:1837–1840

  45. Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius-Ussing O, Sorensen S, Dano K, Brünner N (1999) Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 91:869–874

  46. Vassalli JD, Belin D (1987) Amiloride selectively inhibits the urokinase-type plasminogen activator. FEBS Lett 214:187–191

  47. Verspaget HW, Sier CFM, Ganesh S, Griffioen G, Lamers CBHW (1995) Prognostic value of plasminogen activators and their inhibitors in colorectal cancer. Eur J Cancer 31A:1105–1109

  48. Viaje A, Slaga TJ, Wigler M, Weinstein IB (1977) Effects of antiinflammatory agents on mouse skin tumor promotion, epidermal DNA synthesis, phorbol ester-induced cellular proliferation and production of plasminogen activator. Cancer Res 37:1530–1536

  49. Yang JL, Seetoo D, Wang Y, Ranson M, Berney CR, Ham JM, Russell PJ, Crowe PJ (2000) 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 89:431–439

  50. Zajicek G (1993) Cancer colon is a disease of the entire colonic mucosa. Cancer J 6:309

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Acknowledgements

We thank the Surgical Department of the “Diego Thompson” Hospital of San Martin for providing samples and Ms. Patricia López for the constructive critical review of the English language of the manuscript. This work was supported by grants from UBACYT and CONICET, Argentina.

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Correspondence to Gabriel Scicolone.

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Scicolone, G., Sanchez, V., Vauthay, L. et al. Tissue-type plasminogen activator activity in morphologically normal tissues adjacent to gastrointestinal carcinomas is associated with the degree of tumor progression. J Cancer Res Clin Oncol 132, 309–319 (2006). https://doi.org/10.1007/s00432-005-0066-4

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Keywords

  • Plasminogen activator
  • Proteases activity
  • Gastrointestinal carcinomas
  • Tumor progression
  • Morphologically normal tissues