350 rub
Journal Technologies of Living Systems №3 for 2012 г.
Article in number:
Prognostic significance of urokinase and tissue type plasminogen activators and their type 1 inhibitor in the tumors of colorectal cancer oatients: results of 10 years follow-up
Keywords: urokinase type plasminogen activator (uPA) tissue type plasminogen activator (tPA) type 1 plasminogen activator inhibitor (PAI-1) colorectal cancer prognosis
Authors:
E.S. Gershtein, V.V. Prorokov, N.E. Kushlinsky
Abstract:
Plasminogen activation and subsequent extracellular matrix degradation in tumor tissue is one of the key mechanisms initiating cancer invasion, metastasizing, and neoangiogenesis. The main components of this proteolitic cascade such as urokinase and tissue type plasminogen activators (uPA and tPA) and one of their tissue inhibitors - PAI-1 - are widely explored as candidate prognostic markers for various types of malignancies including colorectal cancer. Results of 10 years follow-up of 67 colorectal cancer patients in whose tumors and histologically unchanged colon mucosa the content of main plasminogen activation system components (uPA, PAI-1 и tPA) was measured by ELISA directly after surgery were analyzed. Sandwich-type ELISA based on 4 different antibodies developed in the Department of Experimental and Clinical Endocrinology of the Academic Hospital St Radboud, University of Nijmegen (the Netherlands) were used. Rectal cancer was diagnosed in 37, colon cancer - in 30 patients. 2 patients had stage I, 4 - stage II, 47 - stage III, and 18 - stage IV disease. All stage I-III patients were radically operated. Stage IV patients underwent cytoreductive surgery. High tumor PAI-1 concentration was found to be the only significant unfavorable prognostic factor for 5 and 10 years colorectal patients - survival. It was predominantly pronounced in stage III patients, and the differences were the greatest with cut-off level of 4.0 ng/mg protein that corresponded to the upper limit of the unchanged mucosa values (p=0.004): 10 years survival of patients with low tumor PAI-1 comprised 63% (median not reached), and in patients with high marker levels - 12%, median - 42 months. No statistically significant differences were found in stage IV patients, and all 6 stage I-II patients remained alive during the whole follow-up period. We also failed to confirm the prognostic value of PAI-1 in multivariate analysis. Our results substantiate high prognostic significance of PAI-1 measurement demonstrated early in other types of cancer (breast, gastric) and confirm the protective role of this protein in tumor cells promoting their invasive and metastatic behavior.
Pages: 42-49
References
  1. Duffy M.J., Duggan C. The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer // Clin. Biochem. 2004.
    V. 37(7). P. 541 - 548.
  2. Герштейн Е.С., Кушлинский Н.Е., Талаева Ш.Ж., Сандыбаев М.Н. Клиническая роль системы активации плазминогена в опухолях человека // Молекулярная медицина. 2007. № 1. Р. 4 - 8.
  3. Allgayer H. Molecular regulation of an invasion-related molecule-options for tumour staging and clinical strategies // Eur. J. Cancer. 2006. V. 42(7). Р. 811 - 819.
  4. Berger D.H. Plasmin/plasminogen system in colorectal cancer // World J. Surg. 2002. V. 26(7). P.767 - 771.
  5. Cakarovski K., Leung J.Y., Restall C., Carin-Carlson A., Yang E., Perlmutter P. et al. Novel inhibitors of urokinase-type plasminogen activator and matrix metalloproteinase expression in metastatic cancer cell lines // Int. J. Cancer. 2004. V. 110(4). P. 610 - 616.
  6. Jacobsen B., Ploug M. The urokinase receptor and its structural homologue C4.4A in human cancer: expression, prognosis and pharmacological inhibition // Curr. Med. Chem. 2008.  V. 15(25). P. 2559 - 2573.
  7. Fujii T., Obara T., Tanno S., Ura H., Kohgo Y. Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 as a prognostic factor in human colorectal carcinomas // Hepatogastroenterology. 1999. V. 46(28).  P. 2299 - 2308.
  8. Harvey S., Kohga S., Sait S.N., Markus G., Hurd T.C., Martinick M. et al. Co-expression of urokinase with haptoglobin in human carcinomas // J. Surg. Res. 2009. V. 152(2). P. 189 - 197.
  9. Mulcahy H.E., Duffy M.J., Gibbons D., McCarthy P., Parfrey N.A., O'Donoghue D.P. et al. Urokinase-type plasminogen activator and outcome in Dukes' B colorectal cancer // Lancet. 1994.
    V. 344(8922). P. 583 - 584.
  10. Skelly M.M., Troy A., Duffy M.J., Mulcahy H.E., Duggan C., Connell T.G. et al. Urokinase-type plasminogen activator in colorectal cancer: relationship with clinicopathological features and patient outcome // Clin. Cancer Res. 1997.  V. 3(10). P. 1837 - 1840.
  11. Baker E.A., Bergin F.G., Leaper D.J. Plasminogen activator system, vascular endothelial growth factor, and colorectal cancer progression // Mol. Pathol. 2000. V. 53(6). P. 307 - 312.
  12. Langenskiold M., Holmdahl L., Angenete E.,  Falk P., Nordgren S., Ivarsson M.L. Differential prognostic impact of uPA and PAI-1 in colon and rectal cancer // Tumour Biol. 2009. V. 30(4).  P.210 - 220.
  13. Zlobec I., Minoo P., Baumhoer D., Baker K., Terracciano L., Jass J.R. et al. Multimarker phenotype predicts adverse survival in patients with lymph node-negative colorectal cancer // Cancer. 2008. V.112(3). P. 495 - 502.
  14. Yang J.L., Seetoo D., Wang Y., Ranson M., Berney C.R., Ham J.M. 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. V.89(5). P. 431 - 439.
  15. Fernebro E., Madsen R.R., Ferno M., Brunner N., Bendahl P., Christensen I.J. et al. Prognostic importance of the soluble plasminogen activator receptor, suPAR, in plasma from rectal cancer patients // Eur. J. Cancer. 2001. V. 37(4).  P. 486 - 491.
  16. Zlobec I., Holler S., Tornillo L., Terracciano L., Lugli A. Combined histomorphologic and immunohistochemical phenotype to predict the presence of vascular invasion in colon cancer // Dis. Colon Rectum. 2009. V. 52(6). P. 1114 - 1121.
  17. Herszenyi L., Farinati F., Cardin R., Istvan G., Molnar L.D., Hritz I. et al. Tumor marker utility and prognostic relevance of cathepsin B, cathepsin L, urokinase-type plasminogen activator, plasminogen activator inhibitor type-1, CEA and CA 19-9 in colorectal cancer // BMC Cancer. 2008. V. 8. P. 194.
  18. Papadopoulou S., Scorilas A., Yotis J., Arnogianaki N., Plataniotis G., Agnanti N. et al. Significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) expression in human colorectal carcinomas // Tumour Biol. 2002. V. 23(3). P. 170 - 178.
  19. Verspaget H.W., Sier C.F., Ganesh S., Griffioen G., Lamers C.B. Prognostic value of plasminogen activators and their inhibitors in colorectal cancer // Eur. J. Cancer. 1995. V. 31A(7 - 8).  P. 1105 - 1109.
  20. Герштейн Е.С., Пророков В.В., Голубченко О.В., Кушлинский Н.Е. Активаторы плазминогена урокиназного и тканевого типов и их ингибитор PAI-1 при раке толстой кишки: взаимосвязь с основными клинико-морфологи­ческими факторами // Вестник Российского онкологического научного центра им. Н.Н.Блохина РАМН. 2002. № 2. С. 31 - 36.