Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;75(12):1793–1801. doi: 10.1038/bjc.1997.306

Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer.

S Ganesh 1, C F Sier 1, M M Heerding 1, J H van Krieken 1, G Griffioen 1, K Welvaart 1, C J van de Velde 1, J H Verheijen 1, C B Lamers 1, H W Verspaget 1
PMCID: PMC2223607  PMID: 9192984

Abstract

Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.

Full text

PDF
1793

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beahrs O. H. Staging of cancer of the colon and rectum. Cancer. 1992 Sep 1;70(5 Suppl):1393–1396. doi: 10.1002/1097-0142(19920901)70:3+<1393::aid-cncr2820701530>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  2. Beart R. W., Jr Colon, rectum, and anus. Cancer. 1990 Feb 1;65(3 Suppl):684–688. doi: 10.1002/1097-0142(19900201)65:3+<684::aid-cncr2820651311>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  3. Beart R. W., Jr, van Heerden J. A., Beahrs O. H. Evolution in the pathologic staging of carcinoma of the colon. Surg Gynecol Obstet. 1978 Feb;146(2):257–259. [PubMed] [Google Scholar]
  4. Binnema D. J., van Iersel J. J., Dooijewaard G. Quantitation of urokinase antigen in plasma and culture media by use of an ELISA. Thromb Res. 1986 Sep 1;43(5):569–577. doi: 10.1016/0049-3848(86)90077-0. [DOI] [PubMed] [Google Scholar]
  5. Bouchet C., Spyratos F., Martin P. M., Hacène K., Gentile A., Oglobine J. Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas. Br J Cancer. 1994 Feb;69(2):398–405. doi: 10.1038/bjc.1994.74. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Crowley C. W., Cohen R. L., Lucas B. K., Liu G., Shuman M. A., Levinson A. D. Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5021–5025. doi: 10.1073/pnas.90.11.5021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DUKES C. E., BUSSEY H. J. The spread of rectal cancer and its effect on prognosis. Br J Cancer. 1958 Sep;12(3):309–320. doi: 10.1038/bjc.1958.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  9. Enblad P., Adami H. O., Bergström R., Glimelius B., Krusemo U., Påhlman L. Improved survival of patients with cancers of the colon and rectum? J Natl Cancer Inst. 1988 Jun 15;80(8):586–591. doi: 10.1093/jnci/80.8.586. [DOI] [PubMed] [Google Scholar]
  10. Fisher B., Wolmark N., Rockette H., Redmond C., Deutsch M., Wickerham D. L., Fisher E. R., Caplan R., Jones J., Lerner H. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988 Mar 2;80(1):21–29. doi: 10.1093/jnci/80.1.21. [DOI] [PubMed] [Google Scholar]
  11. Foekens J. A., Buessecker F., Peters H. A., Krainick U., van Putten W. L., Look M. P., Klijn J. G., Kramer M. D. Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer. Cancer Res. 1995 Apr 1;55(7):1423–1427. [PubMed] [Google Scholar]
  12. Foekens J. A., Schmitt M., van Putten W. L., Peters H. A., Bontenbal M., Jänicke F., Klijn J. G. Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res. 1992 Nov 1;52(21):6101–6105. [PubMed] [Google Scholar]
  13. Ganesh S., Sier C. F., Griffioen G., Vloedgraven H. J., de Boer A., Welvaart K., van de Velde C. J., van Krieken J. H., Verheijen J. H., Lamers C. B. Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res. 1994 Aug 1;54(15):4065–4071. [PubMed] [Google Scholar]
  14. Ganesh S., Sier C. F., Heerding M. M., van Krieken J. H., Griffioen G., Welvaart K., van de Velde C. J., Verheijen J. H., Lamers C. B., Verspaget H. W. Prognostic value of the plasminogen activation system in patients with gastric carcinoma. Cancer. 1996 Mar 15;77(6):1035–1043. doi: 10.1002/(sici)1097-0142(19960315)77:6<1035::aid-cncr5>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  15. Greenwald P. Colon cancer overview. Cancer. 1992 Sep 1;70(5 Suppl):1206–1215. doi: 10.1002/1097-0142(19920901)70:3+<1206::aid-cncr2820701504>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  16. Grøndahl-Hansen J., Christensen I. J., Rosenquist C., Brünner N., Mouridsen H. T., Danø K., Blichert-Toft M. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res. 1993 Jun 1;53(11):2513–2521. [PubMed] [Google Scholar]
  17. Hart G. Spinal cord injury: impact on clients' significant others. Rehabil Nurs. 1981 Jan-Feb;6(1):11–15. doi: 10.1002/j.2048-7940.1981.tb01389.x. [DOI] [PubMed] [Google Scholar]
  18. Hasui Y., Marutsuka K., Suzumiya J., Kitada S., Osada Y., Sumiyoshi A. The content of urokinase-type plasminogen activator antigen as a prognostic factor in urinary bladder cancer. Int J Cancer. 1992 Apr 1;50(6):871–873. doi: 10.1002/ijc.2910500607. [DOI] [PubMed] [Google Scholar]
  19. Heiss M. M., Babic R., Allgayer H., Gruetzner K. U., Jauch K. W., Loehrs U., Schildberg F. W. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol. 1995 Aug;13(8):2084–2093. doi: 10.1200/JCO.1995.13.8.2084. [DOI] [PubMed] [Google Scholar]
  20. Hesketh P. J., Bulger K. N. Role of adjuvant therapy in colorectal cancer. Adv Intern Med. 1991;36:219–247. [PubMed] [Google Scholar]
  21. Hind R., Rew D. R., Johnson C. D. Surgical excision alone is adequate treatment for primary colorectal cancer. Ann R Coll Surg Engl. 1992 Jan;74(1):63–67. [PMC free article] [PubMed] [Google Scholar]
  22. Jänicke F., Schmitt M., Graeff H. Clinical relevance of the urokinase-type and tissue-type plasminogen activators and of their type 1 inhibitor in breast cancer. Semin Thromb Hemost. 1991 Jul;17(3):303–312. doi: 10.1055/s-2007-1002624. [DOI] [PubMed] [Google Scholar]
  23. Krook J. E., Moertel C. G., Gunderson L. L., Wieand H. S., Collins R. T., Beart R. W., Kubista T. P., Poon M. A., Meyers W. C., Mailliard J. A. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991 Mar 14;324(11):709–715. doi: 10.1056/NEJM199103143241101. [DOI] [PubMed] [Google Scholar]
  24. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  25. Moertel C. G., Fleming T. R., Macdonald J. S., Haller D. G., Laurie J. A., Goodman P. J., Ungerleider J. S., Emerson W. A., Tormey D. C., Glick J. H. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352–358. doi: 10.1056/NEJM199002083220602. [DOI] [PubMed] [Google Scholar]
  26. Mulcahy H. E., Duffy M. J., Gibbons D., McCarthy P., Parfrey N. A., O'Donoghue D. P., Sheahan K. Urokinase-type plasminogen activator and outcome in Dukes' B colorectal cancer. Lancet. 1994 Aug 27;344(8922):583–584. doi: 10.1016/s0140-6736(94)91968-2. [DOI] [PubMed] [Google Scholar]
  27. Nacopoulou L., Azaris P., Papacharalampous N., Davaris P. Prognostic significance of histologic host response in cancer of the large bowel. Cancer. 1981 Mar 1;47(5):930–936. doi: 10.1002/1097-0142(19810301)47:5<930::aid-cncr2820470519>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  28. Nakamura M., Konno H., Tanaka T., Maruo Y., Nishino N., Aoki K., Baba S., Sakaguchi S., Takada Y., Takada A. Possible role of plasminogen activator inhibitor 2 in the prevention of the metastasis of gastric cancer tissues. Thromb Res. 1992 Mar 15;65(6):709–719. doi: 10.1016/0049-3848(92)90110-v. [DOI] [PubMed] [Google Scholar]
  29. Nekarda H., Schmitt M., Ulm K., Wenninger A., Vogelsang H., Becker K., Roder J. D., Fink U., Siewert J. R. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res. 1994 Jun 1;54(11):2900–2907. [PubMed] [Google Scholar]
  30. Nishino N., Aoki K., Tokura Y., Sakaguchi S., Takada Y., Takada A. The urokinase type of plasminogen activator in cancer of digestive tracts. Thromb Res. 1988 May 15;50(4):527–535. doi: 10.1016/0049-3848(88)90201-0. [DOI] [PubMed] [Google Scholar]
  31. O'Connell M. J., Schaid D. J., Ganju V., Cunningham J., Kovach J. S., Thibodeau S. N. Current status of adjuvant chemotherapy for colorectal cancer. Can molecular markers play a role in predicting prognosis? Cancer. 1992 Sep 15;70(6 Suppl):1732–1739. doi: 10.1002/1097-0142(19920915)70:4+<1732::aid-cncr2820701614>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  32. Ohman U. Colorectal carcinoma. A survey of 1345 cases 1950-1984. Acta Chir Scand. 1985;151(8):675–679. [PubMed] [Google Scholar]
  33. Ossowski L., Russo-Payne H., Wilson E. L. Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse. Cancer Res. 1991 Jan 1;51(1):274–281. [PubMed] [Google Scholar]
  34. Patt Y. Z. Regional hepatic arterial chemotherapy for colorectal cancer metastatic to the liver: the controversy continues. J Clin Oncol. 1993 May;11(5):815–819. doi: 10.1200/JCO.1993.11.5.815. [DOI] [PubMed] [Google Scholar]
  35. Pedersen H., Brünner N., Francis D., Osterlind K., Rønne E., Hansen H. H., Danø K., Grøndahl-Hansen J. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res. 1994 Sep 1;54(17):4671–4675. [PubMed] [Google Scholar]
  36. Ponz de Leon M., Sant M., Micheli A., Sacchetti C., Di Gregorio C., Fante R., Zanghieri G., Melotti G., Gatta G. Clinical and pathologic prognostic indicators in colorectal cancer. A population-based study. Cancer. 1992 Feb 1;69(3):626–635. doi: 10.1002/1097-0142(19920201)69:3<626::aid-cncr2820690305>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  37. Pretlow T. P., Keith E. F., Cryar A. K., Bartolucci A. A., Pitts A. M., Pretlow T. G., 2nd, Kimball P. M., Boohaker E. A. Eosinophil infiltration of human colonic carcinomas as a prognostic indicator. Cancer Res. 1983 Jun;43(6):2997–3000. [PubMed] [Google Scholar]
  38. Rijken D. C., van Hinsbergh V. W., Sens E. H. Quantitation of tissue-type plasminogen activator in human endothelial cell cultures by use of an enzyme immunoassay. Thromb Res. 1984 Jan 15;33(2):145–153. doi: 10.1016/0049-3848(84)90175-0. [DOI] [PubMed] [Google Scholar]
  39. Saksela O. Plasminogen activation and regulation of pericellular proteolysis. Biochim Biophys Acta. 1985 Nov 12;823(1):35–65. doi: 10.1016/0304-419x(85)90014-9. [DOI] [PubMed] [Google Scholar]
  40. Sato T., Nishimura G., Yonemura Y., Nojima N., Ninomiya I., Fujimura T., Sugiyama K., Miwa K., Miyazaki I., Nonomura A. Association of immunohistochemical detection of urokinase-type plasminogen activator with metastasis and prognosis in colorectal cancer. Oncology. 1995 Jul-Aug;52(4):347–352. doi: 10.1159/000227487. [DOI] [PubMed] [Google Scholar]
  41. Schwartz B. S., Bradshaw J. D. Regulation of plasminogen activator inhibitor mRNA levels in lipopolysaccharide-stimulated human monocytes. Correlation with production of the protein. J Biol Chem. 1992 Apr 5;267(10):7089–7094. [PubMed] [Google Scholar]
  42. Sier C. F., Quax P. H., Vloedgraven H. J., Verheijen J. H., Griffioen G., Ganesh S., Lamers C. B., Verspaget H. W. Increased urokinase receptor levels in human gastrointestinal neoplasia and related liver metastases. Invasion Metastasis. 1993;13(6):277–288. [PubMed] [Google Scholar]
  43. Sier C. F., Verspaget H. W., Griffioen G., Ganesh S., Vloedgraven H. J., Lamers C. B. Plasminogen activators in normal tissue and carcinomas of the human oesophagus and stomach. Gut. 1993 Jan;34(1):80–85. doi: 10.1136/gut.34.1.80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sier C. F., Verspaget H. W., Griffioen G., Verheijen J. H., Quax P. H., Dooijewaard G., De Bruin P. A., Lamers C. B. Imbalance of plasminogen activators and their inhibitors in human colorectal neoplasia. Implications of urokinase in colorectal carcinogenesis. Gastroenterology. 1991 Dec;101(6):1522–1528. doi: 10.1016/0016-5085(91)90387-z. [DOI] [PubMed] [Google Scholar]
  45. Sier C. F., Vloedgraven H. J., Ganesh S., Griffioen G., Quax P. H., Verheijen J. H., Dooijewaard G., Welvaart K., van de Velde C. J., Lamers C. B. Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis. Gastroenterology. 1994 Nov;107(5):1449–1456. doi: 10.1016/0016-5085(94)90549-5. [DOI] [PubMed] [Google Scholar]
  46. Sinnige H. A., Mulder N. H. Colorectal carcinoma: an update. Neth J Med. 1991 Jun;38(5-6):217–228. [PubMed] [Google Scholar]
  47. Sumiyoshi K., Baba S., Sakaguchi S., Urano T., Takada Y., Takada A. Increase in levels of plasminogen activator and type-1 plasminogen activator inhibitor in human breast cancer: possible roles in tumor progression and metastasis. Thromb Res. 1991 Jul 1;63(1):59–71. doi: 10.1016/0049-3848(91)90270-7. [DOI] [PubMed] [Google Scholar]
  48. Takai S., Yamamura M., Tanaka K., Kawanishi H., Tsuji M., Nakane Y., Hioki K., Yamamoto M. Plasminogen activators in human gastric cancers: correlation with DNA ploidy and immunohistochemical staining. Int J Cancer. 1991 Apr 22;48(1):20–27. doi: 10.1002/ijc.2910480105. [DOI] [PubMed] [Google Scholar]
  49. Vassalli J. D., Sappino A. P., Belin D. The plasminogen activator/plasmin system. J Clin Invest. 1991 Oct;88(4):1067–1072. doi: 10.1172/JCI115405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Verheijen J. H., Mullaart E., Chang G. T., Kluft C., Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemost. 1982 Dec 27;48(3):266–269. [PubMed] [Google Scholar]
  51. Watt A. G., House A. K. Colonic carcinoma: a quantitative assessment of lymphocyte infiltration at the periphery of colonic tumors related to prognosis. Cancer. 1978 Jan;41(1):279–282. doi: 10.1002/1097-0142(197801)41:1<279::aid-cncr2820410139>3.0.co;2-b. [DOI] [PubMed] [Google Scholar]
  52. Wiggers T., Arends J. W., Volovics A. Regression analysis of prognostic factors in colorectal cancer after curative resections. Dis Colon Rectum. 1988 Jan;31(1):33–41. doi: 10.1007/BF02552567. [DOI] [PubMed] [Google Scholar]
  53. Williams S. T., Beart R. W., Jr Staging of colorectal cancer. Semin Surg Oncol. 1992 Mar-Apr;8(2):89–93. doi: 10.1002/ssu.2980080208. [DOI] [PubMed] [Google Scholar]
  54. Winawer S. J., Zauber A. G., Stewart E., O'Brien M. J. The natural history of colorectal cancer. Opportunities for intervention. Cancer. 1991 Feb 15;67(4 Suppl):1143–1149. doi: 10.1002/1097-0142(19910215)67:4+<1143::aid-cncr2820671507>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  55. Wolmark N., Fisher B., Rockette H., Redmond C., Wickerham D. L., Fisher E. R., Jones J., Glass A., Lerner H., Lawrence W. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988 Mar 2;80(1):30–36. doi: 10.1093/jnci/80.1.30. [DOI] [PubMed] [Google Scholar]
  56. de Bruin P. A., Crama-Bohbouth G., Verspaget H. W., Verheijen J. H., Dooijewaard G., Weterman I. T., Lamers C. B. Plasminogen activators in the intestine of patients with inflammatory bowel disease. Thromb Haemost. 1988 Oct 31;60(2):262–266. [PubMed] [Google Scholar]
  57. de Bruin P. A., Griffioen G., Verspaget H. W., Verheijen J. H., Lamers C. B. Plasminogen activators and tumor development in the human colon: activity levels in normal mucosa, adenomatous polyps, and adenocarcinomas. Cancer Res. 1987 Sep 1;47(17):4654–4657. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES