Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;76(6):805–811. doi: 10.1038/bjc.1997.466

Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer--a predictor of tumour stage.

P Ring 1, K Johansson 1, M Höyhtyä 1, K Rubin 1, G Lindmark 1
PMCID: PMC2228035  PMID: 9310250

Abstract

The aim of this study was to investigate whether immunohistochemical staining patterns of tissue inhibitor of metalloproteinases TIMP-2 and matrix metalloproteinases MMP-2 and MMP-9 can be predictors of tumour stage and survival time in colorectal cancer. Frozen tumour sections from 212 patients operated on between January 1987 and November 1990 were investigated. Three mouse monoclonal antibodies--T2-101 against TIMP-2, CA-4001 against MMP-2 and GE-213 against MMP-9--were used. Positive expression of TIMP-2 (a) in basement membranes and (b) diffusely in stroma with (c) subglandular enhancement was found significantly (P < 0.01, P < 0.05, P < 0.05) more often in localized tumours than in tumours with regional or distant metastases. Neither pattern correlated with tumour differentiation. Patterns (a) and (c) correlated with longer survival time (P < 0.05); (b) reached near significance (P < 0.07). When the survival analyses were restricted to potentially cured patients, neither pattern could foretell death from cancer. Positive expression of MMP-2 in tumour epithelium and of MMP-9 in tumour-infiltrating macrophages were both independent of tumour stage and were without correlation with survival time. A large number of MMP-9-positive macrophages correlated (P < 0.05) with poor tumour differentiation, whereas weak or absent epithelial MMP-2 staining reached near significance (P < 0.08). Exploration of TIMP-2 expression is valuable for the discrimination between macroscopically localized and metastatic colorectal cancer, but it cannot predict which of the potentially cured patients are likely to have micrometastases. MMP-2 and MMP-9 stainings are of minor value in staging and prognostic prediction.

Full text

PDF
805

Images in this article

806Figure 1
on p.806
807Figure 2
on p.807
808Figure 3
on p.808

Selected References

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

  1. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995 Oct;7(5):728–735. doi: 10.1016/0955-0674(95)80116-2. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. De Clerck Y. A., Shimada H., Taylor S. M., Langley K. E. Matrix metalloproteinases and their inhibitors in tumor progression. Ann N Y Acad Sci. 1994 Sep 6;732:222–232. doi: 10.1111/j.1749-6632.1994.tb24738.x. [DOI] [PubMed] [Google Scholar]
  4. Emmert-Buck M. R., Roth M. J., Zhuang Z., Campo E., Rozhin J., Sloane B. F., Liotta L. A., Stetler-Stevenson W. G. Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples. Am J Pathol. 1994 Dec;145(6):1285–1290. [PMC free article] [PubMed] [Google Scholar]
  5. Fridman R., Bird R. E., Hoyhtya M., Oelkuct M., Komarek D., Liang C. M., Berman M. L., Liotta L. A., Stetler-Stevenson W. G., Fuerst T. R. Expression of human recombinant 72 kDa gelatinase and tissue inhibitor of metalloproteinase-2 (TIMP-2): characterization of complex and free enzyme. Biochem J. 1993 Jan 15;289(Pt 2):411–416. doi: 10.1042/bj2890411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Furcht L. T., Skubitz A. P., Fields G. B. Tumor cell invasion, matrix metalloproteinases, and the dogma. Lab Invest. 1994 Jun;70(6):781–783. [PubMed] [Google Scholar]
  7. Glimelius B., Isacsson U., Jung B., Påhlman L. Radiotherapy in addition to radical surgery in rectal cancer. Acta Oncol. 1995;34(5):565–570. doi: 10.3109/02841869509094030. [DOI] [PubMed] [Google Scholar]
  8. Goldberg G. I., Eisen A. Z. Extracellular matrix metalloproteinases in tumor invasion and metastasis. Cancer Treat Res. 1991;53:421–440. doi: 10.1007/978-1-4615-3940-7_20. [DOI] [PubMed] [Google Scholar]
  9. Havenith M. G., Arends J. W., Simon R., Volovics A., Wiggers T., Bosman F. T. Type IV collagen immunoreactivity in colorectal cancer. Prognostic value of basement membrane deposition. Cancer. 1988 Nov 15;62(10):2207–2211. doi: 10.1002/1097-0142(19881115)62:10<2207::aid-cncr2820621023>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  10. Hayakawa T. Tissue inhibitors of metalloproteinases and their cell growth-promoting activity. Cell Struct Funct. 1994 Jun;19(3):109–114. doi: 10.1247/csf.19.109. [DOI] [PubMed] [Google Scholar]
  11. Höyhtyä M., Fridman R., Komarek D., Porter-Jordan K., Stetler-Stevenson W. G., Liotta L. A., Liang C. M. Immunohistochemical localization of matrix metalloproteinase 2 and its specific inhibitor TIMP-2 in neoplastic tissues with monoclonal antibodies. Int J Cancer. 1994 Feb 15;56(4):500–505. doi: 10.1002/ijc.2910560408. [DOI] [PubMed] [Google Scholar]
  12. Jessup J. M. Cathepsin B and other proteases in human colorectal carcinoma. Am J Pathol. 1994 Aug;145(2):253–262. [PMC free article] [PubMed] [Google Scholar]
  13. Kossakowska A. E., Huchcroft S. A., Urbanski S. J., Edwards D. R. Comparative analysis of the expression patterns of metalloproteinases and their inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary carcinomas and malignant non-Hodgkin's lymphomas in humans. Br J Cancer. 1996 Jun;73(11):1401–1408. doi: 10.1038/bjc.1996.266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Liabakk N. B., Talbot I., Smith R. A., Wilkinson K., Balkwill F. Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res. 1996 Jan 1;56(1):190–196. [PubMed] [Google Scholar]
  15. Lindmark G., Gerdin B., Påhlman L., Bergström R., Glimelius B. Prognostic predictors in colorectal cancer. Dis Colon Rectum. 1994 Dec;37(12):1219–1227. doi: 10.1007/BF02257785. [DOI] [PubMed] [Google Scholar]
  16. Liotta L. A., Stetler-Stevenson W. G. Metalloproteinases and cancer invasion. Semin Cancer Biol. 1990 Apr;1(2):99–106. [PubMed] [Google Scholar]
  17. Liotta L. A. Tumor invasion and metastases: role of the basement membrane. Warner-Lambert Parke-Davis Award lecture. Am J Pathol. 1984 Dec;117(3):339–348. [PMC free article] [PubMed] [Google Scholar]
  18. Liotta L. A., Wewer U., Rao N. C., Schiffmann E., Stracke M., Guirguis R., Thorgeirsson U., Muschel R., Sobel M. Biochemical mechanisms of tumor invasion and metastases. Prog Clin Biol Res. 1988;256:3–16. [PubMed] [Google Scholar]
  19. Margulies I. M., Höyhtyä M., Evans C., Stracke M. L., Liotta L. A., Stetler-Stevenson W. G. Urinary type IV collagenase: elevated levels are associated with bladder transitional cell carcinoma. Cancer Epidemiol Biomarkers Prev. 1992 Sep-Oct;1(6):467–474. [PubMed] [Google Scholar]
  20. Nakajima M., Morikawa K., Fabra A., Bucana C. D., Fidler I. J. Influence of organ environment on extracellular matrix degradative activity and metastasis of human colon carcinoma cells. J Natl Cancer Inst. 1990 Dec 19;82(24):1890–1898. doi: 10.1093/jnci/82.24.1890. [DOI] [PubMed] [Google Scholar]
  21. Newell K. J., Witty J. P., Rodgers W. H., Matrisian L. M. Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol Carcinog. 1994 Aug;10(4):199–206. doi: 10.1002/mc.2940100404. [DOI] [PubMed] [Google Scholar]
  22. Newland R. C., Chapuis P. H., Smyth E. J. The prognostic value of substaging colorectal carcinoma. A prospective study of 1117 cases with standardized pathology. Cancer. 1987 Aug 15;60(4):852–857. doi: 10.1002/1097-0142(19870815)60:4<852::aid-cncr2820600422>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  23. Nicolson G. L. Tumor and host molecules important in the organ preference of metastasis. Semin Cancer Biol. 1991 Jun;2(3):143–154. [PubMed] [Google Scholar]
  24. Nielsen B. S., Timshel S., Kjeldsen L., Sehested M., Pyke C., Borregaard N., Danø K. 92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer. Int J Cancer. 1996 Jan 3;65(1):57–62. doi: 10.1002/(SICI)1097-0215(19960103)65:1<57::AID-IJC10>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  25. Nigam A. K., Pignatelli M., Boulos P. B. Current concepts in metastasis. Gut. 1994 Jul;35(7):996–1000. doi: 10.1136/gut.35.7.996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nikkari S. T., Höyhtyä M., Isola J., Nikkari T. Macrophages contain 92-kd gelatinase (MMP-9) at the site of degenerated internal elastic lamina in temporal arteritis. Am J Pathol. 1996 Nov;149(5):1427–1433. [PMC free article] [PubMed] [Google Scholar]
  27. Peto R., Pike M. C., Armitage P., Breslow N. E., Cox D. R., Howard S. V., Mantel N., McPherson K., Peto J., Smith P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977 Jan;35(1):1–39. doi: 10.1038/bjc.1977.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Poulsom R., Pignatelli M., Stetler-Stevenson W. G., Liotta L. A., Wright P. A., Jeffery R. E., Longcroft J. M., Rogers L., Stamp G. W. Stromal expression of 72 kda type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia. Am J Pathol. 1992 Aug;141(2):389–396. [PMC free article] [PubMed] [Google Scholar]
  29. Pyke C., Ralfkiaer E., Tryggvason K., Danø K. Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. Am J Pathol. 1993 Feb;142(2):359–365. [PMC free article] [PubMed] [Google Scholar]
  30. Stetler-Stevenson W. G., Liotta L. A., Kleiner D. E., Jr Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J. 1993 Dec;7(15):1434–1441. doi: 10.1096/fasebj.7.15.8262328. [DOI] [PubMed] [Google Scholar]
  31. Swallow C. J., Murray M. P., Guillem J. G. Metastatic colorectal cancer cells induce matrix metalloproteinase release by human monocytes. Clin Exp Metastasis. 1996 Jan;14(1):3–11. doi: 10.1007/BF00157680. [DOI] [PubMed] [Google Scholar]
  32. Thorgeirsson U. P., Lindsay C. K., Cottam D. W., Gomez D. E. Tumor invasion, proteolysis, and angiogenesis. J Neurooncol. 1994;18(2):89–103. doi: 10.1007/BF01050415. [DOI] [PubMed] [Google Scholar]
  33. Tryggvason K., Höyhtyä M., Pyke C. Type IV collagenases in invasive tumors. Breast Cancer Res Treat. 1993;24(3):209–218. doi: 10.1007/BF01833261. [DOI] [PubMed] [Google Scholar]
  34. Urbanski S. J., Edwards D. R., Hershfield N., Huchcroft S. A., Shaffer E., Sutherland L., Kossakowska A. E. Expression pattern of metalloproteinases and their inhibitors changes with the progression of human sporadic colorectal neoplasia. Diagn Mol Pathol. 1993 Jun;2(2):81–89. [PubMed] [Google Scholar]
  35. Woessner J. F., Jr The family of matrix metalloproteinases. Ann N Y Acad Sci. 1994 Sep 6;732:11–21. doi: 10.1111/j.1749-6632.1994.tb24720.x. [DOI] [PubMed] [Google Scholar]
  36. van der Stappen J. W., Hendriks T., Wobbes T. Correlation between collagenolytic activity and grade of histological differentiation in colorectal tumors. Int J Cancer. 1990 Jun 15;45(6):1071–1078. doi: 10.1002/ijc.2910450616. [DOI] [PubMed] [Google Scholar]

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

RESOURCES