Research Article| Volume 42, ISSUE 12, P1889-1896, August 2006

Tissue inhibitor of metalloproteinases-1 in the postoperative monitoring of colorectal cancer


      The aim of this study was to investigate whether the pre- and postoperative plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) were associated with outcome in colorectal cancer (CRC). Pre- and postoperative plasma TIMP-1 from 280 curatively resected CRC patients and carcinoembryonic antigen (CEA) in corresponding serum samples were measured and correlated with patient outcome (death, local recurrence (LR) and distant metastases (DM)). The results showed that the course of plasma TIMP-1 from pre- to postoperative levels correlated with patient outcome (P = 0.005). However, postoperative plasma TIMP-1 alone was strongly associated with patient outcome, high TIMP-1 predicting short survival (P = 0.002). Combining postoperative TIMP-1 and CEA demonstrated that high TIMP-1 and CEA levels predicted poor outcome (P < 0.0001); multivariate analysis identifying both parameters as strong prognostic factors for survival, LR and DM (P < 0.0001). In conclusion, postoperative plasma TIMP-1 predicts patient outcome both alone and in combination with CEA. Postoperative TIMP-1 may be a marker of residual disease after primary surgery for CRC.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Midgley R.
        • Kerr D.
        Colorectal cancer.
        Lancet. 1999; 353: 391-399
        • Berman J.M.
        • Cheung R.J.
        • Weinberg D.S.
        Surveillance after colorectal cancer resection.
        Lancet. 2000; 355: 395-399
        • Benson III, A.B.
        • Desch C.E.
        • Flynn P.J.
        • et al.
        2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines.
        J Clin Oncol. 2000; 18: 3586-3588
        • Duffy M.J.
        • van Dalen A.
        • Haglund C.
        • et al.
        Clinical utility of biochemical markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines.
        Eur J Cancer. 2003; 39: 718-727
        • Safi F.
        • Link K.H.
        • Beger H.G.
        Is follow-up of colorectal cancer patients worthwhile?.
        Dis Colon Rectum. 1993; 36: 636-643
        • Cunningham D.
        • Pyrhonen S.
        • James R.D.
        • et al.
        Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer.
        Lancet. 1998; 352: 1413-1418
        • Welgus H.G.
        • Jeffrey J.J.
        • Eisen A.Z.
        • Roswit W.T.
        • Stricklin G.P.
        Human skin fibroblast collagenase: interaction with substrate and inhibitor.
        Coll Relat Res. 1985; 5: 167-179
        • Birkedal H.H.
        • Moore W.G.
        • Bodden M.K.
        • et al.
        Matrix metalloproteinases: a review.
        Crit Rev Oral Biol Med. 1993; 4: 197-250
        • Docherty A.J.
        • Lyons A.
        • Smith B.J.
        • et al.
        Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity.
        Nature. 1985; 318: 66-69
        • Hayakawa T.
        • Yamashita K.
        • Tanzawa K.
        • Uchijima E.
        • Iwata K.
        Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum.
        FEBS Lett. 1992; 298: 29-32
        • Luparello C.
        • Avanzato G.
        • Carella C.
        • Pucci-Minafra I.
        Tissue inhibitor of metalloprotease (TIMP)-1 and proliferative behaviour of clonal breast cancer cells.
        Breast Cancer Res Treat. 1999; 54: 235-244
        • Guedez L.
        • Stetler-Stevenson W.G.
        • Wolff L.
        • et al.
        In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1.
        J Clin Invest. 1998; 102: 2002-2010
        • Li G.
        • Fridman R.
        • Kim H.R.
        Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells.
        Cancer Res. 1999; 59: 6267-6275
        • Rhee J.S.
        • Diaz R.
        • Korets L.
        • Hodgson J.G.
        • Coussens L.M.
        TIMP-1 alters susceptibility to carcinogenesis.
        Cancer Res. 2004; 64: 952-961
        • Mimori K.
        • Mori M.
        • Shiraishi T.
        • et al.
        Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma.
        Br J Cancer. 1997; 76: 531-536
        • Fong K.M.
        TIMP1 and adverse prognosis in non-small cell lung cancer.
        Clin Cancer Res. 1996; 2: 1369-1372
        • Ree A.H.
        • Florenes V.A.
        • Berg J.P.
        • Maelandsmo G.M.
        • Nesland J.M.
        • Fodstad O.
        High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases.
        Clin Cancer Res. 1997; 3: 1623-1628
        • Hewitt R.E.
        • Leach I.H.
        • Powe D.G.
        • Clark I.M.
        • Cawston T.E.
        • Turner D.R.
        Distribution of collagenase and tissue inhibitor of metalloproteinases (TIMP) in colorectal tumours.
        Int J Cancer. 1991; 49: 666-672
        • Holten-Andersen M.N.
        • Murphy G.
        • Nielsen H.J.
        • et al.
        Quantitation of TIMP-1 in plasma of healthy blood donors and patients with advanced cancer.
        Br J Cancer. 1999; 80: 495-503
        • Holten-Andersen M.N.
        • Christensen I.J.
        • Nielsen H.J.
        • et al.
        Total levels of tissue inhibitor of metalloproteinases 1 in plasma yield high diagnostic sensitivity and specificity in patients with colon cancer.
        Clin Cancer Res. 2002; 8: 156-164
        • Holten-Andersen M.N.
        • Stephens R.W.
        • Nielsen H.J.
        • et al.
        High preoperative plasma tissue inhibitor of metalloproteinase-1 levels are associated with short survival of patients with colorectal cancer.
        Clin Cancer Res. 2000; 6: 4292-4299
        • Holten-Andersen M.N.
        • Christensen I.J.
        • Nilbert M.
        • et al.
        Association between preoperative plasma levels of tissue inhibitor of metalloproteinases 1 and rectal cancer patient survival. a validation study.
        Eur J Cancer. 2004; 40: 64-72
        • Nielsen H.J.
        • McArdle C.S.
        • Moesgaard F.
        The effect of ranitidine on long term survival in primary colorectal cancer.
        Gastrointestinal Cancer. 1998; 2: 227-233
        • Dukes C.E.
        The classification of cancer of the rectum.
        J Pathol Bacteriol. 1932; 35: 323-332
        • Hembry R.M.
        • Murphy G.
        • Reynolds J.J.
        Immunolocalization of tissue inhibitor of metalloproteinases (TIMP) in human cells. Characterization and use of a specific antiserum.
        J Cell Sci. 1985; 73: 105-119
        • Murphy G.
        • Houbrechts A.
        • Cockett M.I.
        • Williamson R.A.
        • O’Shea M.
        • Docherty A.J.
        The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity.
        Biochemistry. 1991; 30: 8097-8102
        • Cooksley S.
        • Hipkiss J.B.
        • Tickle S.P.
        • et al.
        Immunoassays for the detection of human collagenase, stromelysin, tissue inhibitor of metalloproteinases (TIMP) and enzyme-inhibitor complexes.
        Matrix. 1990; 10: 285-291
        • Babson A.L.
        The Cirrus IMMULITE: a new random access automated immunoassay system.
        J Clin Immunoassay. 2000; 14: 83-88
        • Michel P.
        • Merle V.
        • Chiron A.
        • et al.
        Postoperative management of stage II/III colon cancer: a decision analysis.
        Gastroenterology. 1999; 117: 784-793
        • Andersen P.K.
        • Vaeth M.
        Simple parametric and nonparametric models for excess and relative mortality.
        Biometrics. 1989; 45: 523-535