Elsevier

European Journal of Cancer

Volume 42, Issue 12, August 2006, Pages 1889-1896
European Journal of Cancer

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

https://doi.org/10.1016/j.ejca.2006.01.058Get rights and content

Abstract

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.

Introduction

Colorectal cancer (CRC) affects approximately 217,000 individuals in the European Union. Eighty percent of patients with CRC present with potentially curable disease. Nevertheless, despite intended curative surgery, 50% of these patients experience relapse, which is invariably fatal.1, 2 Thus, hundreds of thousands of patients with resected CRC are candidates for surveillance, as it is a commonly held view that early detection of recurrence may allow for early intervention, with the aim of improving survival and quality of life. Major efforts have been put into the establishment of effective tests for detection of recurrent disease at a stage where intervention is not futile. A variety of methods has been employed for postoperative surveillance of CRC. Unfortunately, results from randomised studies of monitoring CRC patients have demonstrated only minimal efficacy.2 Expert Panels of The American Society of Clinical Oncology (ASCO)3 and the European Group of Tumour Markers (EGTM)4 have recommended against the use of many of these tests. Nevertheless, it is recommended that postoperative measurement of serum carcinoembryonic antigen (CEA) is performed every 2–3 months for ⩾2 years in patients with stage II or III disease where resection of liver metastases, if detected, is deemed possible.3, 4 Of note, however, is the fact that approximately 30% of all CRC recurrences do not result in elevated CEA serum levels.5 Thus, it has been stressed by the ASCO and EGTM Expert Panels that new surveillance methods for the detection of CRC recurrences should be developed, evaluated and standardised.3, 4 This statement has gained further weight, as recent data have shown that chemotherapy of metastatic CRC can improve short-term survival and improve quality of life.6

Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a 28 kDa glycoprotein demonstrated to form non-covalent 1:1 stochiometric complexes with the matrix metalloproteinases (MMP),7 thereby inhibiting the matrix degrading properties of these endopeptidases,8 which play a pivotal role in the growth and spread of cancerous disease. However, distinct from the anti-proteolytic property of TIMP-1, recent reports have ascribed different or even opposing functions to the enzyme inhibitor, such as stimulation of cell growth, inhibition of apoptosis and enhancement of tumourgenicity and carcinogenesis, indicating that the role of TIMP-1 in cancer progression may be multifunctional.9, 10, 11, 12, 13, 14 In accordance with a growth-promoting role of TIMP-1, high tumour tissue levels of TIMP-1 mRNA and protein have been reported in various cancer diseases, with high levels of TIMP-1 being associated with poor prognosis.15, 16, 17, 18

Using a validated immunoassay for plasma TIMP-1, we have demonstrated that compared with blood donors, who have TIMP-1 levels distributed within a narrow range, both early and advanced stage CRC patients have significantly increased levels of plasma TIMP-1.19, 20 Furthermore, we have reported that preoperative plasma TIMP-1 is significantly correlated with survival of CRC patients; high plasma TIMP-1 independently predicting poor prognosis.21, 22 The present report aimed to test the usefulness of TIMP-1 levels in postoperative plasma samples as a monitoring marker in surveillance of CRC patients.

Section snippets

Blood donors

Ethylenediaminetetraacetic acid (EDTA) plasma samples were analysed from a total of 808 blood donors for the establishment of the range of TIMP-1 in healthy individuals. A total of 391 males and 417 females were included. The median age was 42 years; however, the age range was wide (18–79 years) and included representative numbers of individuals at both extremes. All donors were apparently in good health, did not receive any medication and participated on a volunteer basis.

CRC patients

In the Danish part of

TIMP-1 levels in healthy donors

The median (range) level of total plasma TIMP-1 in 808 healthy donors was 72 (30–229) ng/ml; 1st and 3rd quartiles: 62 and 86 ng/ml. As seen from Fig. 1, a significant association between plasma TIMP-1, age and gender was demonstrated, using linear regression on the log transformed TIMP-1 levels. Thus, mean TIMP-1 levels increased by 8% per decade (P < 0.0001) in both males and females. Furthermore, healthy male donors had approximately 7% higher TIMP-1 levels (P < 0.0001). Based on plasma TIMP-1

Discussion

Preoperative plasma TIMP-1 has previously been shown to be strongly associated with CRC survival;21, 22 therefore, the present study was undertaken to clarify whether postoperative TIMP-1 in patients surgically treated for CRC would provide clinically useful information. The data showed that the course of plasma TIMP-1 from pre- to postoperative levels was significantly correlated with patient survival independently of other clinicopathological parameters. Furthermore, the course of plasma

Conflict of interest statement

None declared.

Acknowledgements

Support was provided for MNH-A, VJ and NB by: Dagmar Marshall’s Fund, Einar Willumsen’s Fund, Wedell-Wedellsborg’s Fund, The Danish Cancer Society; and for HJN and IJ by: The Danish Cancer Society, The IMK Fund, LEO Pharma Research Fund, Kathrine and Viggo Skovgaards Fund, The Danish Cancer Research Fund, Eva and Henry Frænkels Fund, The Beckett Fund, PA Messerschmidts Fund, The Harboe Fund, Knud and Dagny Gad Andresens Fund, The Kornerup Fund, The Hartmann Bros. Fund, The Danish Pharmacy

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