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Annals of Clinical & Laboratory Science 36:23-30 (2006)
© 2006 Association of Clinical Scientists

Serum TIMP-1 in Gastric Cancer Patients: A Potential Prognostic Biomarker

Chia-Siu Wang1, Tsu-Lan Wu2, Kuo-Chien Tsao2 and Chien-Feng Sun2
1 Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, and2 Department of Clinical Pathology, Chang Gung Memorial Hospital, Linkou, Taiwan

Address correspondence to Chien-Feng Sun, M.D., Dept of Pathology, Chang Gung Memorial Hospital, Linkou Medical Center, 5 Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan; tel 886 3 328 4376; fax 886 3 397 1827; e-mail suncgj{at}adm.cgmh.org.tw.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is over-expressed in many human malignancies, including gastric cancer, and is associated with poor outcome. The purpose of this study was to evaluate the clinical and prognostic significance of preoperative serum TIMP-1 levels in gastric cancer patients. One hundred and seventy gastric cancer patients who underwent gastrectomy between 1996 and 2001 were enrolled in this study. The serum concentration of TIMP-1 protein in these patients and in 116 healthy controls was determined using an enzyme-linked immunoassay (ELISA). When a serum TIMP-1 level >95 percentile of healthy controls was set as the upper cut-off value (348.8 ng/ml), abnormally high serum TIMP-1 were observed in 29 (17.1%) of the gastric cancer patients vs 4.3% of healthy controls (p<0.001). The sensitivity and specificity of serum TIMP-1 as a diagnostic tumor marker were 17.1% and 97.7%, respectively. Serum TIMP-1 was positively associated with morphologic appearance (Borrmann type), tumor size, depth of wall invasion, lymph node metastasis, liver metastasis, and peritoneal seeding. It was also positively associated with lymphatic invasion, perineural invasion, and pathological stage. It was not significantly associated with age, gender, tumor location, or histological type. A higher serum TIMP-1 group was significantly associated with lower survival rates than the lower serum TIMP-1 group (cut-off value at the median; 5-yr survival rate: 32.3% vs 55.6%, log-rank p = 0.0011). When the patients were divided into 2 groups using the 95 percentile TIMP-1 level of controls as the cut-off value, 5-yr survival rates were 24.6% and 47.5% respectively for the higher and lower TIMP-1 groups (log rank p = 0.0147). An elevated preoperative level of serum TIMP-1 was significantly associated with progressive disease, advanced stage, and worse survival in gastric cancer patients. Although it is not a good marker for diagnosis, elevated serum TIMP-1 level shows promise as a marker for prognosis in patients with gastric cancer.

Keywords: gastric cancer, tissue inhibitor of matrix metalloproteinase-1, TIMP-1


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Matrix metalloproteinases (MMPs) have the ability to degrade macromolecules of the extracellular matrix and are responsible for tumor invasion and infiltration [1]. The activity of MMPs is regulated by a group of endogenous proteins that are tissue inhibitors of metalloproteinases (TIMPs) [2]. TIMPs form complexes with different MMPs, resulting in inhibition of protease activity of MMPs [1,2]. Increasing evidence shows that imbalance of MMPs and TIMPs plays an important role in tumor invasion and metastasis [3].

TIMP-1 is a 28.5 kDa glycoprotein that has been studied in many human malignancies, including gastric cancer [4]. It is over-expressed in the supernatant of tissue extracts of breast, gastric, colorectal, and hepatocellular carcinomas [5–8]. TIMP-1 mRNA is elevated in gastric, esophageal, and pancreatic cancer, non-small lung cancer, and non-Hodgkin’s lymphoma) [9–15]. Immunohistochemical studies demonstrate increased TIMP-1 expression in gastric and renal carcinomas [16,17]. Higher TIMP-1 expression is associated with more advanced stages and more aggressive behavior in most of these malignancies [5,9,10,12,14,15,17–20]. Higher TIMP-1 expression is also associated with poor survival in some cancers (gastric, esophageal, breast, and renal carcinomas, and non-small cell lung carcinoma) [5,10,12,14,16,17]. TIMP-1 over-expression was positively correlated with tumor stage, progression, and survival in some studies of gastric cancer patients [10,16], but this was not observed in two reports where tumor cells were assessed for TIMP-1 expression [21,22].

TIMP-1 is ubiquitously present in human peripheral blood and body fluids [2]. The circulating TIMP-1 level has been studied in plasma or serum of patients with various malignancies [7,23–30] To date, only two reports assayed TIMP-1 in the blood of gastric cancer patients [23,31]. In one report, plasma TIMP-1 level was the most important independent prognosticator for survival in patients with gastric cancer [23]. In the other report, serum TIMP-1 levels were significantly higher in patients with diffuse-type gastric cancer (including scirrhous gastric cancer) than in healthy controls or patients with intestinal cancer [31]. Our study was designed to analyze serum TIMP-1 levels in gastric cancer patients and to determine their clinicopathologic correlations. The aim of this study was to test TIMP-1 as a serum marker for gastric cancer.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects.  A total of 170 patients who underwent gastrectomy with gastric cancer between 1996 and 2001 were enrolled. Their median age was 65.1 yr (range 29–89); the ratio of men/women was 112/58. There were 116 healthy controls (58 men, 53 women). Peripheral venous blood of patients was withdrawn before operation. Blood from controls was withdrawn on the day of a physical examination. Blood samples were stored at 4°C prior to centrifugation to separate the serum; the serum samples were then stored at –40°C until analysis.

Measurement of serum TIMP-1.  Serum levels of TIMP-1 were measured with an enzyme-linked immunosorbent assay kit (TIMP-1 ELISA, Oncogene Research Products). The TIMP-1 ELISA is a sandwich immunoassay that employs two monoclonal antibodies. An antibody specific for human TIMP-1 protein is immobilized on the surface of the plastic wells provided in the kit. The serum sample is prediluted 1:800 (v/v) with wash/assay buffer provided in the kit. The diluted serum sample and the standards are pipetted into the wells, where any human TIMP-1 protein present binds to the capture antibody. The unbound material is then washed away. A monoclonal, horseradish peroxidase (HRP)-conjugated anti-TIMP-1 antibody is added to the wells. Horseradish peroxidase catalyzes the conversion of the chromogenic substrate, tetramethylbenzidine from a colorless to a blue solution (which becomes yellow after addition of stopping reagent). The color intensity is proportional to the concentration of human TIMP-1 protein in the serum sample. The color reaction product is quantified using a spectrophotometer. A standard curve is constructed using samples with known concentrations of human TIMP-1 protein. The concentration of TIMP-1 protein in serum is calculated by comparing absorbance of the sample to the standard curve.

Clinicopathological studies.  Resected tumor specimens were studied pathologically according to the criteria described in the Japanese General Rules for Gastric Cancer Study [32] and the UICC’s pTNM classification [33]. The items included age, gender, tumor location, tumor size, gross (Borrmann) type, wall invasion, resection margin, histologic type, lymph node metastasis, vascular invasion, lymphatic invasion, and perineural invasion. The histological features were classified into 2 types: (i) intestinal or differentiated type, consisting of papillary and/or tubular adenocarcinomas, and (ii) diffuse or undifferentiated type, consisting of poorly differentiated, signet-ring cell, and/or mucinous adenocarcinomas.

Statistical analysis  As appropriate, the Mann-Whitney U test or Fisher’s exact test was used for between-group comparisons. Correlations between parameters were tested by Spearman’s correlation coefficient. Follow-up of the patients was carried out until June 2005 or until they died. Only 4 patients were lost to follow-up. Patient survival was expressed as the cumulative 5-yr survival rate. The cancer-specific survival outcome was expressed using the Kaplan-Meier method for all patients, excluding those who died from surgical complications or non-cancer related deaths (n = 10 or 5.7%). The log-rank test was used to compare the prognostic significance of individual variables in regard to survival. Cox’s proportional hazards model was used in a multivariate analysis to identify independent predictors of survival. A p <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
Comparison of serum TIMP-1 levels in patients vs healthy controls  The serum levels (mean ± SD) of TIMP-1 in healthy controls (n = 116) and patients with gastric cancer (n = 170) were, respectively, 251.7 ± 61.8 and 261.7 ± 120.3 ng/ml, which was not a significant difference (p = 0.47). However, extremely high levels of TIMP-1 were found only in the patient group (Fig. 1Go). When a serum TIMP-1 level equal to the 95 percentile value of healthy controls was set as the upper cut-off value, abnormally high levels of serum TIMP-1 were observed in 29 (17.1%) of the patients, compared to 5 (4.3%) of the healthy controls (p = <0.001, Fisher’s exact test). When the 95th percentile (348.8 ng/ml) of serum TIMP-1 values in healthy controls was taken as the cut-off level, the sensitivity, specificity, positive predictive value, and negative predictive value for TIMP-1 as a diagnostic test for gastric cancer were 17.1% (29/170), 97.7% (111/116), 85.3% (29/34), and 44.0% (111/252), respectively.


Figure 1
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  		Fig. 1. Scatterplots of serum TIMP-1 levels in gastric cancer patients (n = 170) and healthy controls (n = 116).

 
Clinicopathological correlations.  Table 1Go shows the association of the serum level of TIMP-1 with various clinicopathological parameters. It was positively associated with morphological appearance (Borrman type) (p = 0.002) and tumor size (p = 0.012) of gastric cancer. It was positively associated with the depth of wall invasion (p < 0.001) (Fig. 2AGo), and lymph node metastasis (p = 0.002) (Fig 2BGo). It was closely associated with distant metastasis (p < 0.001) (Fig. 2CGo), including liver metastasis (p = 0.010) and peritoneal seeding (p <0.001). It was also closely associated with lymphatic invasion (p = 0.008) and perineural invasion (p = 0.001). Overall, it was associated with pathological stage (p <0.001) (Fig. 2DGo). Serum TIMP-1 level was not associated with age (p = 0.295), gender (p = 0.152), tumor location (p = 0.396), histological type (p = 0.082), or vascular invasion (p = 0.065).


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  		Table 1. Clinicopathological correlations of serum TIMP-1 level and 5-yr survival rate in 170 gastric cancer patients.
 

Figure 2
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  		Fig. 2. Scatterplots of serum TIMP-1 level according to: (A) depth of wall invasion (pT) (p <0.001); (B) lymph node status (pN) (p = 0.003); (C) absence or presence of distant metastasis (pM) (p <0.001); and (D) pathological stage (pStage) (p <0.001).

 
Preoperative serum level and survival outcome.  The mean duration of follow-up period for the survivors (n = 68) was 65.8 mo (range, 39–100 mo). In all, 92 patients died as a result of the progression of gastric cancer, 8 patients died due to surgical complications, and two died of causes unrelated to cancer. The overall cumulative 5-yr survival rate of 170 patients with gastric resection was 44.2%. When the patients are divided into 2 groups according to the 95th percentile (348.8 ng/ml) as the cut-off value, the 5-yr survival rate of the lower TIMP-1 group was significantly greater than that of the higher group (47.5% vs. 24.6%; log rank p = 0.0147) (Fig. 3AGo). When the gastric cancer patients were divided into 4 groups according to interquartile ranges of serum TIMP-1 level, the 5-yr survival rate was significantly different in the 4 groups (log rank p = 0.0055). When the patients were divided into 2 groups according to the median TIMP-1 level (239.1 ng/ml) as the cut-off value, the 5-yr survival rate of the lower TIMP-1 group was greater than that of the higher TIMP-1 group (55.6% vs 32.3%; log rank p = 0.0011) (Fig. 3BGo).


Figure 3
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  		Fig. 3. Kaplan–Meier survival curves of two groups of gastric cancer patients: (A) left plot with 95 percentile TIMP-1 (348.8 ng/ml) of healthy controls as cut-off value (log rank p = 0.0147); (B) right plot with median TIMP-1 value (239.1 ng/ml) of patients as cut-off value (log rank p = 0.0022).

 
Table 1Go also lists the results of univariate analyses of prognostic significance of preoperative serum TIMP-1 levels in the 170 gastric cancer patients, including tumor size, depth of wall invasion, lymph node metastasis, distant metastasis, peritoneal seeding, liver metastasis, pathologic stage, vascular invasion, lymphatic invasion (log rank p <0.0001 for all of these variables). Prognostic significance was also found for gross tumor type (log rank p = 0.0001), perineural invasion (log rank p = 0.0013), tumor location (log rank p = 0.0067), histological type (log rank p = 0.0204), and serum TIMP-1 levels, using either the median value of patient data or the 95th percentile values of healthy controls as the cut-off value (log rank p = 0.0011 and 0.0147, respectively). Age and gender were not significant factors. Multivariate analysis showed that only lymph node metastasis and distant metastasis were independent prognostic factors; the preoperative serum TIMP-1 level was not an independent prognostic factor.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
CEA and CA19.9 are the most common tumor markers used in diagnosis and postoperative follow-up of gastric cancer patients [34]. Neither of these markers is sensitive enough for diagnosis of gastric cancer. Abnormal elevations of serum CEA and CA19.9 were present, respectively, in 22.2% and 21.7% of preoperative surgical patients in our previous report [35]. Although closely associated with advanced tumor stage and poor survival, neither is an independent factor for survival, based on our multivariate analysis. Several new biomarkers have been identified for gastric cancer and have contributed to knowledge of the molecular and cellular mechanisms of gastric carcinogenesis and its progression [36]. However, useful biomarkers for early detection and therapy of gastric cancer have not yet been identified.

TIMP-1 levels in peripheral blood have been measured using plasma and serum samples [7,23–31,37–41]. The TIMP-1 concentrations in serum and plasma samples from the same patient are often inconsistent because TIMP-1 protein, which is stored in the {alpha}-granules of platelets, is released upon platelet activation [42]. TIMP-1 levels in serum samples are unaffected by the time from collection to processing, but repeated freezing and thawing has a significant effect on TIMP-1 levels in serum samples [42]. However, TIMP-1 level may increase in plasma samples if not processed within 8 hr [42]. We previously performed a pairwise comparison between serum and plasma levels of TIMP-1 in 41 patients. For both serum and plasma samples, the supernatant was immediately divided into multiple small aliquots following centrifuging. Although TIMP-1 levels in the serum samples were higher than in plasma samples (236.9 ± 97.9 ng/ml vs 217.9 ± 91.6 ng/ml), both data sets were significantly correlated (r = 0.442, p = 0.004).

Elevation of blood TIMP-1 level is considered to result from reactive production of TIMP-1 in cancerous tissues [25]. TIMP-1 protein in the tumor tissue enters the circulation, giving rise to increased plasma TIMP-1 levels [7]. It is postulated that TIMPs are produced mainly from stroma cells in human cancer tissue as a host defense mechanism against invasive malignant cells [11,16,43].

Patients with colorectal, ovary, lung, liver, bladder, or prostate cancers had higher blood TIMP-1 levels than healthy controls [24–26,28,30,35,42]. Plasma TIMP-1 level has been suggested as a tumor marker for early detection of colon cancer due to high sensitivity and specificity [44]. It was suggested as a tumor marker for hepatocellular carcinoma in patients whose serum alpha-fetoprotein levels were not elevated [30]. Patients with soft tissue sarcoma had lower plasma TIMP-1 concentrations than healthy controls [38]. However, no difference was found in blood TIMP-1 levels in breast cancer patients vs healthy controls [39,44]. In the present study, serum TIMP-1 levels in patients with gastric cancer were not significantly higher than healthy controls. However, extremely high TIMP-1 levels were only found in the gastric cancer patients. The sensitivity and specificity of markedly elevated serum TIMP-1 levels were 17.1% and 97.7%, respectively, as a diagnostic marker for gastric cancer. Since high sensitivity and specificity are critical for diagnostic tumor markers, serum TIMP-1 is a potential prognostic factor instead of a serum marker for the diagnosis and early detection of malignancy [45].

High blood levels of TIMP-1 are associated with poor prognosis of various malignancies, including gastric, colorectal, bladder, prostate, ovary, breast, and lung cancers [7,23–26,28,29, 37,40]. TIMP-1 might serve as a serum marker of malignant potential (ie, tumor growth and/or aggressiveness) for these cancers. Blood TIMP-1 levels were identified as an independent prognostic factor in a few series of patients with colorectal, breast, or gastric cancer [7,23,40]. Serum TIMP-1 levels in our patients were a significant prognostic factor in univariate analysis, but not an independent factor in multivariate analysis.

Endogenous TIMPs were the first compounds to be considered for clinical development of matrix metalloproteinase inhibitors in anticancer therapy [46]. However, the dual functions of TIMP-1 with pro- and anti-neoplastic effects during tumor progression makes the therapeutic role of TIMP-1 uncertain [47]. Further, the lack of an effective method for systemic gene delivery of TIMPs has limited the clinical utility of this approach. Instead, the development of synthetic inhibitors of MMPs has been actively pursued and widely tested in clinical trials. At present, several MMP inhibitors are being developed for anticancer therapy [46]. A survival benefit has been observed in patients with gastric cancer who were treated with marimastat, especially in patients who had previously received chemotherapy [48].

The present study shows that exceptionally high serum levels of TIMP-1 in gastric carcinoma patients have a strong association with disease progression. Since TIMP-1 is over-expressed in various malignancies, it is unsuitable as a diagnostic biomarker for any specific tumor. However, serum TIMP-1 shows promise as a prognostic marker of tumor progression or advanced stage of neoplasia.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by grants from the Chang-Gung University, Taoyuan, Taiwan (NMRPD 621 and 9030) and the National Science Council of the Republic of China (NSC89-2314-B-182-059; NSC 89-2314-B-182-113). We thank Dr. Ting-Chang Chang, Biostatistics Consulting Unit, Chang Gung Memorial Hospital, for statistical assistance.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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