Imbalance between serum matrix metalloproteinase-2 and its inhibitor as a predictor of recurrence of urothelial cancer

Abstract

Summary Serum levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) were evaluated as prognostic indicators of the recurrence of urothelial cancer. Sera were obtained from 127 healthy control subjects and 97 urothelial cancer patients who underwent complete resection and were measured for MMP-2 and TIMP-2 using a one-step enzyme immunoassay. The relationship between the serum MMP-2/TIMP-2 ratio and the recurrence of urothelial cancer was examined. The mean serum MMP-2/TIMP-2 ratio in the 31 advanced urothelial cancer patients with recurrence was significantly higher than that in the 22 patients without recurrence (P = 0.0029) and in the 44 superficial bladder cancer patients (P < 0.0001). The 1-and 3-year disease-free survival rates in the patients with high MMP-2/TIMP-2 ratios (50% and 12%) were significantly poorer than those of the patients with normal ratios (82% and 56%) (P=0.0152). Univariate and multivariate analyses of recurrence demonstrated that the serum MMP-2/TIMP-2 ratio is a significant independent indicator of advanced urothelial cancer. Our results indicate that an imbalance between the serum levels of MMP-2 and TIMP-2 could be a new predictor of recurrence in advanced urothelial cancer patients.Keywords: serum; matrix metalloproteinase-2; tissue inhibitor of metalloproteinases-2; urothelial cancer; recurrence Matrix metalloproteinases (MMPs) has been shown to play a role in the degradation of the vascular basement membrane, whose major component is type IV collagen Nakajima et al, 1991). Matrix metalloproteinase-2 (MMP-2, gelatinase A, a 72-kDa type IV collagenase) is produced by both malignant cells and stromal cells such as fibroblasts, macrophages and vascular endothelial cells (Nakajima et al, 1991). Many investigators have demonstrated that human and rodent metastatic malignant cells produce larger amounts of MMP-2 than do non-metastatic cells, both in vitro and in vivo (Liotta et al, 1980;. Tissue inhibitor of metalloproteinases-2 (TIMP-2), an unglycosylated protein of 21-kDa molecular weight, strongly inhibits the biological activity of MMP-2, and was shown to strongly inhibit cancer invasion, metastasis, growth and angiogenesis in some rodent and human tumours (Stetler-Stevenson et al, 1989;DeClerck et al, 1992). Therefore, it is likely that an imbalance in the MMP-2 and TIMP-2 ratio plays an important role in cancer invasion, metastasis and angiogenesis DeClerck et al, 1994). Some investigators have revealed a relationship between the recurrence and the expression of MMP-2 and TIMP-2 in bladder cancer tissues (Davies et al, 1993;Grignon et al, 1996). However, there are no previous reports concerning the relationship between the serum MMP-2/TIMP-2 ratio and the recurrence of human urothelial cancer. In this study, the serum levels of MMP-2 and TIMP-2 were determined in human urothelial cancer patients, and the relationship between the serum MMP-2/TIMP-2 ratio and invasion and metastasis in urothelial cancer was examined. We discuss the diagno...

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