High expression levels of collagenase‐1 and stromelysin‐1 correlate with shorter disease‐free survival in human metastatic melanoma

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading extracellular matrix. Their role has been emphasized in tumor invasion, metastasis and tumor-induced angiogenesis. We studied the expression of collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) in 70 melanoma metastases obtained from 56 patients treated with combined chemoimmunotherapy. The patients were divided into 2 groups using a cut-off point of 0% for MMP-1 expression and 20% for MMP-3 expression. We found that patients with MMP-1 positive metastases (n ‫؍‬ 38) had significantly shorter disease-free survival compared to patients with MMP-1 negative metastases (n ‫؍‬ 18) (median 11.2 vs. 17.0 months, p ‫؍‬ 0.0383). The disease-free survival of patients with high levels of MMP-3 expression in their metastases (>20% positive tumor cells, n ‫؍‬ 14) was also significantly shorter compared to patients with lower levels of expression (n ‫؍‬ 42) (median 5.1 vs. 14.0 months, p ‫؍‬ 0.0294). The expression of MMP-13 did not correlate to survival parameters. We also found that the presence of melanin, a pigment produced by melanocytes, correlated with high expression levels of MMP-1 (p ‫؍‬ 0.0002), MMP-3 (p < 0.0001) and MMP-13 (p ‫؍‬ 0.0009). The high expression levels of MMP-13 were also associated with the presence of visceral metastases (p ‫؍‬ 0.0284). Our findings suggest that MMP-1 and -3 may have a special role in melanoma metastasis formation and thus they could be used to measure the biological activity of the disease. © 2002 Wiley-Liss, Inc. Key words: MMP-1; MMP-3; MMP-13; melanin; metastatic melanoma; disease-free survivalMatrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases that can degrade essentially all extracellular matrix components. At present, the human MMP gene family contains 21 members that can be divided into subgroups of collagenases, gelatinases, stromelysins, membrane-type MMPs (MT-MMPs) and novel MMPs according to their substrate specificity and primary structure. 1,2 There are specific tissue inhibitors of metalloproteinases (TIMPs) that can inhibit the activity of MMPs. The balance between MMPs and their inhibitors is essential in many physiological conditions as well as in pathological conditions such as rheumatoid arthritis, atherosclerosis, tumor invasion, metastasis and tumor-induced neovascularization. 3,4 Members of the collagenase subgroup, i.e., collagenase-1 (MMP-1), collagenase-2 (MMP-8) and collagenase-3 (MMP-13), are only neutral proteinases capable of degrading native fibrillar collagens of types I, II, III and V. After initial cleavage by collagenases followed by denaturation the fibrillar collagens are further degraded by gelatinases. MMP-13 has exceptionally wide substrate specificity compared to other MMPs. In addition to native fibrillar collagens it degrades type IV, X and XIV collagens, tenascin, fibronectin and the aggrecan core protein. 2 Stromelysin-1 (MMP-3) was one of the first proteinases found to be associated with cancer. 5 MMP-3 ...

High Serum Levels of Matrix Metalloproteinase-9 and Matrix Metalloproteinase-1 Are Associated with Rapid Progression in Patients with Metastatic Melanoma

“…In our previous studies, we have found that it was expressed tumor cells in human melanoma metastases (17,18). In the present study, we detected MMP-13 in the serum of patients with metastatic melanoma but also in the serum of healthy controls.…”

“…The expression of MMP-1 and MMP-13 (9), and the expression of gelatinases, in particular (10 -16), has been associated with melanoma progression. In our previous study, we found that high expression levels of MMP-1 and MMP-3 in melanoma metastases correlated with shorter disease-free survival (17). We also observed that a high expression of MMP-1 was associated with favorable treatment response (18).…”

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

“…9 We have also found that high expression levels of MMP-1 or MMP-3 are associated with shorter disease-free survival in the same disease. 90 On the other hand, Arenas-Huertero et al 91 have found that low activity of MMP-2 or MMP-9 are associated with better response to neoadjuvant chemotherapy in SCC of oral cavity.…”

Distinct biological events generated by ECM proteolysis by two homologous collagenases

“…Abnormally elevated levels of MMP-1 or of both MMP-1 and MMP-13 have been associated with different types of cancers and with inflammatory diseases (12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”