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High Serum Levels of Matrix Metalloproteinase-9 and Matrix Imaging, Diagnosis, Prognosis High Serum Levels of Matrix Metalloproteinase-9 and Matrix Metalloproteinase-1Are Associated with Rapid Progression in Patients with Metastatic Melanoma Johanna Nikkola,1, 3 PiaVihinen,1, 3 Meri-SiskoVuoristo,4 Pirkko Kellokumpu-Lehtinen,4 Veli-Matti Ka« ha« ri,2 and Seppo Pyrho« nen1, 3 Abstract Purpose: Matrixmetalloproteinases (MMP) are proteolytic enzymes that play an important role in various aspects of cancer progression. In the present work, we have studied the prognostic significance of serum levels of gelatinase B (MMP-9), collagenase-1 (MMP-1), and collagenase- 3 (MMP-13) in patients with advanced melanoma. Experimental Design:Total pretreatment serum levels of MMP-9 in 71patients and MMP-1and MMP-13 in 48 patients were determined by an assay system based on ELISA. Total MMP levels were also assessed in eight healthy controls. The active and latent forms of MMPs were defined by usingWestern blot analysis and gelatin zymography. Results: Patients with high serum levels of MMP-9 (z376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n =52;medianOS, 29.1versus 45.2 months; P = 0.033). High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P =0.032).SerumlevelsofMMP-1andMMP-13didnotcorrelate with OS. MMP-1and MMP-9 were found mainly in latent forms in serum, whereas the majority of MMP-13 in serum was active (48 kDa) form. MMP-13 was found more often in active form in patients (mean, 99% of the total MMP-13 level) than in controls (mean, 84% of the total MMP-13 level; P < 0.0001). After initiating the therapy, patients with elevated levels of MMP-1 (z29.8 ng/mL, n = 10) progressed more rapidly than patients with lower levels (median, 1.9 versus 3.5 months; P = 0.023). Serum levels of MMP-9 and MMP-13 did not correlate with the time to progression (TTP). In multivariate analysis with age and gender, MMP-9 or MMP-1turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confi- dence interval (95% CI), 1.03-3.3] or TTP (P = 0.023; HR, 2.7; 95% CI,1.15-6.4), respectively. Conclusions: Our findings provide evidence that MMP-1, MMP-9, and MMP-13 play important roles at different phases of metastatic melanoma spread and that serum MMP-9, in particular, could have clinical value in identifying patients at high risk for melanoma progression. Matrix metalloproteinases (MMP) are a family of zinc- MMPs are known to degrade many other cell membrane dependent neutral endopeptidases characterized by their ability and pericellular proteins, including cell membrane precursor to degrade extracellular matrix components. In addition to the forms of growth factors, growth factor binding proteins, various structural components of the extracellular matrix, growth factor receptors, cell adhesion molecules, clotting factors, and proteinase inhibitors as well as their own inactive zymogen forms (1–3). The human MMP family currently Authors’ Affiliations: 1Department of Oncology and Radiotherapy, Turku consists of 23 members, which can be divided into eight University Hospital; 2Departments of Dermatology and Medical Biochemistry and structural classes or, based on their substrate specificity and 3 Molecular Biology and MediCity Research Laboratory, University of Turku,Turku, primary structure, into the more familiar subgroups of Finland and 4Department of Oncology, Tampere University Hospital, Tampere, Finland collagenases, gelatinases, stromelysins, MT-MMPs, and novel Received 12/15/04; accepted 12/15/04. MMPs. MMPs are synthesized as inactive zymogens, which are Grant support: Academy of Finland, the Finnish Cancer Foundation, Finnish activated predominantly pericellularly by other MMPs or Cultural Foundation, Finnish Life and Pension Insurance Companies, the Paulo serine proteinases. The activity of MMPs is specifically Foundation, Sigrid Juselius Foundation, Turku Finnish University Society, Turku inhibited by tissue inhibitors of metalloproteinase and by Graduate School of Clinical Science, Turku University Central Hospital, and Turku University Foundation. nonspecific proteinase inhibitors (e.g., a2-macroglobulin). The The costs of publication of this article were defrayed in part by the payment of page balance between MMPs and their inhibitors is essential in charges. This article must therefore be hereby marked advertisement in accordance many physiologic conditions where rapid remodeling of with 18 U.S.C. Section 1734 solely to indicate this fact. extracellular matrix is required and it is disturbed in Requests for reprints: Pia Vihinen, Department of Oncology and Radiotherapy, pathologic conditions such as cancer. Turku University Hospital, Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland. Phone: 358-2-313-0000; Fax: 358-2-313-2809; E-mail: [email protected]. Collagenases (MMP-1, MMP-8, and MMP-13) are the F 2005 American Association for Cancer Research. principal extracellular proteinases capable of degrading native Clin Cancer Res 2005;11(14) July 15, 2005 5158 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2005 American Association for Cancer Research. Serum MMP-1, MMP-9, and MMP-13 in Metastatic Melanoma fibrillar type I, II, III, and V collagens. In addition, MMP-13 can Table 1. Characteristics of patients degrade a wide variety of other matrix substrates. After initial cleavage by collagenases, fibrillar collagens are denatured into Variable nN* gelatin and further degraded by gelatinases [i.e., gelatinase A Patients 48 23 (MMP-2) and gelatinase B (MMP-9)]. MMP-1 is expressed by Gender various types of cells in culture and in vivo (4). The expression Male 29 16 of MMP-9 is more restricted. It is produced by epithelial cells Female 19 7 such as migrating keratinocytes and is stored in the secretory Age (y) granules of neutrophils and eosinophils (5). MMP-9 also plays Median (range) 62 (25-75) 57 (36-75) an important role in angiogenesis (6). The physiologic Disease-free survival (mo) expression of MMP-13 is limited to situations where rapid Median (range) 11 (0-224) 17 (0-58) and effective remodeling of collagenous matrix is required (i.e., Overall survival (mo) fetal bone development and postnatal bone remodeling; ref. 7). Median (range) 44 (5-265) 40 (16-114) Malignant melanoma, the most aggressive of all skin tumors, Survival after the arises from melanocytes, which are normally located at the initiation of therapy (mo) basal cell layer of the epidermis. Patients with localized primary Median (range) 9 (0.3-73) 10 (2.4-64) melanoma have a favorable prognosis with cure rates up to TTP (mo) 90%. However, the prognosis in locoregional and metastatic Median (range) 2 (0.2-70) 4 (0.9-51) systemic disease is poor with a median survival of 24 and 6 c Previous treatment months, respectively (8). Because current treatment results in No treatment 16 7 advanced melanoma are not satisfactory, novel approaches are Radiotherapy 11 3 needed for therapy as well as for classification of patients into Surgery 32 15 subgroups in which certain types of therapeutic regimens IFN-a 27 would be optimal. Treatment arms The expression and significance of MMPs and their inhibitors Dacarbazine + 12 6 in melanoma has been studied extensively using melanoma cell natural IFN-a lines, mouse models, and tissue samples of patients with Dacarbazine + 11 8 primary or metastatic melanoma. The expression of MMP-1 and recombinant IFN-a MMP-13 (9), and the expression of gelatinases, in particular DOBCb +naturalIFN-a 11 5 (10–16), has been associated with melanoma progression. In DOBC + recombinant IFN-a 14 4 our previous study, we found that high expression levels of Tumor burden MMP-1 and MMP-3 in melanoma metastases correlated with Soft tissue metastases 83 shorter disease-free survival (17). We also observed that a high (skin, s.c., and lymph expression of MMP-1 was associated with favorable treatment node metastases) response (18). Lung metastases 15 2 F soft tissue metastases Serum levels of MMPs are known to be altered in many Other metastases 25 18 human pathologic conditions. Elevated serum levels of MMPs Number of metastatic sites have been reported in, for example, polycystic kidney disease One site 12 3 (19), systemic sclerosis (20), rheumatoid arthritis (21), and Two or more sites 36 20 cancer. In some diseases, such as acute viral hepatitis, however, Metastatic sites serum levels of MMPs are reduced (22). In comparison with Bone 13 6 healthy controls, the serum levels of MMP-9 are elevated in Liver 20 13 head and neck squamous cell carcinoma (23, 24) and in colon Lung 23 13 (25), gastric (26), bladder, breast, and prostate cancer (27). Skin/subcutis 16 7 Furthermore, elevated MMP-9 serum levels have been shown to Other sites 34 18 correlate with poor survival in stage I to II non–small cell lung Treatment response cancer patients (28). Complete response 60 There are few studies analyzing the serum levels of MMPs in Partial response 32 patients with metastatic melanoma and their results have been Stable disease 14 11 partly controversial. Vuoristo et al. (29) studied the serum Progressive disease 21 9 levels of MMP-2 in 50 patients with advanced melanoma and Not evaluated 41found that serum MMP-2 had not a role as a prognostic marker. On the other hand, in a study on a larger patient material, Wollina et al. (30) found that the serum levels of MMP-2 were *An additional group of 23 patients was analyzed for total MMP-9 serum levels. significantly higher in patients with metastatic melanoma than cTen patients had both radiotherapy and surgery; one patient had surgery in patients with localized melanoma. In addition, somewhat combined with IFN-a and one patient had both radiotherapy and surgery com- higher MMP-2 levels were noted in patients with more bined with IFN-a.
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