High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma.
OBJECTIVE
Matrix metalloproteinases (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.


METHODS
Total pretreatment serum levels of MMP-9 in 71 patients and MMP-1 and 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 using Western blot analysis and gelatin zymography.


RESULTS
Patients with high serum levels of MMP-9 (> or = 376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n = 52; median OS, 29.1 versus 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). Serum levels of MMP-1 and MMP-13 did not correlate with OS. MMP-1 and 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 (> or = 29.8 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-1 turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confidence 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.
Nikkola
Johanna
J
Department of Oncology and Radiotherapy, Turku University Hospital, Finland.
Vihinen
Pia
P
Vuoristo
Meri-Sisko
MS
Kellokumpu-Lehtinen
Pirkko
P
Kähäri
Veli-Matti
VM
Pyrhönen
Seppo
S
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000097:blood*; D016022:Case-Control Studies; D017364:Collagenases / Q000096:biosynthesis / Q000097:blood; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000097:blood*; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000097:blood*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1