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

Abstract

Purpose: 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. 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; 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-1and 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 (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% 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.

Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium

“…Matrix metalloproteinases (MMPs) are highly expressed in many cancers, and their up-regulations are associated with invasive tumor growth and poor prognosis (15)(16)(17). MMP-1, a zinc-dependent matrix metalloprotease, is an interstitial collagenase.…”

A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells

“…Another explanation is that the abundant collagen content and high intradiscal pressure of the discs act as mechanical barriers against tumor invasion. However, metastatic cancer cells secrete matrix metalloproteinases, such as collagenase, that can destroy extracellular matrix components of the discs during metastasis or progression [5,11,17,23]. Therefore, these findings suggest that there may be a mechanism other than the disc's anatomic characteristics that confer its resistance to metastases.…”

Late SV40 Factor (LSF) Enhances Angiogenesis by Transcriptionally Up-regulating Matrix Metalloproteinase-9 (MMP-9)

“…Among the MMPs, MMP-9 is overexpressed in many tumors including HCC and studies using knock-out mouse models have confirmed the role of MMP-9 in invasive, aggressive, and metastatic tumors (6 -11). High serum levels of MMP-9 is linked to rapid progression, poor survival, and secondary metastasis in multiple cancer indications (12)(13)(14). Tumor-induced angiogenesis is important to sustain growth of solid tumors when they become invasive and metastatic and the functional role of MMPs in tumor angiogenesis is well established (15).…”