Matrix Metalloproteinases: Biologic Activity and Clinical Implications

Abstract

Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.

Matrix metalloproteinases in neuroinflammation

“…Inflammatory processes lead to the induction of collagenase (MMP-1), stromelysin-1 (MMP-3), matrilysin (MMP-7), and MMP-9. Control of the inducible MMPs occurs at multiple sites, including activator protein-1 (AP-1), nuclear factor-B (NF-B), and PEA-3 (Ets-1) sites (Nelson et al, 2000) (Fig. 2).…”

“…These inhibitors tend to be poorly soluble. Clinical trials of MMP inhibitors in cancer have been disappointing (Nelson et al, 2000).…”

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

“…MMPs contribute to invasion and metastasis of tumor cells facilitating the degradation of the surrounding BM and ECM barriers, allowing migration and spreading of cancer cells (Chang and Werb, 2001). They are also involved in the regulation of cell proliferation, release of growth factors and angiogenesis (Nelson et al, 2000;Stetler-Stevenson and Yu, 2001). MMP activity is regulated at several levels, most notably, by the proteolytic cleavage of inactive proforms into mature active forms and by interaction with the endogenous tissue inhibitors of metalloproteinases (TIMPs) (Nagase and Woessner, 1999).…”

Serum matrix metalloproteinase‐9 in head and neck squamous cell carcinomais a prognostic marker

“…They are able to degrade connective tissue, among other substrates the basement membrane collagen, which appears to play a key role in tumor cell invasion and in the process of metastasis. [4][5][6][7][8] Gelatinases have also been associated with tumor angiogenesis, especially gelatinase B. 9,10 Increased expression of MMP-2 and MMP-9 immunoreactive protein in various cancer tissues has been found to be associated with shortened survival and shortened relapse-free times in patients suffering from these cancers.…”