Physiological roles of matrix metalloproteinases: implications for tumor growth and metastasis

Abstract

Physiological processes involving remodelling of the extracellular matrix, such as wound healing, embryogenesis, angiogenesis, and the female reproductive cycle, require the activity of matrix metalloproteinases (MMPs). This group of proteases degrades basal membranes and connective tissues and plays an essential role in the homeostasis of the extracellular matrix. An imbalance in the expression or activity of MMPs can have important consequences in diseases such as multiple sclerosis, Alzheimer's disease, or the development of cancers. Because of the pathophysiological importance of MMPs, their activity is highly controlled in order to confine them to specific areas. An activation cascade, initiated by the proteolysis of plasminogen, cleaves proMMPs, and every step is controlled by specific activators or inhibitors. MMPs destabilize the organization of the extracellular matrix and influence the development of cancer by contributing to cell migration, tumor cell proliferation, and angiogenesis. Accordingly, these proteases possess an important role in cell-matrix interactions by affecting fundamental processes such as cell differentiation and proliferation. Therefore, the characterization of MMPs involved in specific types and stages of tumors will significantly improve the diagnosis and treatment of these cancers in humans.

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

“…13 In addition, Ras regulates the expression and activity of different MMPs. These metalloproteinases play key roles in matrix remodeling processes that are essential for tumor growth and invasion.…”

“…These metalloproteinases play key roles in matrix remodeling processes that are essential for tumor growth and invasion. 13 Consequently, the effects of SCH-66336 on the secretion of 2 gelatinases, MMP-2 and MMP-9, were investigated. Gelatin zymography showed that increasing doses of SCH-66336 gradually reduced levels of secreted pro-MMP-2 from PC-3 cells (Fig.…”

“…6,7,12 MMPs, TIMPs and serine proteases of the plasminogen activation system, including uPA, uPAR, PAI-1 and plasmin, play pivotal roles in ECM remodeling during cancer invasion, metastasis and angiogenesis. [13][14][15][16][17] Components of the plasminogen activation system are regulated by Ras isoforms. For example, transfection of NIH-3T3 fibroblast cells with constitutively active H-Ras stimulates uPAR transcription about 4-fold, 18 while disruption of mutated K-ras by homologous recombination downregulates uPAR expression.…”

“…22 In addition, cell transfection with an activated H-ras increases MMP-9 gelatinolytic activity. 23,24 Since MMP activity is stimulated by uPA and plasmin, 13,14,16,17 plasmin, uPA, uPAR and MMPs could be regulated by FTIs through inhibition of Ras prenylation and activity.…”

Proteolysis of AA Amyloid Fibril Proteins by Matrix Metalloproteinases-1, -2, and -3

“…An imbalance in the expression and/or activity of MMPs can have important consequences in the development of diseases such as cancer and Alzheimer's disease, a cerebral amyloid disease. [1][2][3][4] Amyloidoses are characterized by local, organ-limited, or generalized proteinaceous deposits of autologous origin showing fibrillar protein deposits with specific tinctorial and structural properties. [5][6][7] Approximately 45% of all generalized amyloidoses are secondary or AA amyloidosis, 8 -11 and the acute-phase protein serum amyloid A (SAA) is the precursor of the AA fibril protein deposited in this disease.…”