By Jean-Michel Foidart, Ruth J. Muschel
In recent times, serine proteases and matrix metalloproteinases (MMPs) have won significant consciousness in tumor biology. for many of those proteases, their expression is a competent indication of ongoing tissue home improvement. This booklet presents a finished evaluate of the mechanisms of motion of proteases and their inhibitors in tumor biology. the 1st half offers the reader with a selective review of the molecular biology of serine proteases, MMPs and their physiological inhibitors. an important proteases and their physiological in addition to artificial inhibitors are evaluated within the so much correct types of experimental and human melanoma. The scientific facets also are taken into consideration. This quantity deals an replace in this difficult element of melanoma therapy, its curiosity bias, and attainable medical implication.
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In a sarcoma model system in which MMP-9 expression correlated with the ability to metastasize, over-expression of MMP-9 those cell lines lacking MMP-9 expression induced metastatic potential. Tumor growth was unaffected (Bernhard et al, 1994). Similar experiments in melanoma cells also demonstrated the ability of MMP-9 to augment metastasis (MacDougall et al, 1999). In complementary experiments, downregulation of MMP-9 using a ribozyme, curtailed metastasis in a sarcoma model system or a prostatic carcinoma model, while this down regulation did not alter tumor growth rate (Hua and Muschel, 1996; Sehgal et al, 1998).
SUBSTRATES Initially the MMPs were defined by their ability to degrade extracellular matrix and both MMP-2 and 9 fit that pattern with activity against denatured collagens of many types including collagens Type IV and V, elastin, gelatin, and fibronectin. More recently however a variety of additional non-matrix physiological targets have been identified including basic fibroblast growth factor, the cell surface protein galectin and a variety of proteins affecting inflammation. Specificity can be discerned.
Altogether, these data suggest that plasmin-mediated 29 proteolysis is essential, but not sufficient for tumor growth and angiogenesis. This could be due to a functional overlap between plasmin and certain MMPs in matrix degradation (Dano et al, 1999). Evidence for a role of uPA in malignant progression was provided by Shapiro et al (1996), in carcinogen-induced melanocytic neoplasms. However, more than 95% of cellular blue nevi invaded the underlying tissues in wild-type and uPA-deficient mice.