Matrix Metalloproteinases and Their Inhibitors in Turnover and Degradation of Extracellular Matrix - Extracellular Matrix Degradation - page 15

not well understood. Most likely, as occurs for essentially all extracellular proteins
(see Chap. 8), inhibited MMPs would be internalized, sorted to lysosomes, and
degraded. Indeed, preformed complexes of MMP2/TIMP2 are internalized by low
density lipoprotein receptor-related protein (LRP) (Emonard et al. 2004 ), a member
of the low density lipoprotein receptor superfamily that mediates endocytosis of a
variety of extracellular proteins. But could endocytosis also be used to directly
silence MMP activity? The answer is clearly yes. In particular, internalization,
sorting, and recycling are critical mechanisms controlling the activity of transmem-
brane MMPs at the cell surface (Deschamps et al. 2005 ; Galvez et al. 2004 ; Jiang
et al. 2001 ; Lafleur et al. 2006 ; Osenkowski et al. 2004 ; Wang et al. 2004 ).
Furthermore, MMP2, MMP9, MMP13, and MMP14 are internalized by LRP-
mediated endocytosis (Barmina et al. 1999 ; Hahn-Dantona et al. 2001 ; Van den
Steen et al. 2006 ; Yang et al. 2001 ), and by other cell surface-associated proteins as
well. In fact, as discussed in Chap. 8, it is quite likely that endocytosis is the
principal means for turnover, remodeling, and clearance of ECM, and the function
of MMPs, as we have proposed, is more confined to processing steps to control
protein activity.
1.6 Significance
Because they are thought to have the ability to degrade ECM, MMPs have
been often implicated as contributing to tumor progression and metastasis,
supposedly by breaking down tissue barriers that would otherwise restrain inva-
sion (Coussens et al. 2002 ; Egeblad and Werb 2002 ). Consequently, many
pharmaceutical companies developed programs to target MMPs in cancer. Sev-
eral drugs, all designed to directly block MMP catalytic activity, were tested in
phase III clinical trials; however, none were effective (Coussens et al. 2002 ). In
fact, in one study, patients taking the MMP inhibitor died at a rate higher than
those on the placebo.
The key shortcoming of the MMP inhibitor trials is that these drugs lack
specificity. They not only block the activity of all MMPs, but also inhibit the
activity of the related ADAM and ADAMTS proteinases as well as other metal-
loenzymes and even unrelated enzymes (Saghatelian et al. 2004 ). Despite the
largely disappointing clinical trials, several studies in mice and cell models have
convincingly demonstrated that specific MMPs are indeed essential mediators of
tumor progression and invasion (Coussens et al. 2002 ; Hotary et al. 2002 ; Hotary
et al. 2003 ; Wilson et al. 1997 ). In a complex tissue environment, like cancer,
several cell types (resident, inflammatory, tumor) express several, different MMPs,
and these proteinase can either promote or restrain disease or repair processes by
affecting multiple and apparently opposing processes by the same cell at the same
time (Coussens et al. 2002 ; Egeblad and Werb 2002 ; Parks et al. 2004 ). Clearly,
some of the functions of MMPs involve their ability to act on ECM, but consi-
dering the wide range of potential substrates outside of the cell, and the power of