TIMPs are the primary inhibitors of collagenases, as well as all other MMPs.67 To date, there have been four human TIMPs identified (TIMPs 1-4), all with similar secondary structure but with somewhat different inhibitory capabilities against the various MMPs (Fig. 11.1). TIMPs bind MMP active sites, forming stoichiometric, noncovalent complexes. By doing so, TIMPs comprise the third part of the MMP regulatory triad, the other parts consisting of MMP expression and activation. The best evidence that MMPs play a critical role in tumor progression is the ability of TIMPs to block tumor progression. This was demonstrated by Schultz et al, who used recombinant TIMP-1 to block tumor invasion in vitro and in vivo.68 Similarly, Khokha et al used antisense cDNA constructs to block TIMP expression in mouse 3T3 cells, and found that decreased TIMP expression correlated with increased invasiveness in vitro and in vivo.69 TIMP levels in metastatic cells lines have repeatedly been shown to inversely correlate with invasiveness,70-72 and increasing TIMP levels in such cells by transfection inhibits invasiveness.73,74 Interestingly, Koop et al have demonstrated that melanoma cells overexpressing TIMP-1 extravasate as efficiently as parent cells, but show significantly reduced tumor growth after extravasation.15 This suggests that transit through the endothelial basement membrane may not require MMP activity, but subsequent steps in metastasis do. This is consistent with a possible role for interstitial collagenase involvement in digesting stromal extracellular matrix. In contrast, Kawamata et al recently showed that TIMP-overexpressing bladder carcinoma cells extravasate poorly, but grow, invade, and metastasize similarly to parental cell lines.28 These discrepancies between the two studies may be due to differences in TIMP cDNA expression levels, relative MMP/ TIMP ratios, and tumor environments. In addition to TIMPs, a number of synthetic MMP inhibitors have been successfully used to block tumor invasion and metastasis.75 Taken together, these studies strongly support the role of MMPs in various aspects of tumor growth, invasion, and metastasis. While some of this inhibition may result from the ability of TIMPs and synthetic inhibitors to block tumor migration through tissue, it is now clear that angio-genesis, which is a critical factor for tumor survival and growth, is itself dependent on MMP activity.
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