Expression and biological significance of tissue inhibitors of metalloproteinases

Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependen t proteases that are involved in degrading extracellular matrix (ECM). Tiss ue inhibitors of metalloproteinases (TIMPs) are naturally occurring protein s that inhibit MMP activity by binding noncovalently with the active forms of MMPs at molar equivalence. Of the four TIMPs characterized so far, TIMP- 1 and TIMP-2 participate in the inhibition of tumor growth, invasion, and m etastasis. They also promote growth, inhibit angiogenesis, and modulate cel l morphology. TIMP-3 is unique among the TIMPs in being a component of the ECM itself and in suppressing tumor cell growth. TIMP-1, the most recently discovered TIMP, has its gene allocated to human chromosome 3p25 and is per haps the most tissue-specific of the TIMPs being expressed largely in the h eart. Synthetic low-molecular weight MMP inhibitors with a hydroxamate stru cture that mimics collagen have reduced the tumor burden and altered the gr owth of primary tumors in animal models. Understanding the biological signi ficance of TIMPs and their involvement in tumorigenicity will be valuable f or the development of effective novel therapeutic strategies for controllin g tumor growth and metastasis. This chapter provides a brief review of the four TIMPs characterized thus far, focuses on their roles in tumorigenesis and angiogenesis and concludes with a brief look at the use of synthetic MM P inhibitors in cancer treatment.