Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent proteases that are involved in degrading extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring proteins 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 metastasis. They also promote growth, inhibit angiogenesis, and modulate cell morphology. TIMP-3 is unique among the TIMPs in being a component of the ECM itself and in suppressing tumor cell growth. TIMP-4, the most recently discovered TIMP, has its gene allocated to human chromosome 3p25 and is perhaps the most tissue-specific of the TIMPs being expressed largely in the heart. Synthetic low-molecular-weight MMP inhibitors with a hydroxamate structure that mimics collagen have reduced the tumor burden and altered the growth of primary tumors in animal models. Understanding the biological significance of TIMPs and their involvement in tumorigenicity will be valuable for the development of effective novel therapeutic strategies for controlling 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 MMP inhibitors in cancer treatment.
Volume 135, 2023
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