TIMPs as Modular Inhibitors of Angiogenesis

Children'S Hospital Boston, Boston MA

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Abstract

Matrix metalloproteinases (MMPs), the multigene family of Zn+2-dependent endopeptidases, have been implicated by our group and others in the regulation of angiogenesis. Regulation of MMP activity is achieved at the transcriptional level as well as by a family of endogenous inhibitors, the TIMPs. Despite their universal ability to inhibit the activity of their cognate enzymes, TIMPs differ significantly in their ability to inhibit critical and required processes of angiogenesis. For example, although each of the TIMPs studied can inhibit EC migration, TIMP-2 is unique in its ability to potently inhibit capillary EC proliferation driven by angiogenic mitogens. Through structure-function analyses we have now demonstrated that the inhibition of endothelial cell proliferation by TIMP-2 is independent of its MMP inhibitory activity and that TIMP-2 possesses an additional anti-angiogenic activity that may be receptor-mediated. In addition, we have identified two TIMP-2 peptides that are novel and potent inhibitors of angiogenesis in vivo. We now propose to identify the mechanism by which TIMP-2 and its anti-angiogenic peptides inhibit angiogenesis. In the context of Aim 1, we will test the hypothesis that this activity is receptor-mediated using a variety of biochemical strategies. Aim 2 of this proposal will test the hypothesis that these novel TIMP-2 anti-angiogenic domains can suppress the growth and progression of prostate tumor growth in vivo using the TRAMP and LNCaP model systems. Finally, based on our finding that MMPs can be detected in the urine of cancer patients and tumor-bearing animals and are predictive of disease status, we will test the hypothesis that TIMP-2 and its inhibitory peptides might also serve as markers of tumor progression by analyzing urines obtained from the mice being studied in Aim 2, as well as the urines of patients suffering from urologic cancers (Aim 3). The Specific Aims of this proposal are: 1. To determine the mechanism(s) of action by which TIMP-2 and its angio-inhibitory peptides inhibit angiogenesis. 2. To determine whether novel anti-angiogenic domains of TIMP-2 inhibit prostate cancer growth and progression in vivo. 3. To determine whether urinary MMPs and TIMP peptides predict tumor presence, progression and therapeutic efficacy in animal models of prostate cancer and in human patients with urogenital cancers.