Matrix Metalloproteinases

MMPs have been implicated in promoting angiogenesis as well as tumor growth and metastasis. Capillary endothe-lial cells (EC), under the influence of angiogenic mitogens, secrete MMPs, and the proteolytic activity of these enzymes facilitates the sprouting of EC out from the parent venule as well as the migration of these cells at the leading edge of the new capillary sprout through the ECM during angiogenesis (Figure 1). For example, MMP-2 activity has been shown to be concentrated at the invadopodia of a variety of cell lines. In addition, MMP activity is required for cancer cell migration and invasion through extracellular spaces as well as for the cell's ability to invade a nearby blood vessel, extravasate at a distant site, and then to finally invade the distant tissue in order to seed a new metastatic lesion. MMPs have also been shown to cleave membrane-bound growth factors, such as HB-EGF and TGFb, as well as to release angiogenic mitogens (bFGF) deposited in the matrix.

Recent studies have demonstrated that MMPs are also important at the earliest stages of the angiogenic program called the angiogenic switch. In a model of tumor progression that recapitulates the earliest events associated with the onset of neovascularization, our laboratory has shown that MMP-2 is a critical component of the angiogenic switch. In this study, both MMP-2 protein and activity were significantly upregulated during the transition from a preangio-genic to an angiogenic tumor [2]. Since that report, other groups have shown that MMP-9 may be a regulator of the angiogenic switch in a pancreatic tumor model [3]. Taken together, these data support the conclusion that MMP activity is one of the earliest and most sustained activities in angiogenesis. Because MMP activity is required for angio-genesis and tumor growth, it is not surprising that MMPs can be found in the urine of cancer patients and that they are independent predictors of disease status [4]. MMPs were reproducibly detected in the urine of cancer patients and correlated with disease status but were not found in the urine of healthy age-matched, sex-matched controls or in the urine of patients who showed no evidence of disease at the time of sampling and testing.

These studies highlight the importance of MMPs as regulators of angiogenesis and subsequent tumor progression. Based on these data, MMP activity represents a potentially powerful target for cancer therapy. In fact, it has been shown that a shift in the proteolytic balance in favor of the MMP inhibitors would effectively block angiogenesis, and several synthetic inhibitors of MMPs have been tested in clinical

Figure 1 Role of MMPs in angiogenesis, tumor growth and metastasis.

trials designed to determine their efficacy in the treatment of solid tumors and metastasis. Unfortunately, the indiscriminate use of synthetic MMP inhibitors has proven to be less successful than originally anticipated and has also resulted in side effects that preclude their use at therapeutically effective doses. Current clinical trials are testing certain of these inhibitors in combination therapies. However, it is possible that their broad specificity and, in some cases, limited bioavailability may ultimately mean that this generation of synthetic MMP inhibitors will not be as promising as once hoped. In light of these disappointing outcomes, there is renewed interest in the endogenous MMP inhibitors, which, although larger in size, may offer advantages over synthetics, with respect to both a reduction of cytotoxicity and their lack of immunogenicity as a function of their being a part of a naturally occurring protein.

Although MMPs are routinely regarded as being proan-giogenic molecules, MMPs have also recently been shown to process antiangiogenic fragments from their inactive parent molecule, suggesting that they can also function as negative regulators of angiogenesis. For example, we have shown that MMP-2 can proteolytically cleave plasminogen to yield the endogenous inhibitor, angiostatin. Other groups have reported that, depending on tumor type, additional MMP family members also share this activity. Similarly, MMPs have been shown to participate in the processing of endostatin from collagen XVIII.

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