The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2

WG Stetler-Stevenson - Cancer and Metastasis Reviews, 2008 - Springer
WG Stetler-Stevenson
Cancer and Metastasis Reviews, 2008Springer
Proteolytic remodeling of the extracellular matrix is an important component of disease
progression in many chronic disease states and is the initiating event in the formation of the
tumor microenvironment in cancer. It is the balance of extracellular matrix degrading
enzymes, the matrix metalloproteinases (MMPs) and their endogenous inhibitors that
determine the extent of tissue remodeling. Unchecked MMP activity can result in significant
tissue damage, facilitate disease progression and is associated with host responses to …
Abstract
Proteolytic remodeling of the extracellular matrix is an important component of disease progression in many chronic disease states and is the initiating event in the formation of the tumor microenvironment in cancer. It is the balance of extracellular matrix degrading enzymes, the matrix metalloproteinases (MMPs) and their endogenous inhibitors that determine the extent of tissue remodeling. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury such as angiogenesis and inflammation. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that the tissue inhibitor of metalloproteinases-2 (TIMP-2) inhibits the mitogenic response of human microvascular endothelial cells to growth factors, such as VEGF-A and FGF-2 in vitro and angiogenesis in vivo. The mechanism of this effect is independent of metalloproteinase inhibition. Our lab is the first to demonstrate a cell-surface signaling receptor for a member of the TIMP family and suggest that TIMP-2 functions to regulate cellular responses to growth factors. These new findings are discussed in terms of a model of TIMP-2 regulation of cellular functions in the tumor microenvironment.
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