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

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.

Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression

“…Overexpression of various MMPs, particularly MMP-2, is correlated with poor prognosis in many types of cancer, including adrenocortical cancer, breast cancer, and thyroid malignancies [32,33] . In many types of tumors, the expression level of MMP-9 is markedly higher than in normal tissues [34,35] .…”

Polymorphisms in MMP-2 and TIMP-2 in Turkish patients with prostate cancer

“…The ECM is involved in vital biological processes, such as cell proliferation, differentiation, morphogenesis, tissue repair, and remodeling; it acts as a reservoir of biological active molecules. Many MMPs are associated with pathological destruction of ECM components (3)(4)(5)(6). The activity of MMPs is controlled by specific endogenous inhibitors, called tissue inhibitors of metalloproteinases (TIMPs).…”

Analysis of the MMP-dependent and independent functions of tissue inhibitor of metalloproteinase-2 on the invasiveness of breast cancer cells

“…Accordingly, an attempt was made to create synthetic MMP inhibitors as a cancer therapy. However, clinical trials of these synthetic MMP inhibitors did not produce significant results for reasons not yet understood (Stetler-Stevenson 2008). The failure of synthetic MMP inhibitors as a cancer therapy, along with the many roles of TIMP-2, highlights that our understanding of TIMP and MMP biology is incomplete and more complicated than initially thought (Dove 2002).…”