The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis

Abstract

Metalloproteases are important in many aspects of biology, ranging from cell proliferation, differentiation and remodeling of the extracellular matrix (ECM) to vascularization and cell migration. These events occur several times during organogenesis in both normal development and during tumor progression. Mechanisms of metalloprotease action underlying these events include the proteolytic cleavage of growth factors so that they can become available to cells not in direct physical contact, degradation of the ECM so that founder cells can move across tissues into nearby stroma, and regulated receptor cleavage to terminate migratory signaling. Most of these processes require a delicate balance between the functions of matrix metalloproteases (MMPs) or metalloprotease-disintegrins (ADAMs) and natural tissue inhibitors of metalloproteases (TIMPs). In this review, we discuss recent progress in identifying an essential role for metalloproteases in axon outgrowth, as an example of a focal invasive event. We also discuss the evolving concept of how MMPs might regulate stem cell fate during tumor development.

Figure 1. The switches between states of development and physiology and between states of physiology and pathology by controlling the ratio of MMP/ADAM-to-TIMP activities

P indicates the matrix metalloprotease (MMP)/metalloprotease-disintegrin (ADAM) and I indicates the tissue inhibitors of metalloprotease (TIMP). Homeostasis and repair are symbolic of two chemical reactions with the activity of TIMP dictating the shift of the equilibrium. When the function of MMPs is balanced by that of TIMPs, the cells are in a state of physiological quiescence. There is a correlation between upregulation of MMP activity and the progression of cells from normalcy through a series of premalignant steps into invasive cancers. It is unclear whether the malignant cells can be redirected into the program of a normal state. Cells in red represent invasive capacity acquired during developmental and pathological states, and the cell in green represents quiescence.

Figure 2. Crosstalk between stromal and malignant epithelial cells

Most of the proteases complexed at the invasive front are contributed by the stromal cells (fibroblasts, inflammatory cells and endothelial cells). The invading carcinoma cells use these enzymes to disrupt basement membranes, invade nearby tissues and metastasize to different organs. The production of matrix metalloproteases (MMPs) by stroma is regulated by tumor cells through the expression of chemokines, cytokines and extracellular matrix metalloprotease inducer (EMMPRIN). The influence of tissue inhibitors of metalloprotease (TIMP) on the invasive behavior of tumorigenic cells is cell-autonomous, depending only on the TIMP genotype of the tumor and not that of the host. Arrows indicate the exchange of chemokines or cytokines or EMMPRIN and enzymes between the participating cells, modifying the adjacent extracellular matrix (ECM) and releasing cell-surface and matrix-bound molecules by proteolytic cleavage. Membrane-type (MT) MMPs and metalloprotease-disintegrins (ADAMs) are transmembrane proteases, the best-known substrates of which are other transmembrane proteins (e.g. transmembrane ligands). Metalloprotease-mediated ligand release from the surface of the carcinoma cell regulates autocrine signaling. MMPs and ADAM-like proteases with thrombospondin domains (ADAM-TS) are secreted proteases, the best-known substrates of which are extracellular matrix proteins.