Metalloproteinases and their roles in human cancer

Abstract

It is now widely appreciated that members of the matrix metalloproteinase (MMP) family of enzymes play a key role in cancer development and progression along with many of the hallmarks associated with them. The activity of these enzymes has been directly implicated in extracellular matrix remodeling, the processing of growth factors and receptors, the modulation of cell migration, proliferation, and invasion, the epithelial to mesenchymal transition, the regulation of immune responses, and the control of angiogenesis. Certain MMP family members have been validated as biomarkers of a variety of human cancers including those of the breast, brain, pancreas, prostate, ovary, and others. The related metalloproteinases, the A disintegrin and metalloproteinases (ADAMs), share a number of these functions as well. Here, we explore these essential metalloproteinases and some of their disease-associated activities in detail as well as some of their complementary translational potential. Anat Rec, 303:1557-1572, 2020.Matrix metalloproteinases (MMPs) are a multigene family of metal-dependent endopeptidases that play important and diverse roles in normal physiological and pathological processes. The classic domain structure of MMP family members can be found in Figure 1 (Roy et al., 2009). MMPs include an amino-terminal signal peptide required for secretion, a pro-domain that mediates latency via a cysteine-switch mechanism and a Zn 2+ -dependent catalytic domain that is responsible for enzymatic function. A majority of MMPs also contain a C-terminal hemopexinlike domain that provides substrate specificity. MMP activity is the rate-limiting step in extracellular matrix (ECM) degradation and it can regulate the activity of other proteases, growth factors, cytokines, and cell-surface ligands

Syndecan-1 (CD138), Carcinomas and EMT

“…This is apparently derived from shedding at the cell surface of epithelial and/or stromal cells. Syndecans are exquisitely sensitive to a number of proteinases, notably MMPs, and there are many instances of upregulated MMP expression in tumor progression [65,66]. A "hot spot" for MMP cleavage of syndecan-1 (and other syndecans) lies in a membrane proximal region.…”

Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood–Brain Barrier

“…We hypothesized that upon transcytosis through the brain endothelium, breast cancer-derived EVs can change the behavior of astrocytes to prepare a microenvironment supportive of tumor cell growth. It is widely acknowledged that matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), can contribute to tumor progression and metastasis [28][29][30][31]. Through modulating the ECM, these enzymes and their inhibitors can trigger different signaling pathways and promote the tumor-supporting microenvironment [5,32].…”

The Yin-Yang Regulation of Reactive Oxygen Species and MicroRNAs in Cancer

“…Cancer cells go through epithelial to mesenchymal transition (EMT) before migrating to distant sites of the body. During the EMT process, expression of matrix metalloproteinases (MMPs) is increased to mediate degradation and reorganization of extracellular matrix and their elevated activation is associated with tumor growth, angiogenesis, invasion, and metastasis [30]. ROS play a significant role in the EMT process in which they regulate the expression of MMPs and their inhibitors tissue inhibitor of metalloproteinases (TIMP) [31].…”