Abstract
Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell–matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.
Highlights
Solid tumors are complex structures of cancerous cells that are surrounded by a vascularized dynamic tumor stroma containing various non-malignant cells such as fibroblasts and myeloid cells
After a precancerous cell has undergone epithelialto-mesenchymal transition (EMT) and has become cancerous, it breaches the basement membrane (BM) and invades the stromal extracellular matrix (ECM), which becomes possible by reorganization of integrin-containing cell-matrix adhesome structures and recruitment of ECM-degrading MMPs to them
Among the various extracellular proteases, MMPs are of outstanding importance, as they considerably affect the integrity of the ECM, the phenotype, and behavior of matrix-embedded cells and tissue turnover by degrading ECM proteins and selectively releasing cell surface-bound cytokines, growth factors, or their receptors [15]
Summary
Solid tumors are complex structures of cancerous cells that are surrounded by a vascularized dynamic tumor stroma containing various non-malignant cells such as fibroblasts and myeloid cells. Tumor progression and metastasis depend on highly regulated and complex remodeling of the TME by pericellular proteolysis, i.e., cleavage, processing, or shedding of cell adhesion molecules, growth factors, cytokines, and kinases. Among the various extracellular proteases, MMPs are of outstanding importance, as they considerably affect the integrity of the ECM, the phenotype, and behavior of matrix-embedded cells and tissue turnover by degrading ECM proteins and selectively releasing cell surface-bound cytokines, growth factors, or their receptors [15] Depending on their type, these can have gelatinolytic and even collagenolytic activity towards the ECM. MMPs and especially MMP-14 decisively influence the balance between cell adhesion and pericellular proteolysis of the ECM For this purpose, the matrix receptors and proteases involved are interrelated in specialized adhesome structures called invadosomes [24]. The pericellular proteolysis that these invadosomes cause and cell adhesion are two interdependent factors that determine the TME and, the prognosis for cancer patients
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