Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion

Abstract

Cells adhere to one another and/or to matrices that surround them. Regulation of cell-cell (intercellular) and cell-matrix adhesion is tightly controlled in normal cells, however, defects in cell adhesion are common in the majority of humancancers. Multilateral communication among tumor cells with the extracellular matrix (ECM) and neighbor cells is accomplished through adhesion molecules, ECM components, proteolytic enzymes and their endogenous inhibitors. There is sufficient evidence to suggest that reduced adherence is a tumor cell propertyengaged during tumor progression. Tumor cells acquire the ability to change shape, detach and easily move through spaces disorganizing the normal tissue architecture. This property is due to changes in expression levels of adhesion molecules and/or due to elevated levels of secreted proteolytic enzymes, including matrix metalloproteinases (MMPs). Among other roles, MMPsdegrade the ECMand, therefore, prepare the path for tumor cells to migrate, invade and spread to distant secondary areas, where they form metastasis. Tissue Inhibitors of Metalloproteinases or TIMPs control MMP activities and, therefore, minimize matrix degradation. Both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell progression including tumor angiogenesis. In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Tissue inhibitors of metalloproteinases (TIMPs) are natural MMPs endogenous inhibitors involved in MMP-mediated ECM turnover, tissue remodeling and cellular behavior (Bourboulia and Stetler-Stevenson, 2010;Brew and Nagase, 2010). In humans four different TIMPs have been found, namely TIMP-1, TIMP-2, TIMP-3 and TIMP-4, which share about 40% homology in sequencer (see Table 5).…”

“…MMP-2, consistently with the broad spectrum of targets, behaves as a multifunctional enzyme able to modulate the initial as well as the advanced phases of the pathology (Björklund and Koivunen, 2005). In the early phases MMP-2 is crucial in creating a favorable microenvironment for cancer cells growth and contributes to the epithelial-mesenchimal transition (EMT), as demonstrated for renal tubular epithelial cells and breast epithelial cells (Bourboulia and Stetler-Stevenson, 2010;Kim et al, 2011bKim et al, , 2007. The acquisition of a mesenchimal phenotype is a hallmark of cancer cells, which lose their tissue-specific morphology in favor of a un-differentiated phenotype suitable for migration and invasiveness (Min et al, 2008;Tang et al, 2011).…”

Human Leucine Zipper Protein sLZIP Induces Migration and Invasion of Cervical Cancer Cells via Expression of Matrix Metalloproteinase-9

“…The interactions of cells with the extracellular matrix (ECM) 3 are critical for the normal development and function of organisms (1,2). Modulation of cell-matrix interactions occurs through the action of unique proteolytic systems responsible for hydrolysis of a variety of ECM components (1,3).…”

“…Modulation of cell-matrix interactions occurs through the action of unique proteolytic systems responsible for hydrolysis of a variety of ECM components (1,3). Proteolytic degradation of ECM and basement membranes is a crucial event in tumor invasion, metastasis, and angiogenesis (4,5).…”

MMP-9 genetic polymorphism may confer susceptibility to COPD

“…MMP-9 may affect airflow limitation through degradation of alveolar ECM and components of the basement membrane, thus resulting in emphysema (Elkington et al, 2011). As the major rate-limiting enzyme in the MMP family, MMP-9 and its inhibitory factor TIMP-1 play essential roles in remodeling airflows, and MMP-9 may contribute to inflammation and flow choking by increasing inflammatory corpuscles in the airway lumen or airway wall, damaging the epithelial/endothelial structure (Bourboulia and Stetler-Stevenson, 2010;Yao et al, 2013). Genetic polymorphisms of MMP-9 may affect the expression and activity of MMP-9.…”