Matrix metalloproteinases and their expression in mammary gland

The matrix metalloproteinases (MMPs) are a family of zine-dependent endopeptidases that play a key role in both normal and pathological processes involving tissue remodeling events.The expression of these proteolytic enzymes is highly regulated by a balance between extracellular matrix (ECM) deposition and its degradation,and is controlled by growth factors,cytokines,hormones,as well as interactions with the ECM macromolecules.Furthermore,the activity of the MMPs is regulated by their natural endogenous inhibitors,which are members of the tissue inhibitor of metalloproteinases (TIMP) family.In the normal mammary gland,MMPs are expressed during ductal development,lobulo-alveolar development in pregnancy and involution after lactation.Under pathological conditions,such as tumorigenesis,the dysregulated expression of MMPs play a role in tumor initiation,progression and malignant conversion as well as facilitating invasion and metastasis of malignant cells through degradation of the ECM and basement membranes.     

Matrix metalloproteinases in squamous cell carcinoma

Controlled degradation of extracellular matrix (ECM) is essential in many physiological situations including developmental tissue remodeling, angiogenesis, tissue repair, and normal turnover of ECM. In addition, degradation of matrix components is an important feature of tumor growth, invasion, metastasis, and tumor-induced angiogenesis. Matrix metallo-proteinases (MMPs) are a family of zinc-dependent neutral endopeptidases, which are collectively capable of degrading essentially all ECM components. MMPs apparently play an important role in all the above mentioned aspects of tumor development. In addition, there is recent evidence that MMP activity is required for tumor cell survival. At present, several MMP inhibitors are in clinical trials of malignant tumors of different histogenetic origin. In this review we discuss the current view on the role of MMPs and their inhibitors in development and invasion of squamous cell carcinomas, as a basis for prognostication and therapeutic intervention in these tumors.     

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

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.     

Type IV collagenases (MMP-2 and MMP-9) and their substrates--intracellular proteins, hormones, cytokines, chemokines and their receptors

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that cleave protein components of extracellular matrix such as collagens, laminin, fibronectin, proteoglycans and contribute to cell migration by eliminating the surrounding extracellular matrix and basement membrane barriers. However, the extracellular matrix is not simply an extracellular scaffold because, for example, it contains sites that can bind growth factors; therefore, degradation of the extracellular matrix components by MMPs can alter cellular behavior. MMPs also cleave a variety of non-ECM proteins, including cytokines, chemokines, and growth factors, activating or inactivating them, or generating other products that have biological consequences. The immune system is also influenced by MMPs. For that reason, the function of MMPs is much more complex and subtle than simple demolition. MMPs are essential for embryonic development and morphogenesis, however, exuberant expression of these enzymes has been associated with a variety of destructive diseases, including tumor progression, cardiovascular diseases and autoimmune diseases.     

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that cleave nearly all components of the extracellular matrix as well as many other soluble and cell‐associated proteins. MMPs have been implicated in normal physiological processes, including development, and in the acquisition and progression of the malignant phenotype. Disappointing results from a series of clinical trials testing small molecule, broad spectrum MMP inhibitors as cancer therapeutics led to a re‐evaluation of how MMPs function in the tumor microenvironment, and ongoing research continues to reveal that these proteins play complex roles in cancer development and progression. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the MMP family and its biological regulators, the tissue inhibitors of metalloproteinases (TIMPs). We then summarize recent research from model systems that elucidate how specific MMPs drive the malignant phenotype of breast cancer cells, including acquisition of cancer stem cell features and induction of the epithelial–mesenchymal transition, and we also outline clinical studies that implicate specific MMPs in breast cancer outcomes. We conclude by discussing ongoing strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold. J. Cell. Biochem. 118: 3531–3548, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.     

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis.

The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.     

Structural basis of matrix metalloproteinases and tissue inhibitors of metalloproteinases

The matrix metalloproteinases (MMPs) constitute a family of secreted/cell-surface-anchored multidomain zinc endopeptidases, all of which exhibit a catalytic domain of a common metzincin-like topology, and which are involved in degradation of the extracellular matrix but also in a number of other biologic processes. Normally, the proteolytic activity of the MMPs is precisely regulated by their main endogenous protein inhibitors, in particular the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in serious diseases such as arthritis, tumor growth, and tumor metastasis, rendering the MMPs attractive targets for inhibition therapy. Knowledge of their tertiary structures is crucial for a full understanding of their functional properties and their associations with dysfunctions. Since the reports of the first atomic structures of MMPs and TIMPs in 1994, considerable structural information has become available about both of these families of substances. Many of the MMP structures have been determined as complexes with synthetic inhibitors, facilitating knowledge-based drug design. This review focuses on the currently available 3D structural information about MMPs and TIMPs.     

Physiological roles of matrix metalloproteinases: implications for tumor growth and metastasis.

Physiological processes involving remodelling of the extracellular matrix, such as wound healing, embryogenesis, angiogenesis, and the female reproductive cycle, require the activity of matrix metalloproteinases (MMPs). This group of proteases degrades basal membranes and connective tissues and plays an essential role in the homeostasis of the extracellular matrix. An imbalance in the expression or activity of MMPs can have important consequences in diseases such as multiple sclerosis, Alzheimer's disease, or the development of cancers. Because of the pathophysiological importance of MMPs, their activity is highly controlled in order to confine them to specific areas. An activation cascade, initiated by the proteolysis of plasminogen, cleaves proMMPs, and every step is controlled by specific activators or inhibitors. MMPs destabilize the organization of the extracellular matrix and influence the development of cancer by contributing to cell migration, tumor cell proliferation, and angiogenesis. Accordingly, these proteases possess an important role in cell-matrix interactions by affecting fundamental processes such as cell differentiation and proliferation. Therefore, the characterization of MMPs involved in specific types and stages of tumors will significantly improve the diagnosis and treatment of these cancers in humans.     

Matrix metalloproteinases in stem cell regulation and cancer

Since Gross and Lapiere firstly discovered matrix metalloproteinases (MMPs) as important collagenolytic enzymes during amphibian tadpole morphogenesis in 1962, this intriguing family of extracellular proteinases has been implicated in various processes of developmental biology. However, the pathogenic roles of MMPs in human diseases such as cancer have also garnered widespread attention. The most straightforward explanation for their role in cancer is that MMPs, through extracellular matrix degradation, pave the way for tumor cell invasion and metastasis. While this notion may be true for many circumstances, we now know that, depending on the context, MMPs may employ additional modes of functionality. Here, we will give an update on the function of MMPs in development and cancer, which may directly regulate signaling pathways that control tissue homeostasis and may even work in a non-proteolytic manner. These novel findings about the functionality of MMPs have important implications for MMP inhibitor design and may allow us to revisit MMPs as drug targets in the context of cancer and other diseases.     

基质金属蛋白酶在乳腺癌上皮间质转化中的作用

基质金属蛋白酶(matrix metalloproteinase,MMP)能够分解并修饰细胞外基质及细胞连接,促进上皮细胞从周围组织中分离出来。在乳腺癌中MMP表达量升高,刺激肿瘤发生,引起癌症细胞的入侵和转移。上皮细胞-间质细胞转化(epithelial-mesenchymal transition,EMT)的激活与肿瘤的发生也有关。最近的研究表明MMP在乳腺的发育和致病的EMT过程中充当促进因子和介质的角色。本文主要概括最新的关于MMP是如何调节乳腺癌细胞的运动、入侵和EMT所驱动的乳腺癌发育的研究,为更好地理解MMP在乳腺癌发病过程中的作用提供依据。     

Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors

The balance between matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), is largely responsible for the remodeling of tissues. Deregulation of this balance is a characteristic of extensive tissue degradation in certain degenerative diseases. To analyze the role of MMPs and TIMPs in tissue remodeling under normal and pathological conditions, it is important to have reliable detection methods. This review will focus on zymographical techniques for the analysis of MMPs and TIMPs. MMPs can be analyzed with several zymographical techniques, but substrate zymography is the most commonly used. This technique identifies MMPs by the degradation of their preferential substrate and by their molecular weight. Several substrates that can be used for zymography are described. Reverse zymography, which detects TIMPs by their ability to inhibit MMPs, is also discussed. Finally, in situ zymography is described, which is used to localize MMPs in tissue sections. Common problems encountered during sample preparation, zymography itself and the data analysis are discussed. Hints are given to improve the sensitivity and accuracy of zymographical methods. In conclusion, zymography is a valuable tool for research purposes and for the development of new diagnostic techniques and therapies for pathological conditions such as rheumatoid and osteoarthritis, and tumor progression.     

Matrix metalloproteinases in tumor-host cell communication

The microenvironment or stroma immediately surrounding tumor cells consists of a three-dimensional extracellular matrix (ECM) and stromal cells such as fibroblasts and inflammatory cells. The matrix metalloproteinases (MMPs) constitute a family of over 24 members, which collectively are capable of degrading virtually the entire ECM. Strict regulation of MMP expression is critical in order to maintain proper ECM homeostasis, but in disease states such as cancer there is often a high level of MMP activity at the tumor-stroma interface. Several studies have documented the importance of MMP-mediated ECM destruction in the successful dissemination of several tumor types, but it has become increasingly clear that they are also involved in earlier stages of tumorigenesis. MMPs are implicated in a wide variety of roles that can assist tumor initiation, growth, migration, angiogenesis, the selection of apoptosis-resistant subpopulations, and in invasion and metastasis. Interestingly, the factors responsible for many of these effects are derived from the cell surfaces of the tumor or stromal cells or are embedded in the ECM. Therefore, the MMPs can no longer be thought of solely as ECM destructionists, but as part of an elegant communication system through which the tumor interacts with the stroma.     

Signal transduction and cell‐type specific regulation of matrix metalloproteinase gene expression: Can MMPs be good for you?

An abundance of literature over the past several years indicates a growing interest in the role of matrix metalloproteinases (MMPs) in normal physiology and in disease pathology. MMPs were originally defined by their ability to degrade the extracellular matrix, but it is now well documented that their substrates extend far beyond matrix components. Recent reviews discuss the structure and function of the MMP family members, as well as the promoter sequences that control gene expression. Thus, we focus on the signal transduction pathways that confer differential cell-type expression of MMPs, as well as on some novel non-matrix degrading functions of MMPs, particularly their intracellular location where they may contribute to apoptosis. In addition, increasing data implicate MMPs as "good guys", protective agents in some cancers and in helping to resolve acute pathologic conditions. Despite the intricate and complicated roles of MMPs in physiology and pathology, the goal of designing therapeutics that can selectively target MMPs remains a major focus. Developing MMP inhibitors with targeted specificity will be difficult; success will depend on understanding the role of these enzymes in homeostasis and on the careful delineation of mechanisms by which this family of enzymes mediates disease pathology.     

Role of matrix metalloproteinases in melanoma cell invasion

Cutaneous melanomas are notorious for their tendency to metastasize. Essential steps in this process are the degradation of basement membranes and remodeling of the extracellular matrix (ECM) by proteolytic enzymes such as matrix metalloproteinases (MMPs), which are regulated by their tissue inhibitors (TIMPs). An MMP expression is not restricted to tumor cells but is also found in stromal cells, indicating that stroma-derived proteases may contribute to melanoma progression. The MMPs have been shown to interact with a broad range of non-matrix proteins including adhesion molecules, growth factors and mediators of angiogenesis and apoptosis. In this review, we evaluate new insights into the interplay of MMPs and their molecular partners in melanoma progression.     

Matrix metalloproteinases: multifunctional contributors to tumor progression

Matrix metalloproteinases (MMPs) are a family of extracellular matrix degrading proteinases. Owing to their matrix-degrading abilities and high expression in advanced tumors, MMPs were originally implicated in invasion and metastasis during cancer progression. However, recent work extends a role for MMPs during multiple stages of tumor progression to include other functions such as growth, angiogenesis and migration. Based on studies in animal models implicating MMP activity in cancer, synthetic MMP inhibitors are currently being tested in a clinical setting.     

Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression

Tissue inhibitor of metalloproteinases (TIMPs; TIMP-1, -2, -3 and -4) are endogenous inhibitor for matrix metalloproteinases (MMPs) that are responsible for remodeling the extracellular matrix (ECM) and involved in migration, invasion and metastasis of tumor cells. Unlike under normal conditions, the imbalance between MMPs and TIMPs is associated with various diseased states. Among TIMPs, TIMP-1, a 184-residue protein, is the only N-linked glycoprotein with glycosylation sites at N30 and N78. The structural analysis of the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1 suggests new possibilities of the role of TIMP-1 glycan moieties as a tuner for the proteolytic activities by MMPs. Because the TIMP-1 glycosylation participate in the interaction, aberrant glycosylation of TIMP-1 presumably affects the interaction, thereby leading to pathogenic dysfunction in cancer cells. TIMP-1 has not only the cell proliferation activities but also anti-oncogenic properties. Cancer cells appear to utilize these bilateral aspects of TIMP-1 for cancer progression; an elevated TIMP-1 level exerts to cancer development via MMP-independent pathway during the early phase of tumor formation, whereas it is the aberrant glycosylation of TIMP-1 that overcome the high anti-proteolytic burden. The aberrant glycosylation of TIMP-1 can thus be used as staging and/or prognostic biomarker in colon cancer. [BMB Reports 2012; 45(11): 623-628]     

Remodeling the model organism: matrix metalloproteinase functions in invertebrates

The matrix metalloproteinase (MMP) family of extracellular proteases is conserved throughout the animal kingdom. Studies of invertebrate MMPs have demonstrated they are involved in tissue remodeling. In Drosophila, MMPs are required for histolysis, tracheal growth, tissue invasion, axon guidance, and dendritic remodeling. Recent work demonstrates that MMPs also participate in Drosophila tumor invasion. In Caenorhabditis elegans an MMP is involved in anchor cell invasion; a Hydra MMP is important for regeneration and maintaining cell identity; and a sea urchin MMP degrades matrix to allow hatching. In worms and in flies, MMPs are regulated by the JNK pathway.     

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

The process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases(MMPs). Degradation of extracellular matrix(ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metallopro-teinase(TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK(reversion including cysteinerich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2,-9 and-14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species(ROS) through mitochondrial dysfunction leading to altered protease/anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows.