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Current Opinion in Nephrology and... May 2002Angiogenesis is a prominent feature of numerous diseases, including cancer and arthritis, and appears to play an important role in kidney disease and hypertension. The... (Review)
Review
Angiogenesis is a prominent feature of numerous diseases, including cancer and arthritis, and appears to play an important role in kidney disease and hypertension. The matrix metalloproteinases, especially matrix metalloproteinase-2, play a vital role during angiogenesis by degrading the surrounding extracellular matrix and allowing endothelial cell invasion. Membrane type 1 matrix metalloproteinase directly degrades matrix components as well as activating matrix metalloproteinase-2 on the cell surface. The integrin receptors, particularly alpha(v)beta(3), can recruit and possibly activate matrix metalloproteinases to localized microdomains on the cell membrane. This restricts matrix metalloproteinase activity to the pericellular region, preventing excessive matrix degradation which would otherwise impede endothelial invasion. Inhibitors of matrix metalloproteinase activity may actually promote cell invasion by preventing uncontrolled matrix degradation. In addition to degrading the matrix, matrix metalloproteinases produce protein fragments that impede their angiogenic action. These multiple regulatory pathways permit fine control over cell invasion during angiogenesis and provide new, precise strategies for targeting abnormal angiogenesis, through control of matrix metalloproteinase activity.
Topics: Humans; Matrix Metalloproteinases; Neovascularization, Physiologic
PubMed: 11981259
DOI: 10.1097/00041552-200205000-00005 -
Oncogene Dec 2000Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in... (Review)
Review
Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in tumor invasion and metastasis. Based on this evidence, the pharmaceutical industry produced several well tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated. Bayer and Agouron have discontinued their ongoing Phase III drug trials of MMPIs in advanced cancer. In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established. Our understanding of MMP pathophysiology in cancer has expanded considerably in the past 10 years. Current views indicate that: (1) most MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cancer cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; and (3) MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix. MMPs have a dual function in tumor angiogenesis: MMP-2 and MT1-MMP are required in breaking down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In spite of considerable recent progress in identifying multiple roles of MMPs in disease, our understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials focus on: (1) patients with early stage cancer; (2) the use of MMPIs along with chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI therapy; and (4) identification of biomarkers that reflect activation or inhibition of MMPs in vivo.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Models, Biological; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Stromal Cells
PubMed: 11426650
DOI: 10.1038/sj.onc.1204097 -
Oral Oncology Sep 2022Locoregional and lymphovascular involvement of invasive head and neck squamous cell carcinoma (HNSCC) complicates curative treatment. Matrix metalloproteinase (MMP) 9 is...
OBJECTIVES
Locoregional and lymphovascular involvement of invasive head and neck squamous cell carcinoma (HNSCC) complicates curative treatment. Matrix metalloproteinase (MMP) 9 is a negative prognostic marker in HNSCC and targets multiple extracellular matrix (ECM) substrates, where it contributes to breaching basement membrane and stromal barriers enabling invasive spread. Andecaliximab (ADX) is a second-generation MMP9 inhibitor well tolerated in clinical trials of gastric and pancreatic adenocarcinoma. The impact of selective MMP9 targeting by ADX in HNSCC has not been evaluated.
MATERIALS AND METHODS
Established and patient-derived xenograft (PDX) cell lines were utilized in HNSCC invasion assays to determine the inhibitory ability of MMP9-mediated invasion by ADX. MMP9 expression was confirmed using immunohistochemistry (IHC) and immunoblotting. ECM degradation was evaluated with confocal microscopy. Cell invasion from tumor spheroids was monitored by phase microscopy. Histological evaluation was used to determine ADX efficacy in three-dimensional organotypic cultures containing cancer associated fibroblasts (CAFs).
RESULTS
MMP9 was expressed in all established and PDX-derived cell lines. While the broad spectrum clinical MMP inhibitor marimastat (BB2516) blocked HNSCC invadopodia function and tumor spheroid invasion, ADX treatment failed to inhibit invadopodia-based matrix degradation, tumor cell or fibroblast-driven ECM invasion in collagen I-based matrices.
CONCLUSION
ADX monotherapy was ineffective at blocking initial MMP-dependent events of HNSCC invasion, likely due to redundant functions of additional non-targeted MMPs produced by tumor cells and microenvironment. Combination of ADX with existing and emerging therapies targeting additional MMP activation pathways may warrant future investigation.
Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Pancreatic Neoplasms; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment
PubMed: 35803110
DOI: 10.1016/j.oraloncology.2022.106008 -
Recent Patents on Anti-cancer Drug... Jun 2007Matrix metalloproteinases (MMPs) are involved in numerous pathophysiological processes, including cancer and cardiovascular disease. MMPs proteolyze multiple targets,... (Review)
Review
Matrix metalloproteinases (MMPs) are involved in numerous pathophysiological processes, including cancer and cardiovascular disease. MMPs proteolyze multiple targets, including extracellular matrix, cytokines, and growth factors. Due to a high clinical relevance, MMPs have long been a target for pharmaceutical intervention. Although numerous drug therapies to inhibit MMPs have been explored, only one agent (doxycycline hyclate) is currently approved for clinical use. Multiple reasons potentially explain the lack of success in developing MMP inhibitors, including issues with selectivity and specificity and the presence of multiple substrates with conflicting functions. Major recent advances in the MMP field include an increased understanding of MMP biology, the improved establishment of parameters to adequately evaluate efficacy, and methods to enhance inhibitor design. This review will explore the latest research and patents targeted at MMP inhibition, and will focus on both direct and indirect mechanisms to block MMPs.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Structure; Neoplasms; Patents as Topic
PubMed: 18221058
DOI: 10.2174/157489207780832423 -
Journal of Cancer Research and... 2016The family of human matrix metalloproteinases (MMPs) comprises several tightly regulated classes of proteases. These enzymes and their specific inhibitors play important... (Review)
Review
The family of human matrix metalloproteinases (MMPs) comprises several tightly regulated classes of proteases. These enzymes and their specific inhibitors play important roles in tumor progression and the metastatic process by facilitating extracellular matrix (ECM) degradation. As scientific understanding of the MMPs has advanced, therapeutic strategies focusing on blocking these enzymes by MMP inhibitors (MMPIs) have rapidly developed. This paper reviews MMPs in detail. Their perspectives in therapeutic intervention in cancer are also mentioned.
Topics: Carcinogenesis; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms
PubMed: 27072206
DOI: 10.4103/0973-1482.157337 -
Frontiers in Bioscience : a Journal and... Jan 2007Matrix metalloproteinases can degrade and modify almost all components of the extracellular matrix hence their enzymatic activity is tightly regulated under... (Review)
Review
Matrix metalloproteinases can degrade and modify almost all components of the extracellular matrix hence their enzymatic activity is tightly regulated under physiological conditions. Primary modes of enzyme regulation include transcriptional control, zymogen activation and dynamic inhibition by tissue inhibitors of matrix metalloproteinases. Recent studies have demonstrated that mechanical regulation of matrix metalloproteinases largely operate through these regulatory pathways. Over the last decade a large cohort of studies have been conducted on many tissue/cell types using diverse loading parameters in vivo and in vitro suggesting that mechanical load is essential in maintaining normal tissue function via the matrix metalloproteinases. However there may be a mechanically-regulated homeostasis, with cells responding to and interpreting growth factors and other biochemical signals within the context of mechanical forces to provide a suitable cellular matrix metalloproteinase response. On the contrary, mechanical overload can result in unrestrained matrix metalloproteinase activities eventually leading to matrix degradation, mechanical dysfunction and failure of the tissue. In this chapter, the effect of mechanical load on matrix metalloproteinase expression will be reviewed, and the signal transduction pathways involved in modulating the metabolic homeostasis of various tissues including blood vessels, intervertebral disc and components of the synovial joint with emphasis on articular cartilage discussed. Both mechanically-induced stimulation and inhibition of matrix metalloproteinases will be discussed and placed into context with their potential relevance to disease.
Topics: Animals; Cartilage, Articular; Gene Expression Regulation; Humans; Matrix Metalloproteinases; Mechanotransduction, Cellular; Osteoarthritis; Tissue Inhibitor of Metalloproteinases
PubMed: 17127313
DOI: 10.2741/2078 -
Biochemistry May 2015Although collagenolytic matrix metalloproteinases (MMPs) possess common domain organizations, there are subtle differences in their processing of collagenous...
Although collagenolytic matrix metalloproteinases (MMPs) possess common domain organizations, there are subtle differences in their processing of collagenous triple-helical substrates. In this study, we have incorporated peptoid residues into collagen model triple-helical peptides and examined MMP activities toward these peptomeric chimeras. Several different peptoid residues were incorporated into triple-helical substrates at subsites P3, P1, P1', and P10' individually or in combination, and the effects of the peptoid residues were evaluated on the activities of full-length MMP-1, MMP-8, MMP-13, and MMP-14/MT1-MMP. Most peptomers showed little discrimination between MMPs. However, a peptomer containing N-methyl Gly (sarcosine) in the P1' subsite and N-isobutyl Gly (NLeu) in the P10' subsite was hydrolyzed efficiently only by MMP-13 [nomenclature relative to the α1(I)772-786 sequence]. Cleavage site analysis showed hydrolysis at the Gly-Gln bond, indicating a shifted binding of the triple helix compared to the parent sequence. Favorable hydrolysis by MMP-13 was not due to sequence specificity or instability of the substrate triple helix but rather was based on the specific interactions of the P7' peptoid residue with the MMP-13 hemopexin-like domain. A fluorescence resonance energy transfer triple-helical peptomer was constructed and found to be readily processed by MMP-13, not cleaved by MMP-1 and MMP-8, and weakly hydrolyzed by MT1-MMP. The influence of the triple-helical structure containing peptoid residues on the interaction between MMP subsites and individual substrate residues may provide additional information about the mechanism of collagenolysis, the understanding of collagen specificity, and the design of selective MMP probes.
Topics: Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Matrix Metalloproteinase 14; Matrix Metalloproteinase 8; Matrix Metalloproteinases; Peptides; Substrate Specificity
PubMed: 25897652
DOI: 10.1021/acs.biochem.5b00110 -
Arthritis Research 2002The role of matrix metalloproteinases in the degradative events invoked in the cartilage and bone of arthritic joints has long been appreciated and attempts at the... (Review)
Review
The role of matrix metalloproteinases in the degradative events invoked in the cartilage and bone of arthritic joints has long been appreciated and attempts at the development of proteinase inhibitors as potential therapeutic agents have been made. However, the spectrum of these enzymes orchestrating connective tissue turnover and general biology is much larger than anticipated. Biochemical studies of the individual members of the matrix metalloproteinase family are now underway, ultimately leading to a more detailed understanding of the function of their domain structures and to defining their specific role in cellular systems and the way that they are regulated. Coupled with a more comprehensive and detailed study of proteinase expression in different cells of joint tissues during the progress of arthritic diseases, it will be possible for the future development and application of highly specific proteinase inhibitors to be directed at specific key cellular events.
Topics: Arthritis, Rheumatoid; Humans; Matrix Metalloproteinases; Protein Structure, Tertiary
PubMed: 12110122
DOI: 10.1186/ar572 -
Methods in Molecular Biology (Clifton,... 2001
Review
Topics: Amino Acid Motifs; Animals; Binding Sites; Catalytic Domain; Collagen; Collagenases; Fibronectins; Genetic Techniques; Hemopexin; Humans; Kinetics; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Models, Molecular; Protein Structure, Tertiary
PubMed: 11217327
DOI: No ID Found -
Matrix Biology : Journal of the... Dec 2000The matrix metalloproteinases (MMPs) can degrade a range of extracellular matrix proteins and have been implicated in connective tissue destruction and remodelling... (Review)
Review
The matrix metalloproteinases (MMPs) can degrade a range of extracellular matrix proteins and have been implicated in connective tissue destruction and remodelling associated with cancer invasion and metastasis, cartilage destruction in arthritis, atherosclerotic plaque rupture, and the development of aneurysms. Recently, naturally occurring sequence variation has been detected in the promoter of a number of MMP genes. These genetic polymorphisms have been shown to have allele-specific effects on the transcriptional activities of MMP gene promoters, and to be associated with susceptibility to coronary heart disease, aneurysms and cancers. These findings indicate that variation in the MMP genes may contribute to inter-individual differences in susceptibility to these common, complex diseases, likely through effects on the balance between the synthesis and degradation of extracellular matrix proteins.
Topics: Disease Susceptibility; Gene Expression Regulation, Enzymologic; Humans; Matrix Metalloproteinase 1; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Metalloendopeptidases; Polymorphism, Genetic; Promoter Regions, Genetic
PubMed: 11102751
DOI: 10.1016/s0945-053x(00)00102-5