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      Selected Matrix Metalloproteinases (MMP-2, MMP-7) and Their Inhibitor (TIMP-2) in Adult and Pediatric Cancer

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          Abstract

          The tumor microenvironment (TME) consists of numerous biologically relevant elements. One of the most important components of the TME is the extracellular matrix (ECM). The compounds of the ECM create a network that provides structural and biochemical support to surrounding cells. The most important substances involved in the regulation of the ECM degradation process are matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs). The disruption of the physiological balance between MMP activation and deactivation could lead to progression of various diseases such as cardiovascular disease, cancer, fibrosis arthritis, chronic tissue ulcers, pathologies of the nervous system (such as stroke and Alzheimer’s disease), periodontitis, and atheroma. MMP-TIMP imbalance results in matrix proteolysis associated with various pathological processes such as tumor invasion. The present review discusses the involvement of two MMPs, MMP-2 and MMP-7, in cancer pathogenesis. These two MMPs have been proven in several studies, conducted mostly on adults, to make an important contribution to cancer development and progression. In the current review, several studies that indicate the importance of MMP-TIMP balance determination for the pediatric population are also highlighted. The authors of this review believe that carrying out biochemical and clinical studies focused on metalloproteinases and their inhibitors in tumors in children will be of great relevance for future patient diagnosis, determination of a prognosis, and monitoring of therapy.

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          Most cited references96

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          Physiology and pathophysiology of matrix metalloproteases

          Matrix metalloproteases (MMPs) comprise a family of enzymes that cleave protein substrates based on a conserved mechanism involving activation of an active site-bound water molecule by a Zn2+ ion. Although the catalytic domain of MMPs is structurally highly similar, there are many differences with respect to substrate specificity, cellular and tissue localization, membrane binding and regulation that make this a very versatile family of enzymes with a multitude of physiological functions, many of which are still not fully understood. Essentially, all members of the MMP family have been linked to disease development, notably to cancer metastasis, chronic inflammation and the ensuing tissue damage as well as to neurological disorders. This has stimulated a flurry of studies into MMP inhibitors as therapeutic agents, as well as into measuring MMP levels as diagnostic or prognostic markers. As with most protein families, deciphering the function(s) of MMPs is difficult, as they can modify many proteins. Which of these reactions are physiologically or pathophysiologically relevant is often not clear, although studies on knockout animals, human genetic and epigenetic, as well as biochemical studies using natural or synthetic inhibitors have provided insight to a great extent. In this review, we will give an overview of 23 members of the human MMP family and describe functions, linkages to disease and structural and mechanistic features. MMPs can be grouped into soluble (including matrilysins) and membrane-anchored species. We adhere to the ‘MMP nomenclature’ and provide the reader with reference to the many, often diverse, names for this enzyme family in the introduction.
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            Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer.

            The matrix metalloproteinase (MMP) family of enzymes is comprised of critically important extracellular matrix remodeling proteases whose activity has been implicated in a number of key normal and pathologic processes. The latter include tumor growth, progression, and metastasis as well as the dysregulated angiogenesis that is associated with these events. As a result, these proteases have come to represent important therapeutic and diagnostic targets for the treatment and detection of human cancers. In this review, we summarize the literature that establishes these enzymes as important clinical targets, discuss the complexity surrounding their choice as such, and chronicle the development strategies and outcomes of their clinical testing to date. The status of the MMP inhibitors currently in US Food and Drug Administration approved clinical trials is presented and reviewed. We also discuss the more recent and successful targeting of this enzyme family as diagnostic and prognostic predictors of human cancer, its status, and its stage. This analysis includes a wide variety of human cancers and a number of human sample types including tissue, plasma, serum, and urine.
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              TIMPs: versatile extracellular regulators in cancer

              A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell
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                Author and article information

                Journal
                Diagnostics (Basel)
                Diagnostics (Basel)
                diagnostics
                Diagnostics
                MDPI
                2075-4418
                31 July 2020
                August 2020
                : 10
                : 8
                : 547
                Affiliations
                [1 ]Department of Pediatrics, Hematology and Oncology, Faculty of Medicine, Medical University of Gdańsk, 7 Dębinki Street, 80-952 Gdańsk, Poland; miekus@ 123456gumed.edu.pl (A.K.); edrozynska@ 123456gumed.edu.pl (E.A.-D.)
                [2 ]University Clinical Centre, 7 Debinki Street, 80-952 Gdansk, Poland
                [3 ]Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland; natalia.miekus-purwin@ 123456gumed.edu.pl
                [4 ]Faculty of Health Sciences, Medical University of Gdańsk, Maria Sklodowska-Curie Street 3a, 80-210 Gdańsk, Poland
                Author notes
                [* ]Correspondence: jstefanowicz@ 123456gumed.edu.pl ; Tel.: +48-58-349-28-08
                Author information
                https://orcid.org/0000-0002-9605-3259
                https://orcid.org/0000-0001-8014-4263
                Article
                diagnostics-10-00547
                10.3390/diagnostics10080547
                7460349
                32751899
                3e62d152-aa4e-4aa1-a278-3b0226b7943b
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 05 July 2020
                : 29 July 2020
                Categories
                Review

                tumor microenvironment,metalloproteinases,tissue inhibitors of metalloproteinases,pediatric cancer

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