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      The regulation of MMP targeting to invadopodia during cancer metastasis

      review-article
      ,
      Frontiers in Cell and Developmental Biology
      Frontiers Media S.A.
      MMP9, MMP2, Rab40B, membrane traffic, invadopodia, cancer, metastasis

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          Abstract

          The dissemination of cancer cells from the primary tumor to a distant site, known as metastasis, is the main cause of mortality in cancer patients. Metastasis is a very complex cellular process that involves many steps, including the breaching of the basement membrane (BM) to allow the movement of cells through tissues. The BM breach occurs via highly regulated and localized remodeling of the extracellular matrix (ECM), which is mediated by formation of structures, known as invadopodia, and targeted secretion of matrix metalloproteinases (MMPs). Recently, invadopodia have emerged as key cellular structures that regulate the metastasis of many cancers. Furthermore, targeting of various cytoskeletal modulators and MMPs has been shown to play a major role in regulating invadopodia function. Here, we highlight recent findings regarding the regulation of protein targeting during invadopodia formation and function.

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          Most cited references96

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          How matrix metalloproteinases regulate cell behavior.

          The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.
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            Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.

            Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs. © 2010 The Authors Journal compilation © 2010 FEBS.
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              Basement membranes: structure, assembly and role in tumour angiogenesis.

              In recent years, the basement membrane (BM)--a specialized form of extracellular matrix (ECM)--has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                02 February 2015
                2015
                : 3
                : 4
                Affiliations
                Department of Cell and Developmental Biology, School of Medicine, Anschutz Medical Campus, University of Colorado Denver Aurora, CO, USA
                Author notes

                Edited by: Irina Kaverina, Vanderbilt University Medical Center, USA

                Reviewed by: Frederique Gaits-Iacovoni, Institut National de la Santé et de la Recherche Médicale U1048, France; Sébastien Roger, University of Tours, France

                *Correspondence: Rytis Prekeris, Department of Cell and Developmental Biology, School of Medicine, Anschutz Medical Campus, University of Colorado Denver, 12801 East 17th Avenue, Bldg. RC-1, Room L18-12402, Aurora, CO, USA e-mail: Rytis.Prekeris@ 123456ucdenver.edu

                This article was submitted to Membrane Traffic, a section of the journal Frontiers in Cell and Developmental Biology.

                Article
                10.3389/fcell.2015.00004
                4313772
                25699257
                9185a6e3-fcc7-4b0f-8922-459a28efb649
                Copyright © 2015 Jacob and Prekeris.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 November 2014
                : 09 January 2015
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 108, Pages: 9, Words: 7633
                Categories
                Cell and Developmental Biology
                Review Article

                mmp9,mmp2,rab40b,membrane traffic,invadopodia,cancer,metastasis
                mmp9, mmp2, rab40b, membrane traffic, invadopodia, cancer, metastasis

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