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      Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer

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          Abstract

          The glycosaminoglycan hyaluronan (HA), a major component of extracellular matrices, and cell surface receptors of HA have been proposed to have pivotal roles in cell proliferation, migration, and invasion, which are necessary for inflammation and cancer progression. CD44 and receptor for HA-mediated motility (RHAMM) are the two main HA-receptors whose biological functions in human and murine inflammations and tumor cells have been investigated comprehensively. HA was initially considered to be only an inert component of connective tissues, but is now known as a “dynamic” molecule with a constant turnover in many tissues through rapid metabolism that involves HA molecules of various sizes: high molecular weight HA (HMW HA), low molecular weight HA, and oligosaccharides. The intracellular signaling pathways initiated by HA interactions with CD44 and RHAMM that lead to inflammatory and tumorigenic responses are complex. Interestingly, these molecules have dual functions in inflammations and tumorigenesis. For example, the presence of CD44 is involved in initiation of arthritis, while the absence of CD44 by genetic deletion in an arthritis mouse model increases rather than decreases disease severity. Similar dual functions of CD44 exist in initiation and progression of cancer. RHAMM overexpression is most commonly linked to cancer progression, whereas loss of RHAMM is associated with malignant peripheral nerve sheath tumor growth. HA may similarly perform dual functions. An abundance of HMW HA can promote malignant cell proliferation and development of cancer, whereas antagonists to HA-CD44 signaling inhibit tumor cell growth in vitro and in vivo by interfering with HMW HA-CD44 interaction. This review describes the roles of HA interactions with CD44 and RHAMM in inflammatory responses and tumor development/progression, and how therapeutic strategies that block these key inflammatory/tumorigenic processes may be developed in rodent and human diseases.

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          Graphene: Status and Prospects

          A. K. Geim (2010)
          Graphene is a wonder material with many superlatives to its name. It is the thinnest material in the universe and the strongest ever measured. Its charge carriers exhibit giant intrinsic mobility, have the smallest effective mass (it is zero) and can travel micrometer-long distances without scattering at room temperature. Graphene can sustain current densities 6 orders higher than copper, shows record thermal conductivity and stiffness, is impermeable to gases and reconciles such conflicting qualities as brittleness and ductility. Electron transport in graphene is described by a Dirac-like equation, which allows the investigation of relativistic quantum phenomena in a bench-top experiment. What are other surprises that graphene keeps in store for us? This review analyses recent trends in graphene research and applications, and attempts to identify future directions in which the field is likely to develop.
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            CD44: from adhesion molecules to signalling regulators.

            Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes--not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.
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              CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.

              Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1α (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/β-catenin pathway, which promotes migration and metastasis. CD44v6(-) progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                06 May 2015
                2015
                : 6
                Affiliations
                [1] 1Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina , Charleston, SC, USA
                [2] 2Department of Biomedical Engineering, Cleveland Clinic, Cleveland , Ohio, OH, USA
                Author notes

                Edited by: David Naor, Hebrew University of Jerusalem, Israel

                Reviewed by: Toru Hiraga, Matsumoto Dental University, Japan; Carmela Ricciardelli, University of Adelaide, Australia

                *Correspondence: Suniti Misra and Shibnath Ghatak, Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA, misra@ 123456musc.edu ; ghatak@ 123456musc.edu

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2015.00201
                4422082
                25999946
                7adda860-823d-412e-80fb-69005d85c0c7
                Copyright © 2015 Misra, Hascall, Markwald and Ghatak.

                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.

                Page count
                Figures: 8, Tables: 4, Equations: 0, References: 401, Pages: 31, Words: 26481
                Funding
                Funded by: 1R03CA167722-01A1
                Funded by: P20RR021949
                Funded by: P20RR016434
                Funded by: P20RR16461-05
                Funded by: RO1-HL033756-24
                Funded by: A1 PO1HL107147
                Funded by: EPS 0903795
                Categories
                Immunology
                Review

                Immunology
                hyaluronan,cd44,rhamm,inflammation,cancer
                Immunology
                hyaluronan, cd44, rhamm, inflammation, cancer

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