title: Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer.
abstract: Synthesis, deposition, and interactions of hyaluronan (HA) with its cellular receptor CD44 are crucial events that regulate the onset and progression of tumors. The intracellular signaling pathways initiated by HA interactions with CD44 leading to tumorigenic responses are complex. Moreover, HA molecules may perform dual functions depending on their concentration and size. Overexpression of variant isoforms of CD44 (CD44v) is most commonly linked to cancer progression, whereas their loss is associated with inhibition of tumor growth. In this review, we highlight that the regulation of HA synthases (HASes) by post-translational modifications, such as O-GlcNAcylation and ubiquitination, environmental factors and the action of microRNAs is important for HA synthesis and secretion in the tumor microenvironment. Moreover, we focus on the roles and interactions of CD44 with various proteins that reside extra- and intracellularly, as well as on cellular membranes with particular reference to the CD44-HA axis in cancer stem cell functions, and the importance of CD44/CD44v6 targeting to inhibit tumorigenesis.
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100, Italy.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Karousou
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Suniti
authors.initials: S
authors.lastname: Misra
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Shibnath
authors.initials: S
authors.lastname: Ghatak
authors.affiliation: Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital F-46, SE-141 86 Stockholm, Sweden.
authors.forename: Katalin
authors.initials: K
authors.lastname: Dobra
authors.affiliation: Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Götte
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Vigetti
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Passi
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.affiliation: Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500 Patras, Greece. Electronic address: skandalis@upatras.gr.
authors.forename: Spyros S
authors.initials: SS
authors.lastname: Skandalis
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D000076002:Hyaluronan Synthases / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D059016:Tumor Microenvironment; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D035683:MicroRNAs; D006820:Hyaluronic Acid; D000076002:Hyaluronan Synthases
keywords: CD44; Cancer; Cancer stem cells; Hyaluronan; Hyaluronan synthase; Tissue-specific-targeting