title: Hyaluronan/Hyaladherins - a Promising Axis for Targeted Drug Delivery in Cancer.
abstract: BACKGROUND
  Hyaluronan (HA), a glycosaminoglycan, is a key extracellular matrix (ECM) component, and has been established to contribute to fibrotic, angiogenic, inflammatory as well as processes supporting cancer development. The changes in HA deposition in different tumors have been widely studied. Indeed, a multitude of reports demonstrate that HA expression is increased in different neoplasmatic tissues including lung, colon, prostate and breast cancer. The aims of this paper are to critically and in depth discuss aspects of HA metabolism in cancer and recent developments of its utilization in cancer therapy.
  
  
  METHODS
  Up to date research and online content are reviewed.
  
  
  RESULTS
  The cellular roles of HA are perpetrated through molecular interactions with HA-binding proteins, called hyaladherins, including CD44 receptor as well as receptor for hyaluronan-mediated motility (RHAMM). HA binding can be followed by receptor-mediated endocytosis. Importantly, hyaladherins show an altered expression in tumor tissues. Indeed, post-translational alterations in CD44 structure have been suggested to regulate the equilibrium between the "inactive" low affinity state and the "active" high affinity state of the HA binding capacity. In this concept HA fragments can be utilized as specific targeting ligands for efficient and safe drug delivery in cancer.
  
  
  CONCLUSIONS
  HA-drug bioconjugates and nanoparticles have emerged as a promising platform for drug delivery during cancer treatment as demonstrated in various pre-clinical studies. Recent developments from clinical trials indicate that the utilization of specific HA-drug bioconjugates might be approved for the medical practice in the nearest future.
authors.affiliation: Department of Anatomy- Histology-Embryology, Faculty of Medicine, University of Crete, P.O. Box: 71003, Heraklion, Greece. dnikitovic@med.uoc.gr.
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikitovic
authors.forename: Katerina
authors.initials: K
authors.lastname: Kouvidi
authors.forename: Rafaela-Maria
authors.initials: RM
authors.lastname: Kavasi
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Berdiaki
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004337:Drug Carriers; D016326:Extracellular Matrix Proteins / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000187:drug effects; D006820:Hyaluronic Acid / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D004337:Drug Carriers; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid