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Cellular and Molecular Biology

The importance of RHAMM in the normal brain and gliomas: physiological and pathological roles

Abstract

Although the literature about the functions of hyaluronan and the CD44 receptor in the brain and brain tumours is extensive, the role of the receptor for hyaluronan-mediated motility (RHAMM) in neural stem cells and gliomas remain poorly explored. RHAMM is considered a multifunctional receptor which performs various biological functions in several normal tissues and plays a significant role in cancer development and progression. RHAMM was first identified for its ability to bind to hyaluronate, the extracellular matrix component associated with cell motility control. Nevertheless, additional functions of this protein imply the interaction with different partners or cell structures to regulate other biological processes, such as mitotic-spindle assembly, gene expression regulation, cell-cycle control and proliferation. In this review, we summarise the role of RHAMM in normal brain development and the adult brain, focusing on the neural stem and progenitor cells, and discuss the current knowledge on RHAMM involvement in glioblastoma progression, the most aggressive glioma of the central nervous system. Understanding the implications of RHAMM in the brain could be useful to design new therapeutic approaches to improve the prognosis and quality of life of glioblastoma patients.

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Fig. 1: RHAMM in the central nervous system.
Fig. 2: Role of RHAMM in neural stem cells.
Fig. 3: The implication of RHAMM in GBM progression.
Fig. 4: Similarities between the roles of RHAMM in neural stem/progenitor cells and GBM cells.

Data availability

The datasets used and/or analysed during this study are available from the corresponding author upon reasonable request.

References

  1. He Z, Mei L, Connell M, Maxwell CA. Hyaluronan mediated motility receptor (HMMR) encodes an evolutionarily conserved homeostasis, mitosis, and meiosis regulator rather than a hyaluronan receptor. Cells 2020;9:819.

    Article  CAS  PubMed Central  Google Scholar 

  2. Messam BJ, Tolg C, McCarthy JB, Nelson AC, Turley EA. RHAMM is a multifunctional protein that regulates cancer progression. Int J Mol Sci. 2021;22:10313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cheung WF, Cruz TF, Turley EA. Receptor for hyaluronan-mediated motility (RHAMM), a hyaladherin that regulates cell responses to growth factors. Biochem Soc Trans. 1999;27:135–42.

    Article  CAS  PubMed  Google Scholar 

  4. Hardwick C, Hoare K, Owens R, Hohn HP, Hopok M, Moore D, et al. Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol. 1992;117:1343–50.

    Article  CAS  PubMed  Google Scholar 

  5. Hofmann M, Assmann V, Fieber C, Sleeman JP, Moll J, Ponta H, et al. Problems with RHAMM: a new link between surface adhesion and oncogenesis? Cell. 1998;95:591–2.

    Article  CAS  PubMed  Google Scholar 

  6. Assmann V, Jenkinson D, Marshall JF, Hart IR. The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments. J Cell Sci. 1999;3954:3943–54.

    Article  Google Scholar 

  7. Maxwell CA, Rasmussen E, Zhan F, Keats JJ, Adamia S, Strachan E, et al. RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma. Blood. 2004;104:1151–8.

    Article  CAS  PubMed  Google Scholar 

  8. Wang C, Thor AD, Moore DH, Zhao Y, Kerschmann R, Stern R, et al. The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. Clin Cancer Res. 1998;4:567–76.

    CAS  PubMed  Google Scholar 

  9. Zhang S, Chang MCY, Zylka D, Turley S, Harrison R, Turley EA. The hyaluronan receptor RHAMM regulates extracellular-regulated kinase. J Biol Chem. 1998;273:11342–8.

    Article  CAS  PubMed  Google Scholar 

  10. Yang B, Zhang L, Turley EA. Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. J Biol Chem. 1993;268:8617–23.

    Article  CAS  PubMed  Google Scholar 

  11. Yang B, Yang BL, Savani RC, Turley EA. Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. EMBO J. 1994;13:286–96.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zaman A, Cui Z, Foley JP, Zhao H, Grimm PC, DeLisser HM, et al. Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury. Am J Respir Cell Mol Biol. 2005;33:447–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pibuel M, Poodts D, Díaz M, Molinari Y, Franco P, Hajos S, et al. Antitumor effect of 4MU on glioblastoma cells is mediated by senescence induction and CD44, RHAMM and p-ERK modulation. Cell Death Discov. 2021;7:280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hamilton SR, Fard SF, Paiwand FF, Tolg C, Veiseh M, Wang C, et al. The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. J Biol Chem. 2007;282:16667–80.

    Article  CAS  PubMed  Google Scholar 

  15. Hatano H, Shigeishi H, Kudo Y, Higashikawa K, Tobiume K, Takata T, et al. RHAMM/ERK interaction induces proliferative activities of cementifying fibroma cells through a mechanism based on the CD44-EGFR. Lab Invest. 2011;91:379–91.

    Article  CAS  PubMed  Google Scholar 

  16. Manzanares D, Monzon M, Savani RC, Salathe M. Apical oxidative hyaluronan degradation stimulates airway ciliary beating via RHAMM and RON. Am J Respir Cell Mol Biol. 2007;37:160–8.

  17. Park D, Kim Y, Kim H, Lee Y, Choe J, Hahn J, et al. Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGF β receptor interaction via CD44-PKC δ. Mol Cells. 2012;33:563–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Savani RC, Cao G, Pooler PM, Zaman A, Zhou Z, Delisser HM. Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis. J Biol Chem. 2001;276:36770–8.

    Article  CAS  PubMed  Google Scholar 

  19. Buttermore ST, Hoffman MS, Kumar A, Champeaux A, Nicosia SV, Kruk PA. Increased RHAMM expression relates to ovarian cancer progression. J Ovarian Res. 2017;10:1–11.

  20. Maxwell CA, McCarthy J, Turley E. Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? J Cell Sci. 2008;121:925–32.

    Article  CAS  PubMed  Google Scholar 

  21. Twarock S, Tammi M, Savani RC, Fischer JW. Hyaluronan stabilizes focal adhesions, filopodia, and the proliferative phenotype in esophageal squamous carcinoma cells. J Biol Chem. 2010;285:23276–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Groen AC, Cameron LA, Coughlin M, Miyamoto DT, Mitchison TJ, Ohi R. XRHAMM functions in ran-dependent microtubule nucleation and pole formation during anastral spindle assembly. Curr Biol. 2004;14:1801–11.

    Article  CAS  PubMed  Google Scholar 

  23. Song L, Rape M. Regulated degradation of spindle assembly factors by the anaphase-promoting complex. Mol Cell. 2010;38:369–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fulcher LJ, He Z, Mei L, Macartney TJ, Wood NT, Prescott AR, et al. FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning. EMBO Rep. 2019;20:e47495.

  25. Dunsch AK, Hammond D, Lloyd J, Schermelleh L, Gruneberg U, Barr FA. Dynein light chain 1 and a spindle-associated adaptor promote dynein asymmetry and spindle orientation. J Cell Biol. 2012;198:1039–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li H, Kroll T, Moll J, Frappart L, Herrlich P, Heuer H, et al. Spindle misorientation of cerebral and cerebellar progenitors is a mechanistic cause of megalencephaly. Stem Cell Rep. 2017;9:1071–80.

    Article  CAS  Google Scholar 

  27. Connell M, Chen H, Jiang J, Kuan CW, Fotovati A, Chu TLH, et al. HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development. eLife 2017;6:1–27.

    Article  Google Scholar 

  28. Kouvidi K, Nikitovic D, Berdiaki A, Tzanakakis GN. Hyaluronan/RHAMM interactions in mesenchymal tumor pathogenesis: role of growth factors. Adv Cancer Res. 2014;123:319–49.

  29. Tolg C, Hamilton SR, Morningstar L, Zhang J, Zhang S, Esguerra KV, et al. RHAMM promotes interphase microtubule instability and mitotic spindle integrity through MEK1/ERK1/2 activity. J Biol Chem. 2010;285:26461–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Safieddine A, Coleno E, Salloum S, Imbert A, Traboulsi AM, Kwon OS, et al. A choreography of centrosomal mRNAs reveals a conserved localization mechanism involving active polysome transport. Nat Commun. 2021;12:1–21.

  31. Chouaib R, Safieddine A, Pichon X, Imbert A, Kwon OS, Samacoits A, et al. A dual protein-mRNA localization screen reveals compartmentalized translation and widespread co-translational RNA targeting. Dev Cell. 2020;54:773–91.e5.

    Article  CAS  PubMed  Google Scholar 

  32. Chen H, Connell M, Mei L, Reid GSD, Maxwell CA. The nonmotor adaptor HMMR dampens Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation. Mol Biol Cell. 2018;29:786–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Maxwell CA, Keats JJ, Crainie M, Sun X, Yen T, Shibuya E, et al. RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability. Mol Biol Cell. 2003;14:2262–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Eibes S, Gallisà-Suñé N, Rosas-Salvans M, Martínez-Delgado P, Vernos I, Roig J. Nek9 phosphorylation defines a new role for TPX2 in Eg5-dependent centrosome separation before nuclear envelope breakdown. Curr Biol. 2018;28:121–9.e4.

    Article  CAS  PubMed  Google Scholar 

  35. Joukov V, Groen AC, Prokhorova T, Gerson R, White E, Rodriguez A, et al. The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly. Cell. 2006;127:539–52.

    Article  CAS  PubMed  Google Scholar 

  36. Maxwell CA, Benítez J, Gómez-Baldó L, Osorio A, Bonifaci N, Fernández-Ramires R, et al. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biol. 2011;9:e1001199.

  37. Scrofani J, Sardon T, Meunier S, Vernos I. Microtubule nucleation in mitosis by a RanGTP-dependent protein complex. Curr Biol. 2015;25:131–40.

    Article  CAS  PubMed  Google Scholar 

  38. Pujana MA, Han JDJ, Starita LM, Stevens KN, Tewari M, Ahn JS, et al. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet. 2007;39:1338–49.

    Article  CAS  PubMed  Google Scholar 

  39. Li H, Frappart L, Moll J, Winkler A, Kroll T, Hamann J, et al. Impaired planar germ cell division in the testis, caused by dissociation of RHAMM from the spindle, results in hypofertility and seminoma. Cancer Res. 2016;76:6382–95.

    Article  CAS  PubMed  Google Scholar 

  40. Jiang J, Mohan P, Maxwell CA. The cytoskeletal protein RHAMM and ERK1/2 activity maintain the pluripotency of murine embryonic stem cells. PLoS ONE. 2013;8:e73548.

  41. National Library of Medicine. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=3161, 2022 Sept (6-Sep-2022).

  42. The Human Protein Atlas. https://www.proteinatlas.org/ENSG00000072571-HMMR/tissue, 2022 Sept, (2020).

  43. Mele V, Sokol L, Kölzer VH, Pfaff D, Muraro MG, Keller I, et al. The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer. Oncotarget. 2017;8:70617–29.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Morera DS, Hennig MS, Talukder A, Lokeshwar SD, Wang J, Garcia-Roig M, et al. Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets. Br J Cancer. 2017;117:1507–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dai BsZ, Wang K, Gao Y. The critical role of B4GALT4 in promoting microtubule spindle assembly in HCC through the regulation of PLK1 and RHAMM expression. J Cell Physiol. 2022;237:617–36.

    Article  CAS  PubMed  Google Scholar 

  46. Mascaró M, Pibuel MA, Lompardía SL, Díaz M, Zotta E, Bianconi MI, et al. Low molecular weight hyaluronan induces migration of human choriocarcinoma JEG-3 cells mediated by RHAMM as well as by PI3K and MAPK pathways. Histochem Cell Biol. 2017;148:173–87.

    Article  PubMed  Google Scholar 

  47. Willemen Y, Van den Bergh JMJ, Bonte SM, Anguille S, Heirman C, Stein BMH, et al. The tumor-associated antigen RHAMM (HMMR/CD168) is expressed by monocyte-derived dendritic cells and presented to T cells. Oncotarget. 2016;7:1–11.

    Article  Google Scholar 

  48. Schwertfeger K, Cowman M, Telmer P, Turley E, McCarthy J. Hyaluronan, inflammation, and breast cancer progression. Front Immunol. 2015;6:236.

  49. Wartenberg M, Cibin S, Zlobec I, Vassella E, Eppenberger-Castori S, Terracciano L, et al. Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance. Clin Cancer Res. 2018;24:4444–54.

    Article  CAS  PubMed  Google Scholar 

  50. Lompardía SL, Papademetrio DL, Mascaró M, Del Carmen Álvarez EM, Hajos SE. Human leukemic cell lines synthesize hyaluronan to avoid senescence and resist chemotherapy. Glycobiology. 2013;23:1463–76.

  51. Akiyama Y, Jung S, Salhia B, Lee S, Hubbard S, Taylor M, et al. Hyaluronate receptors mediating glioma cell migration and proliferation. J Neurooncol. 2001;53:115–27.

    Article  CAS  PubMed  Google Scholar 

  52. Misra S, Hascall VC, Markwald RR, Ghatak S, Ghatak S. Interactions between hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and cancer. Front Immunol. 2015;6:201.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Klarić M, Haller H, Brnčić Fischer A, Babarović E, Prijić A, Eminović S. The role of CD44 and RHAMM in endometrial (endometrioid type) cancer: an immunohistochemical study. Appl Immunohistochem Mol Morphol AIMM. 2019;27:606–12.

    Article  PubMed  Google Scholar 

  54. Pibuel MA, Poodts D, Díaz M, Hajos. SE, Lompardía SL. The scrambled story between hyaluronan and glioblastoma. J Biol Chem. 2021;296:100549.

  55. Carvalho A, Soares da Costa D, Paulo P, Reis R, Pashkuleva I. Co-localization and crosstalk between CD44 and RHAMM depend on hyaluronan presentation. Acta Biomater. 2021;119:114–24.

    Article  CAS  PubMed  Google Scholar 

  56. Sohr S, Engeland K. RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell Cycle. 2008;7:3448–60.

    Article  CAS  PubMed  Google Scholar 

  57. Turley EA. RHAMM and CD44 peptides-analytic tools and potential drugs. Front Biosci. 2012;17:1775–94.

    Article  CAS  Google Scholar 

  58. Esguerra K, Tolg C, Akentieva N, Price ML, Choi-Fong C, Lewis JD, et al. Identification, design and synthesis of tubulin-derived peptides as novel hyaluronan mimetic ligands for the receptor for hyaluronan-mediated motility (RHAMM/HMMR). Integr Biol. 2015;7:1547–60.

    Article  CAS  Google Scholar 

  59. Hauser-Kawaguchi A, Tolg C, Peart T, Milne M, Turley E, Luyt LG. A truncated RHAMM protein for discovering novel therapeutic peptides. Bioorg Med Chem. 2018;26:5194–203.

    Article  CAS  PubMed  Google Scholar 

  60. Greiner J, Ringhoffer M, Taniguchi M, Schmitt A, Kirchner D, Krähn G, et al. Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Exp Hematol. 2002;30:1029–35.

    Article  CAS  PubMed  Google Scholar 

  61. Anguille S, Van Tendeloo V, Berneman ZN. Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia. Leukemia. 2012;26:2186–96.

    Article  CAS  PubMed  Google Scholar 

  62. Amano T, Kajiwara K, Yoshikawa K, Morioka J, Nomura S, Fujisawa H, et al. Antitumor effects of vaccination with dendritic cells transfected with modified receptor for hyaluronan-mediated motility mRNA in a mouse glioma model. J Neurosurg. 2007;106:638–45.

    Article  CAS  PubMed  Google Scholar 

  63. Schmitt M, Schmitt A, Rojewski MT, Chen J, Giannopoulos K, Fei F, et al. RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. Blood. 2008;111:1357–65.

    Article  CAS  PubMed  Google Scholar 

  64. Tabarkiewicz J, Giannopoulos K. Definition of a target for immunotherapy and results of the first Peptide vaccination study in chronic lymphocytic leukemia. Transpl Proc. 2010;42:3293–6.

    Article  CAS  Google Scholar 

  65. Roex M, Hageman L, Veld S, van Egmond E, Hoogstraten C, Stemberger C, et al. A minority of T cells recognizing tumor-associated antigens presented in self-HLA can provoke antitumor reactivity. Blood. 2020;136:455–67.

    Article  PubMed  Google Scholar 

  66. Snauwaert S, Vanhee S, Goetgeluk G, Verstichel G, Van Caeneghem Y, Velghe I, et al. RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. Haematologica. 2012;97:1539–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Long KR, Newland B, Florio M, Kalebic N, Langen B, Kolterer A, et al. Extracellular matrix components HAPLN1, lumican, and collagen I cause hyaluronic acid-dependent folding of the developing human neocortex. Neuron. 2018;99:702–19.e7.

    Article  CAS  PubMed  Google Scholar 

  68. Lynn BD, Li X, Cattini PA, Turley EA, Nagy JI. Identification of sequence, protein isoforms, and distribution of the hyaluronan-binding protein RHAMM in adult and developing rat brain. J Comp Neurol. 2001;439:315–30.

    Article  CAS  PubMed  Google Scholar 

  69. Lynn BD, Turley EA, Nagy JI. Subcellular distribution, calmodulin interaction, and mitochondrial association of the hyaluronan-binding protein RHAMM in rat brain. J Neurosci Res. 2001;65:6–16.

    Article  CAS  PubMed  Google Scholar 

  70. Turley EA, Hossain MZ, Sorokan T, Jordan LM, Nagy JI. Astrocyte and microglial motility in vitro is functionally dependent on the hyaluronan receptor RHAMM. Glia. 1994;12:68–80.

    Article  CAS  PubMed  Google Scholar 

  71. Al’Qteishat A, Gaffney J, Krupinski J, Rubio F, West D, Kumar S, et al. Changes in hyaluronan production and metabolism following ischaemic stroke in man. Brain. 2006;129:2158–76.

    Article  PubMed  Google Scholar 

  72. Lindwall C, Olsson M, Osman A, Kuhn H, Curtis M. Selective expression of hyaluronan and receptor for hyaluronan mediated motility (Rhamm) in the adult mouse subventricular zone and rostral migratory stream and in ischemic cortex. Brain Res. 2013;1503:62–77.

    Article  CAS  PubMed  Google Scholar 

  73. Nagy JI, Hacking J, Frankenstein U, Turley EA. Requirement of the hyaluronan receptor RHAMM in neurite extension and motility as demonstrated in primary neurons and neuronal cell lines. J Neurosci. 1995;15:241–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Prager A, Hagenlocher C, Ott T, Schambony A, Feistel K. hmmr mediates anterior neural tube closure and morphogenesis in the frog Xenopus. Dev Biol. 2017;430:188–201.

    Article  CAS  PubMed  Google Scholar 

  75. Toba S, Hirotsune S. A unique role of dynein and nud family proteins in corticogenesis. Neuropathology. 2012;32:432–9.

    Article  PubMed  Google Scholar 

  76. Casini P, Nardi I, Ori M. RHAMM mRNA expression in proliferating and migrating cells of the developing central nervous system. Gene Expr Patterns. 2010;10:93–7.

    Article  CAS  PubMed  Google Scholar 

  77. Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson A, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci. 1996;16:7599–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. García-Verdugo J, Doetsch F, Wichterle H, Lim D, Alvarez-Buylla A. Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol. 1998;36:234–48.

    Article  PubMed  Google Scholar 

  79. Doetsch F, Caillé I, Lim D, García-Verdugo J, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97:703–16.

    Article  CAS  PubMed  Google Scholar 

  80. Gage F. Mammalian neural stem cells. Science. 2000;287:1433–8.

    Article  CAS  PubMed  Google Scholar 

  81. Maslov A, Barone T, Plunkett R, Pruitt S. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci. 2004;24:1726–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Theocharidis U, Long KR, Ffrench-Constant C, Faissner A. Regulation of the neural stem cell compartment by extracellular matrix constituents. Prog Brain Res. 2014;214:3–28.

    Article  PubMed  Google Scholar 

  83. Faissner A, Reinhard J. The extracellular matrix compartment of neural stem and glial progenitor cells. Glia. 2015;63:1330–49.

    Article  PubMed  Google Scholar 

  84. Su W, Matsumoto S, Sorg B, Sherman LS. Distinct roles for hyaluronan in neural stem cell niches and perineuronal nets. Matrix Biol. 2019;78–79:272–83.

    Article  PubMed  Google Scholar 

  85. Peters A, Sherman LS. Diverse roles for hyaluronan and hyaluronan receptors in the developing and adult nervous system. Int J Mol Sci. 2020;21:1–21.

    Article  Google Scholar 

  86. Nagy JI, Price ML, Staines WA, Lynn BD, Granholm AC. The hyaluronan receptor RHAMM in noradrenergic fibers contributes to axon growth capacity of locus coeruleus neurons in an intraocular transplant model. Neuroscience. 1998;86:241–55.

    Article  CAS  PubMed  Google Scholar 

  87. Moshayedi P, Carmichael S. Hyaluronan, neural stem cells and tissue reconstruction after acute ischemic stroke. Biomatter. 2013;3:e23863.

  88. Vik-Mo E, Sandberg CJ, Joel M, Stangeland B, Watanabe Y, Mackay-Sim A, et al. A comparative study of the structural organization of spheres derived from the adult human subventricular zone and glioblastoma biopsies. Exp Cell Res. 2011;317:1049–59.

    Article  CAS  PubMed  Google Scholar 

  89. Gimple R, Bhargava S, Dixit D, Rich J. Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancer. Genes Dev. 2019;33:591–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lombard A, Digregorio M, Delcamp C, Rogister B, Piette C, Coppieters N. The subventricular zone, a hideout for adult and pediatric high-grade glioma stem cells. Front Oncol. 2021;10:3197.

    Article  Google Scholar 

  91. Kusne Y, Sanai N. The SVZ and its relationship to stem cell based neuro-oncogenesis. Adv Exp Med Biol. 2015;853:23–32.

    Article  CAS  PubMed  Google Scholar 

  92. Germano I, Swiss V, Casaccia P. Primary brain tumors, neural stem cell, and brain tumor cancer cells: where is the link? Neuropharmacology. 2010;58:903–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chesler D, Berger M, Quinones-Hinojosa A. The potential origin of glioblastoma initiating cells. Front Biosci. 2012;4:190–205.

    Article  Google Scholar 

  94. Bakhshinyan D, Savage N, Salim SK, Venugopal C, Singh SK. The strange case of Jekyll and Hyde: parallels between neural stem cells and glioblastoma-initiating cells. Front Oncol. 2021;10:2983.

    Article  Google Scholar 

  95. Tilghman J, Wu H, Sang Y, Shi X, Guerrero-Cazares H, Quinones-Hinojosa A, et al. HMMR maintains the stemness and tumorigenicity of glioblastoma stem-like cells. Cancer Res. 2014;74:3168–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhou R, Wu X, Skalli O. The hyaluronan receptor RHAMM/IHABP in astrocytoma cells: expression of a tumor-specific variant and association with microtubules. J Neurooncol. 2002;59:15–26.

    Article  PubMed  Google Scholar 

  97. Jung S, Ackerley C, Ivanchuk S, Mondal S, Becker LE, Rutka JT. Tracking the invasiveness of human astrocytoma cells by using green fluorescent protein in an organotypical brain slice model. J Neurosurg. 2001;94:80–9.

    Article  CAS  PubMed  Google Scholar 

  98. Wang D, Narula N, Azzopardi S, Smith RS, Nasar A, Altorki NK, et al. Expression of the receptor for hyaluronic acid mediated motility (RHAMM) is associated with poor prognosis and metastasis in non-small cell lung carcinoma. Oncotarget. 2016;7:39957–69.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Lim EJ, Suh Y, Yoo KC, Lee JH, Kim IG, Kim MJ, et al. Tumor-associated mesenchymal stem-like cells provide extracellular signaling cue for invasiveness of glioblastoma cells. Oncotarget. 2017;8:1438–48.

    Article  PubMed  Google Scholar 

  100. Pibuel MA, Díaz M, Molinari Y, Poodts D, Silvestroff L, Lompardía SL, et al. 4-Methylumbelliferone as a potent and selective antitumor drug on a glioblastoma model. Glycobiology. 2021;31:29–43.

    CAS  PubMed  Google Scholar 

  101. Martínez-Ramos C, Lebourg M. Three-dimensional constructs using hyaluronan cell carrier as a tool for the study of cancer stem cells. J Biomed Mater Res. 2015;103:1249–57.

    Article  Google Scholar 

  102. Yoo KC, Suh Y, An Y, Lee HJ, Jeong YJ, Uddin N, et al. Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation. Oncogene. 2018;37:3317–28.

    Article  CAS  PubMed  Google Scholar 

  103. Fukui M, Ueno K, Suehiro Y, Hamanaka Y, Imai K, Hinoda Y. Anti-tumor activity of dendritic cells transfected with mRNA for receptor for hyaluronan-mediated motility is mediated by CD4+ T cells. Cancer Immunol Immunother. 2006;55:538–46.

    Article  CAS  PubMed  Google Scholar 

  104. Li J, Ji X, Wang H. Targeting long noncoding RNA HMMR-AS1 suppresses and radiosensitizes glioblastoma. Neoplasia. 2018;20:456–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cai Y, Sheng Z, Chen Y, Wang J. LncRNA HMMR-AS1 promotes proliferation and metastasis of lung adenocarcinoma by regulating MiR-138/sirt6 axis. Aging. 2019;11:3041–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Chu ZP, Dai J, Jia LG, Li J, Zhang Y, Zhang ZY, et al. Increased expression of long noncoding RNA HMMR-AS1 in epithelial ovarian cancer: An independent prognostic factor. Eur Rev Med Pharm Sci. 2018;22:8145–50.

    Google Scholar 

  107. Liu W, Ma J, Cheng Y, Zhang H, Luo W, Zhang H. HMMR antisense RNA 1, a novel long noncoding RNA, regulates the progression of basal-like breast cancer cells. Breast Cancer Targets Ther. 2016;8:223–9.

    Article  CAS  Google Scholar 

  108. Li J, Zhou Y, Wang H, Gao Y, Li L, Hee S. COX-2 / sEH dual inhibitor PTUPB suppresses glioblastoma growth by targeting epidermal growth factor receptor and hyaluronan mediated motility receptor. Oncotarget. 2017;8:87353–63.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Bryukhovetskiy I, Shevchenko V. Molecular mechanisms of the effect of TGF-β1 on U87 human glioblastoma cells. Oncol Lett. 2016;12:1581–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kim CS, Jung S, Jung TY, Jang WY, Sun HS, Ryu HH. Characterization of invading glioma cells using molecular analysis of Leading-Edge tissue. J Korean Neurosurg Soc. 2011;50:157–65.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Virga J, Bognár L, Hortobágyi T, Zahuczky G, Cs É. Tumor grade versus expression of invasion-related molecules in astrocytoma. Pathol Oncol Res. 2017;24:35–43.

  112. Virga J, Szivos L, Hortobágyi T, Chalsaraei MK, Zahuczky G, Steiner L, et al. Extracellular matrix differences in glioblastoma patients with different prognoses. Oncol Lett. 2019;17:797–806.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to CONICET, FONCYT and UBA for providing the funding that supported this review.

Funding

This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET-PIP N°053 [Élida Álvarez and Silvia Hajos] and PIP N°0298 [Paula Franco], Universidad de Buenos Aires-UBACYT 20020170100454BA [Silvia Hajos and Silvina Lompardia] and UBACYT 200201190100048BA [Paula Franco], Agencia Nacional de Promoción Científica y Tecnológica PICT-2017-2971 [Lompardía Silvina].

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MAP searched the bibliography, created the figures, analysed the data and wrote the manuscript. DP and YAM performed the edition of figures and analysed the bibliography. MD, AB and SA contributed to the design of the study and edition of the manuscript. SH and SL collaborated in the edition of the manuscript and contributed to the design of the study. PF supervised the work. All authors contributed to the work and have read and approved the final manuscript.

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Correspondence to Matías A. Pibuel.

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Pibuel, M.A., Poodts, D., Molinari, Y. et al. The importance of RHAMM in the normal brain and gliomas: physiological and pathological roles. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-01999-w

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