Skip to main content
SpringerLink
Log in

Chondroitin Sulphate Proteoglycans in the Tumour Microenvironment

  • Chapter
  • First Online:
Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1272))

Abstract

Proteoglycans are macromolecules that are essential for the development of cells, human diseases and malignancies. In particular, chondroitin sulphate proteoglycans (CSPGs) accumulate in tumour stroma and play a key role in tumour growth and invasion by driving multiple oncogenic pathways in tumour cells and promoting crucial interactions in the tumour microenvironment (TME). These pathways involve receptor tyrosine kinase (RTK) signalling via the mitogen-activated protein kinase (MAPK) cascade and integrin signalling via the activation of focal adhesion kinase (FAK), which sustains the activation of extracellular signal-regulated kinases 1/2 (ERK1/2).

Human CSPG4 is a type I transmembrane protein that is associated with the growth and progression of human brain tumours. It regulates cell signalling and migration by interacting with components of the extracellular matrix, extracellular ligands, growth factor receptors, intracellular enzymes and structural proteins. Its overexpression by tumour cells, perivascular cells and precursor/progenitor cells in gliomas suggests that it plays a role in their origin, progression and neo-angiogenesis and its aberrant expression in tumour cells may be a promising biomarker to monitor malignant progression and patient survival.

The aim of this chapter is to review and discuss the role of CSPG4 in the TME of human gliomas, including its potential as a druggable therapeutic target.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Iozzo RV, Sanderson RD (2011) Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med 15(5):1013–1031. https://doi.org/10.1111/j.1582-4934.2010.01236.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK (2010) Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J 277(19):3904–3923. https://doi.org/10.1111/j.1742-4658.2010.07800.x

    Article  CAS  PubMed  Google Scholar 

  3. Wade A, Robinson AE, Engler JR, Petritsch C, James CD, Phillips JJ (2013) Proteoglycans and their roles in brain cancer. FEBS J 280(10):2399–2417. https://doi.org/10.1111/febs.12109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stallcup WB (2002) The NG2 proteoglycan: past insights and future prospects. J Neurocytol 31(6–7):423–435

    CAS  PubMed  Google Scholar 

  5. Campoli M, Ferrone S, Wang X (2010) Functional and clinical relevance of chondroitin sulfate proteoglycan 4. Adv Cancer Res 109:73–121. https://doi.org/10.1016/B978-0-12-380890-5.00003-X

    Article  CAS  PubMed  Google Scholar 

  6. Couchman JR (2010) Transmembrane signaling proteoglycans. Annu Rev Cell Dev Biol 26:89–114. https://doi.org/10.1146/annurev-cellbio-100109-104126

    Article  CAS  PubMed  Google Scholar 

  7. Stallcup WB, Huang FJ (2008) A role for the NG2 proteoglycan in glioma progression. Cell Adhes Migr 2(3):192–201

    Google Scholar 

  8. Trotter J, Karram K, Nishiyama A (2010) NG2 cells: properties, progeny and origin. Brain Res Rev 63(1–2):72–82. https://doi.org/10.1016/j.brainresrev.2009.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang S, Svendsen A, Kmiecik J, Immervoll H, Skaftnesmo KO, Planagumà J, Reed RK, Bjerkvig R, Miletic H, Enger PØ, Rygh CB, Chekenya M (2011) Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma. PLoS One 6:e23062. https://doi.org/10.1371/journal.pone.0023062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nicolosi PA, Dallatomasina A, Perris R (2015) Theranostic impact of NG2/CSPG4 proteoglycan in cancer. Theranostics 5(5):530–544. https://doi.org/10.7150/thno.10824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Poli A, Wang J, Domingues O, Planagumà J, Yan T, Rygh CB, Skaftnesmo KO, Thorsen F, McCormack E, Hentges F, Pedersen PH, Zimmer J, Enger PØ, Chekenya M (2013) Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival. Oncotarget 4(9):1527–1546

    PubMed  PubMed Central  Google Scholar 

  12. Kmiecik J, Gras Navarro A, Poli A, Planagumà JP, Zimmer J, Chekenya M (2014) Combining NK cells and mAb9.2.27 to combat NG2–dependent and anti-inflammatory signals in glioblastoma. Oncoimmunology 3(1):e27185

    PubMed  PubMed Central  Google Scholar 

  13. Rygh CB, Wang J, Thuen M, Gras Navarro A, Huuse EM, Thorsen F, Poli A, Zimmer J, Haraldseth O, Lie SA, Enger PØ, Chekenya M (2014) Dynamic contrast enhanced MRI detects early response to adoptive NK cellular immunotherapy targeting the NG2 proteoglycan in a rat model of glioblastoma. PLoS One 9(9):e108414. https://doi.org/10.1371/journal.pone.0108414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Higgins SC, Fillmore HL, Ashkan K, Butt AM, Pilkington GJ (2015) Dual targeting NG2 and GD3A using Mab-zap immunotoxin results in reduced glioma cell viability in vitro. Anticancer Res 35(1):77–84

    CAS  PubMed  Google Scholar 

  15. Wang Y, Geldres C, Ferrone S, Dotti G (2015) Chondroitin sulfate proteoglycan 4 as a target for chimeric antigen receptor-based T-cell immunotherapy of solid tumors. Expert Opin Ther Targets 19:1339–1350

    CAS  PubMed  Google Scholar 

  16. Pellegatta S, Savoldo B, Di Ianni N, Corbetta C, Chen Y, Patané M, Sun C, Pollo B, Ferrone S, DiMeco F, Finocchiaro G, Dotti G (2018) Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy. Sci Transl Med 10(430):eaao2731

    PubMed  PubMed Central  Google Scholar 

  17. Schlingemann RO, Rietveld FJ, de Waal RM, Ferrone S, Ruiter DJ (1990) Expression of the high molecular weight melanoma-associated antigen by pericytes during angiogenesis in tumors and in healing wounds. Am J Pathol 136(6):1393–1405

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Karamanos NK, Syrokou A, Vanky P, Nurminen M, Hjerpe A (1994) Determination of 24 variously sulfated galactosaminoglycan- and hyaluronan-derived disaccharides by high-performance liquid chromatography. Anal Biochem 221(1):189–199

    CAS  PubMed  Google Scholar 

  19. Lamari FN, Karamanos NK (2006) Structure of chondroitin sulfate. Adv Pharmacol 53:33–48

    CAS  PubMed  Google Scholar 

  20. Maeda N, Ishii M, Nishimura K, Kamimura K (2011) Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem Res 36(7):1228–1240. https://doi.org/10.1007/s11064-010-0324-y

    Article  CAS  PubMed  Google Scholar 

  21. Kwok JC, Warren P, Fawcett JW (2012) Chondroitin sulfate: a key molecule in the brain matrix. Int J Biochem Cell Biol 44(4):582–586. https://doi.org/10.1016/j.biocel.2012.01.004

    Article  CAS  PubMed  Google Scholar 

  22. Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D (1996) Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12(3):241–247

    CAS  PubMed  Google Scholar 

  23. Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M, Cao A, Schlessinger D, Forabosco A (1998) Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome. Dev Dyn 213(4):431–439

    CAS  PubMed  Google Scholar 

  24. Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Döring A, Sloka S, Stirling DP, Rivest S, Yong VW (2012) Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol 72(3):419–432. https://doi.org/10.1002/ana.23599

    Article  CAS  PubMed  Google Scholar 

  25. Kucharova K, Stallcup WB (2010) The NG2 proteoglycan promotes oligodendrocyte progenitor proliferation and developmental myelination. Neuroscience 166(1):185–194. https://doi.org/10.1016/j.neuroscience.2009.12.014

    Article  CAS  PubMed  Google Scholar 

  26. Chang Y, She ZG, Sakimura K, Roberts A, Kucharova K, Rowitch DH, Stallcup WB (2012) Ablation of NG2 proteoglycan leads to deficits in brown fat function and to adult onset obesity. PLoS One 7(1):e30637. https://doi.org/10.1371/journal.pone.0030637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Riccardo F, Tarone L, Iussich S, Giacobino D, Arigoni M, Sammartano F, Morello E, Martano M, Gattino F, Maria R, Ferrone S, Buracco P, Cavallo F (2019) Identification of CSPG4 as a promising target for translational combinatorial approaches in osteosarcoma. Ther Adv Med Oncol 11:1758835919855491. https://doi.org/10.1177/1758835919855491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang J, Price MA, Li GY, Bar-Eli M, Salgia R, Jagedeeswaran R, Carlson JH, Ferrone S, Turley EA, McCarthy JB (2009) Melanoma proteoglycan modifies gene expression to stimulate tumor cell motility, growth, and epithelial-to-mesenchymal transition. Cancer Res 69(19):7538–7547. https://doi.org/10.1158/0008-5472.CAN-08-4626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, Pavão MS, Tzanakakis GN, Karamanos NK (2012) Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J 279(7):1177–1197. https://doi.org/10.1111/j.1742-4658.2012.08529.x

    Article  CAS  PubMed  Google Scholar 

  30. Theocharis AD, Tsolakis I, Tzanakakis GN, Karamanos NK (2006) Chondroitin sulfate as a key molecule in the development of atherosclerosis and cancer progression. Adv Pharmacol 53:281–295

    CAS  PubMed  Google Scholar 

  31. Nikitovic D, Berdiaki A, Spyridaki I, Krasanakis T, Tsatsakis A, Tzanakakis GN (2018) Proteoglycans-biomarkers and targets in cancer therapy. Front Endocrinol (Lausanne) 9:69. https://doi.org/10.3389/fendo.2018.00069

    Article  Google Scholar 

  32. Ida M, Shuo T, Hirano K, Tokita Y, Nakanishi K, Matsui F, Aono S, Fujita H, Fujiwara Y, Kaji T, Oohira A (2006) Identification and functions of chondroitin sulfate in the milieu of neural stem cells. J Biol Chem 281(9):5982–5991

    CAS  PubMed  Google Scholar 

  33. Sirko S, von Holst A, Weber A, Wizenmann A, Theocharidis U, Götz M, Faissner A (2010) Chondroitin sulfates are required for fibroblast growth factor-2-dependent proliferation and maintenance in neural stem cells and for epidermal growth factor-dependent migration of their progeny. Stem Cells 28(4):775–787. https://doi.org/10.1002/stem.309

    Article  CAS  PubMed  Google Scholar 

  34. Yadavilli S, Scafidi J, Becher OJ, Saratsis AM, Hiner RL, Kambhampati M, Mariarita S, MacDonald TJ, Codispoti KE, Magge SN, Jaiswal JK, Packer RJ, Nazarian J (2015) The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma. Oncotarget 6(14):12141–12155

    PubMed  PubMed Central  Google Scholar 

  35. Stallcup WB (1981) The NG2 antigen, a putative lineage marker: immunofluorescent localization in primary cultures of rat brain. Dev Biol 83(1):154–165

    CAS  PubMed  Google Scholar 

  36. Wilson BS, Imai K, Natali PG, Ferrone S (1981) Distribution and molecular characterization of a cell-surface and a cytoplasmic antigen detectable in human melanoma cells with monoclonal antibodies. Int J Cancer 28(3):293–300

    CAS  PubMed  Google Scholar 

  37. Wilson BS, Ruberto G, Ferrone S (1983) Immunochemical characterization of a human high molecular weight--melanoma associated antigen identified with monoclonal antibodies. Cancer Immunol Immunother 14(3):196–201

    CAS  PubMed  Google Scholar 

  38. Nishiyama A, Dahlin KJ, Prince JT, Johnstone SR, Stallcup WB (1991) The primary structure of NG2, a novel membrane-spanning proteoglycan. J Cell Biol 114(2):359–371

    CAS  PubMed  Google Scholar 

  39. Stallcup WB, Dahlin-Huppe K (2001) Chondroitin sulfate and cytoplasmic domain-dependent membrane targeting of the NG2 proteoglycan promotes retraction fiber formation and cell polarization. J Cell Sci 114(Pt 12):2315–2325

    CAS  PubMed  Google Scholar 

  40. Sakry D, Neitz A, Singh J, Frischknecht R, Marongiu D, Binamé F, Perera SS, Endres K, Lutz B, Radyushkin K, Trotter J, Mittmann T (2014) Oligodendrocyte precursor cells modulate the neuronal network by activity-dependent ectodomain cleavage of glial NG2. PLoS Biol 12(11):e1001993. https://doi.org/10.1371/journal.pbio.1001993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Buffo A, Vosko MR, Ertürk D, Hamann GF, Jucker M, Rowitch D, Götz M (2005) Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci U S A 102(50):18183–18188

    CAS  PubMed  PubMed Central  Google Scholar 

  42. You WK, Yotsumoto F, Sakimura K, Adams RH, Stallcup WB (2014) NG2 proteoglycan promotes tumor vascularization via integrin–dependent effects on pericyte function. Angiogenesis 17(1):61–76. https://doi.org/10.1007/s10456-013-9378-1

    Article  CAS  PubMed  Google Scholar 

  43. Sakry D, Trotter J (2016) The role of the NG2 proteoglycan in OPC and CNS network function. Brain Res 1638(Pt B):161–166. https://doi.org/10.1016/j.brainres.2015.06.003

    Article  CAS  PubMed  Google Scholar 

  44. Tillet E, Gential B, Garrone R, Stallcup WB (2002) NG2 proteoglycan mediates beta1 integrin-independent cell adhesion and spreading on collagen VI. J Cell Biochem 86(4):726–736

    CAS  PubMed  Google Scholar 

  45. Fukushi J, Makagiansar IT, Stallcup WB (2004) NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Mol Biol Cell 15(8):3580–3590

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Makagiansar IT, Williams S, Mustelin T, Stallcup WB (2007) Differential phosphorylation of NG2 proteoglycan by ERK and PKCalpha helps balance cell proliferation and migration. J Cell Biol 178(1):155–165

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nakano M, Tamura Y, Yamato M, Kume S, Eguchi A, Takata K, Watanabe Y, Kataoka Y (2017) NG2 glial cells regulate neuroimmunological responses to maintain neuronal function and survival. Sci Rep 7:42041. https://doi.org/10.1038/srep42041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stallcup WB (2017) NG2 proteoglycan enhances brain tumor progression by promoting beta–1 integrin activation in both Cis and Trans orientations. Cancers (Basel) 9(4):E31. https://doi.org/10.3390/cancers9040031

    Article  CAS  Google Scholar 

  49. Yang J, Price MA, Wanshura LEC, He J, Yi M, Welch DR, Li G, Conner S, Sachs J, Turley EA, McCarthy JB (2019) Chondroitin sulfate proteoglycan 4 enhanced melanoma motility and growth requires a cysteine in the core protein transmembrane domain. Melanoma Res 29(4):365–375. https://doi.org/10.1097/CMR.0000000000000574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lin XH, Dahlin-Huppe K, Stallcup WB (1996) Interaction of the NG2 proteoglycan with the actin cytoskeleton. J Cell Biochem 63(4):463–477

    CAS  PubMed  Google Scholar 

  51. Wang X, Wang Y, Yu L, Sakakura K, Visus C, Schwab JH, Ferrone CR, Favoino E, Koya Y, Campoli MR, McCarthy JB, DeLeo AB, Ferrone S (2010) CSPG4 in cancer: multiple roles. Curr Mol Med 10(4):419–429

    CAS  PubMed  Google Scholar 

  52. Stallcup WB, You WK, Kucharova K, Cejudo-Martin P, Yotsumoto F (2016) Proteoglycan-dependent contributions of pericytes and macrophages to brain tumor vascularization and progression. Microcirculation 23(2):122–133. https://doi.org/10.1111/micc.12251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ampofo E, Schmitt BM, Menger MD, Laschke MW (2017) The regulatory mechanisms of NG2/CSPG4 expression. Cell Mol Biol Lett 22:4. https://doi.org/10.1186/s11658-017-0035-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Levine JM, Stallcup WB (1987) Plasticity of developing cerebellar cells in vitro studied with antibodies against the NG2 antigen. J Neurosci 7(9):2721–2731

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Stallcup WB, Beasley L (1987) Bipotential glial precursor cells of the optic nerve express the NG2 proteoglycan. J Neurosci 7(9):2737–2744

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Raff MC, Miller RH, Noble M (1983) A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303(5916):390–396

    CAS  PubMed  Google Scholar 

  57. Nishiyama A, Watanabe M, Yang Z, Bu J (2002) Identity, distribution, and development of polydendrocytes: NG2-expressing glial cells. J Neurocytol 31(6–7):437–455

    CAS  PubMed  Google Scholar 

  58. Peters A (2004) A fourth type of neuroglial cell in the adult central nervous system. J Neurocytol 33(3):345–357

    PubMed  Google Scholar 

  59. Zhu X, Hill RA, Nishiyama A (2008) Cells generate both oligodendrocytes and grey matter astrocytes. Neuron Glia Biol 4(1):19–26. https://doi.org/10.1017/S1740925X09000015

    Article  PubMed  Google Scholar 

  60. Nishiyama A, Lin XH, Giese N, Heldin CH, Stallcup WB (1996) Interaction between NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells is required for optimal response to PDGF. J Neurosci Res 43(3):315–330

    CAS  PubMed  Google Scholar 

  61. Baracskay KL, Kidd GJ, Miller RH, Trapp BD (2007) NG2-positive cells generate A2B5-positive oligodendrocyte precursor cells. Glia 55(10):1001–1010

    PubMed  Google Scholar 

  62. Scherer SS, Braun PE, Grinspan J, Collarini E, Wang DY, Kamholz J (1994) Differential regulation of the 2',3'-cyclic nucleotide 3'-phosphodiesterase gene during oligodendrocyte development. Neuron 12(6):1363–1375

    CAS  PubMed  Google Scholar 

  63. Goretzki L, Burg MA, Grako KA, Stallcup WB (1999) High-affinity binding of basic fibroblast growth factor and platelet-derived growth factor-AA to the core protein of the NG2 proteoglycan. J Biol Chem 274(24):16831–16837

    CAS  PubMed  Google Scholar 

  64. Sugiarto S, Persson AI, Munoz EG, Waldhuber M, Lamagna C, Andor N, Hanecker P, Ayers-Ringler J, Phillips J, Siu J, Lim DA, Vandenberg S, Stallcup W, Berger MS, Bergers G, Weiss WA, Petritsch C (2011) Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 20(3):328–340. https://doi.org/10.1016/j.ccr.2011.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wilson HC, Scolding NJ, Raine CS (2006) Co-expression of PDGF alpha receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions. J Neuroimmunol 176(1–2):162–173

    CAS  PubMed  Google Scholar 

  66. Schiffer D (1997) Brain tumors. Biology, pathology and clinical references, 2nd edn. Springer, Berlin/Heidelberg/New York, pp 1–695

    Google Scholar 

  67. Osterhout DJ, Wolven A, Wolf RM, Resh MD, Chao MV (1999) Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. J Cell Biol 145(6):1209–1218

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Dimou L, Simon C, Kirchhoff F, Takebayashi H, Götz M (2008) Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex. J Neurosci 28(41):10434–10442. https://doi.org/10.1523/JNEUROSCI.2831-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pfeiffer SE, Warrington AE, Bansal R (1993) The oligodendrocyte and its many cellular processes. Trends Cell Biol 3(6):191–197

    CAS  PubMed  Google Scholar 

  70. Paukert M, Bergles DE (2006) Synaptic communication between neurons and NG2+ cells. Curr Opin Neurobiol 16(5):515–521

    CAS  PubMed  Google Scholar 

  71. Gensert JM, Goldman JE (1997) Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19(1):197–203

    CAS  PubMed  Google Scholar 

  72. Redwine JM, Armstrong RC (1998) In vivo proliferation of oligodendrocyte progenitors expressing PDGFalphaR during early remyelination. J Neurobiol 37(3):413–428

    CAS  PubMed  Google Scholar 

  73. Keirstead HS, Levine JM, Blakemore WF (1998) Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia 22(2):161–170

    CAS  PubMed  Google Scholar 

  74. Horner PJ, Thallmair M, Gage FH (2002) Defining the NG2-expressing cell of the adult CNS. J Neurocytol 31(6–7):469–480

    CAS  PubMed  Google Scholar 

  75. Chekenya M, Rooprai HK, Davies D, Levine JM, Butt AM, Pilkington GJ (1999) The NG2 chondroitin sulfate proteoglycan: role in malignant progression of human brain tumours. Int J Dev Neurosci 17(5–6):421–435

    CAS  PubMed  Google Scholar 

  76. Lindberg N, Kastemar M, Olofsson T, Smits A, Uhrbom L (2009) Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene 28(23):2266–2275

    CAS  PubMed  Google Scholar 

  77. Persson AI, Petritsch C, Swartling FJ, Itsara M, Sim FJ, Auvergne R, Goldenberg DD, Vandenberg SR, Nguyen KN, Yakovenko S, Ayers-Ringler J, Nishiyama A, Stallcup WB, Berger MS, Bergers G, McKnight TR, Goldman SA, Weiss WA (2010) Non-stem cell origin for oligodendroglioma. Cancer Cell 18(6):669–682

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, Foreman O, Bronson RT, Nishiyama A, Luo L, Zong H (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146(2):209–221

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lindberg N, Uhrbom L (2013) Oligodendroglioma models. In: Martínez Murillo R, Martínez A (eds) Animal models of brain tumors, neuromethods, vol 77. Humana Press, Totowa, pp 57–82, ISBN 978-1-62703-208-7.

    Google Scholar 

  80. Louis DN, Ohgaki H, Wiestler OD, Cavanee WK (2016) WHO classification of tumours of the central nervous system (revised 4th edn). Lyon, IARC Press, pp 1–408

    Google Scholar 

  81. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9(3):157–173

    CAS  PubMed  Google Scholar 

  82. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Google Scholar 

  83. Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, Holland E (2009) Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS One 4(11):e7752. https://doi.org/10.1371/journal.pone.0007752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, Cancer Genome Atlas Research Network (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Shoshan Y, Nishiyama A, Chang A, Mörk S, Barnett GH, Cowell JK, Trapp BD, Staugaitis SM (1999) Expression of oligodendrocyte progenitor cell antigens by gliomas: implications for the histogenesis of brain tumors. Proc Natl Acad Sci U S A 96(18):10361–10366

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kondo T, Raff M (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289(5485):1754–1757. https://doi.org/10.1126/science.289.5485.1754

    Article  CAS  PubMed  Google Scholar 

  87. Chekenya M, Pilkington GJ (2002) NG2 precursor cells in neoplasia: functional, histogenesis and therapeutic implications for malignant brain tumours. J Neurocytol 31(6–7):507–521

    CAS  PubMed  Google Scholar 

  88. Bouvier C, Bartoli C, Aguirre-Cruz L, Virard I, Colin C, Fernandez C, Gouvernet J, Figarella-Branger D (2003) Shared oligodendrocyte lineage gene expression in gliomas and oligodendrocyte progenitor cells. J Neurosurg 99(2):344–350

    CAS  PubMed  Google Scholar 

  89. Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL, Louis DN, Stiles CD, Rowitch DH (2004) The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J Neuropathol Exp Neurol 63(5):499–509

    CAS  PubMed  Google Scholar 

  90. Guha A, Feldkamp MM, Lau N, Boss G, Pawson A (1997) Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 15(23):2755–2765

    CAS  PubMed  Google Scholar 

  91. Al-Mayhani TF, Heywood RM, Vemireddy V, Lathia JD, Piccirillo SGM, Watts C (2019) A non-hierarchical organization of tumorigenic NG2 cells in glioblastoma promoted by EGFR. Neuro-Oncology 21(6):719–729. https://doi.org/10.1093/neuonc/noy204

    Article  CAS  PubMed  Google Scholar 

  92. Svendsen A, Verhoeff JJ, Immervoll H, Brøgger JC, Kmiecik J, Poli A, Netland IA, Prestegarden L, Planagumà J, Torsvik A, Kjersem AB, Sakariassen PØ, Heggdal JI, Van Furth WR, Bjerkvig R, Lund-Johansen M, Enger PØ, Felsberg J, Brons NH, Tronstad KJ, Waha A, Chekenya M (2011) Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. Acta Neuropathol 122(4):495–510. https://doi.org/10.1007/s00401-011-0867-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tsidulko AY, Kazanskaya GM, Kostromskaya DV, Aidagulova SV, Kiselev RS, Volkov AM, Kobozev VV, Gaitan AS, Krivoshapkin AL, Grigorieva EV (2017) Prognostic relevance of NG2/CSPG4, CD44 and Ki-67 in patients with glioblastoma. Tumour Biol 39(9):1010428317724282. https://doi.org/10.1177/1010428317724282

    Article  CAS  PubMed  Google Scholar 

  94. Guan X, Hasan MN, Maniar S, Jia W, Sun D (2018) Reactive astrocytes in glioblastoma multiforme. Mol Neurobiol 55(8):6927–6938. https://doi.org/10.1007/s12035-018-0880-8

    Article  CAS  PubMed  Google Scholar 

  95. Brandao M, Simon T, Critchley G, Giamas G (2019) Astrocytes, the rising stars of the glioblastoma microenvironment. Glia 67(5):779–790. https://doi.org/10.1002/glia.23520

    Article  PubMed  Google Scholar 

  96. Engelhardt A (1980) Detection of acid mucopolysaccharides in human brain tumors by histochemical methods. Acta Neuropathol 49(3):199–203

    CAS  PubMed  Google Scholar 

  97. Böck P, Jellinger K (1981) Detection of glycosaminoglycans in human gliomas by histochemical methods. Acta Neuropathol Suppl 7:81–84

    PubMed  Google Scholar 

  98. Giordana MT, Bertolotto A, Mauro A, Migheli A, Pezzotta S, Racagni G, Schiffer D (1982) Glycosaminoglycans in human cerebral tumors. Part II. Histochemical findings and correlations. Acta Neuropathol 57(4):299–305

    CAS  PubMed  Google Scholar 

  99. Bertolotto A, Goia L, Schiffer D (1986) Immunohistochemical study of chondroitin sulphate in human gliomas. Acta Neuropathol 72(2):189–196

    CAS  PubMed  Google Scholar 

  100. Giordana MT, Mauro A, Schiffer D (1981) Glycosaminoglycans of brain tumors transplacentally induced by ENU in the rat. Acta Neuropathol Suppl 7:79–80

    CAS  PubMed  Google Scholar 

  101. Mauro A, Bertolotto A, Giordana MT, Magrassi ML, Migheli A, Schiffer D (1983) Biochemical and histochemical evaluation of glycosaminoglycans in brain tumors induced in rats by nitrosourea derivatives. J Neuro-Oncol 1(4):299–306

    CAS  Google Scholar 

  102. Nioka H, Matsumura K, Nakasu S, Handa J (1994) Immunohistochemical localization of glycosaminoglycans in experimental rat glioma models. J Neuro-Oncol 21(3):233–242

    CAS  Google Scholar 

  103. Briançon-Marjollet A, Balenci L, Fernandez M, Estève F, Honnorat J, Farion R, Beaumont M, Barbier E, Rémy C, Baudier J (2010) NG2-expressing glial precursor cells are a new potential oligodendroglioma cell initiating population in N-ethyl-N-nitrosourea-induced gliomagenesis. Carcinogenesis 31(10):1718–1725. https://doi.org/10.1093/carcin/bgq154

    Article  CAS  PubMed  Google Scholar 

  104. Burg MA, Grako KA, Stallcup WB (1998) Expression of the NG2 proteoglycan enhances the growth and metastatic properties of melanoma cells. J Cell Physiol 177(2):299–312

    CAS  PubMed  Google Scholar 

  105. Pilkington GJ (1996) The role of the extracellular matrix in neoplastic glial invasion of the nervous system. Braz J Med Biol Res 29(9):1159–1172

    CAS  PubMed  Google Scholar 

  106. Iida J, Meijne AM, Spiro RC, Roos E, Furcht LT, McCarthy JB (1995) Spreading and focal contact formation of human melanoma cells in response to the stimulation of both melanoma-associated proteoglycan (NG2) and alpha 4 beta 1 integrin. Cancer Res 55(10):2177–2185

    CAS  PubMed  Google Scholar 

  107. Pilkington GJ (1994) Tumour cell migration in the central nervous system. Brain Pathol 4(2):157–166

    CAS  PubMed  Google Scholar 

  108. Kirsch M, Wilson JC, Black P (1997) Platelet-derived growth factor in human brain tumors. J Neuro-Oncol 35(3):289–301

    CAS  Google Scholar 

  109. Grako KA, Stallcup WB (1995) Participation of the NG2 proteoglycan in rat aortic smooth muscle cell responses to platelet-derived growth factor. Exp Cell Res 221(1):231–240

    CAS  PubMed  Google Scholar 

  110. Schmitt BM, Laschke MW, Rössler OG, Huang W, Scheller A, Menger MD, Ampofo E (2018) Nerve/glial antigen (NG) 2 is a crucial regulator of intercellular adhesion molecule (ICAM)-1 expression. Biochim Biophys Acta, Mol Cell Res 1865(1):57–66. https://doi.org/10.1016/j.bbamcr.2017.09.019

    Article  CAS  Google Scholar 

  111. Ozerdem U, Grako KA, Dahlin-Huppe K, Monosov E, Stallcup WB (2001) NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn 222(2):218–227

    CAS  PubMed  Google Scholar 

  112. Ozerdem U, Stallcup WB (2003) Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6(3):241–249

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Pouly S, Prat A, Blain M, Olivier A, Antel J (2001) NG2 immunoreactivity on human brain endothelial cells. Acta Neuropathol 102(4):313–320

    CAS  PubMed  Google Scholar 

  114. Schrappe M, Klier FG, Spiro RC, Waltz TA, Reisfeld RA, Gladson CL (1991) Correlation of chondroitin sulphate proteoglycan expression on proliferating brain capillary endothelial cells with the malignant phenotype of astroglial cells. Cancer Res 51(18):4986–4993

    CAS  PubMed  Google Scholar 

  115. Wesseling P, Schlingemann RO, Rietveld FJ, Link M, Burger PC, Ruiter DJ (1995) Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immune-light and immune-electron microscopic study. J Neuropathol Exp Neurol 54(3):304–310

    CAS  PubMed  Google Scholar 

  116. Virgintino D, Girolamo F, Errede M, Capobianco C, Robertson D, Stallcup WB, Perris R, Roncali L (2007) An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis. Angiogenesis 10(1):35–45

    PubMed  Google Scholar 

  117. Huang FJ, You WK, Bonaldo P, Seyfried TN, Pasquale EB, Stallcup WB (2010) Pericyte deficiencies lead to aberrant tumor vascularizaton in the brain of the NG2 null mouse. Dev Biol 344(2):1035–1046. https://doi.org/10.1016/j.ydbio.2010.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97(6):512–523

    CAS  PubMed  Google Scholar 

  119. Girolamo F, Dallatomasina A, Rizzi M, Errede M, Wälchli T, Mucignat MT, Frei K, Roncali L, Perris R, Virgintino D (2013) Diversified expression of NG2/CSPG4 isoforms in glioblastoma and human foetal brain identifies pericyte subsets. PLoS One 8(12):e84883. https://doi.org/10.1371/journal.pone.0084883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307(1):C25–C38. https://doi.org/10.1152/ajpcell.00084.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Schiffer D, Annovazzi L, Mazzucco M, Mellai M (2015) The microenvironment in gliomas: phenotypic expressions. Cancers (Basel) 7(4):2352–2359. https://doi.org/10.3390/cancers7040896

    Article  CAS  Google Scholar 

  122. Mellai M, Annovazzi L, Boldorini R, Bertero L, Cassoni P, De Blasio P, Biunno I, Schiffer D (2019) SEL1L plays a major role in human malignant gliomas. J Pathol Clin Res 6:17. https://doi.org/10.1002/cjp2.134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, Bao S (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153(1):139–152. https://doi.org/10.1016/j.cell.2013.02.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Schiffer D, Mellai M, Annovazzi L, Caldera V, Piazzi A, Denysenko T, Melcarne A (2014) Stem cell niches in glioblastoma: a neuropathological view. Biomed Res Int 2014:725921. https://doi.org/10.1155/2014/725921

    Article  PubMed  PubMed Central  Google Scholar 

  125. Schiffer D, Annovazzi L, Casalone C, Corona C, Mellai M (2018) Glioblastoma: microenvironment and Niche concept. Cancers (Basel) 11(1):E5. https://doi.org/10.3390/cancers11010005

    Article  CAS  Google Scholar 

  126. Schiffer D, Mellai M, Bovio E, Bisogno I, Casalone C, Annovazzi L (2018) Glioblastoma niches: from the concept to the phenotypical reality. Neurol Sci 39(7):1161–1168. https://doi.org/10.1007/s10072-018-3408-0

    Article  PubMed  Google Scholar 

  127. Schiffer D, Mellai M, Boldorini R, Bisogno I, Grifoni S, Corona C, Bertero L, Cassoni P, Casalone C, Annovazzi L (2018) The significance of chondroitin sulfate proteoglycan 4 (CSPG4) in human gliomas. Int J Mol Sci 19(9):E2724. https://doi.org/10.3390/ijms19092724

    Article  CAS  PubMed  Google Scholar 

  128. Petrovici K, Graf M, Hecht K, Reif S, Pfister K, Schmetzer H (2010) Use of NG2 (7.1) in AML as a tumor marker and its association with a poor prognosis. Cancer Genomics Proteomics 7(4):173–180

    CAS  PubMed  Google Scholar 

  129. Chekenya M, Krakstad C, Svendsen A, Netland IA, Staalesen V, Tysnes BB, Selheim F, Wang J, Sakariassen PØ, Sandal T, Lønning PE, Flatmark T, Enger PØ, Bjerkvig R, Sioud M, Stallcup WB (2008) The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling. Oncogene 27(39):5182–5194. https://doi.org/10.1038/onc.2008.157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yotsumoto F, You WK, Cejudo-Martin P, Kucharova K, Sakimura K, Stallcup WB (2015) NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization. Onco Targets Ther 4(4):e1001204

    Google Scholar 

  131. Beard RE, Zheng Z, Lagisetty KH, Burns WR, Tran E, Hewitt SM, Abate-Daga D, Rosati SF, Fine HA, Ferrone S, Rosenberg SA, Morgan RA (2014) Multiple chimeric antigen receptors successfully target chondroitin sulfate proteoglycan 4 in several different cancer histologies and cancer stem cells. J Immunother Cancer 2:25. https://doi.org/10.1186/2051-1426-2-25

    Article  PubMed  PubMed Central  Google Scholar 

  132. Jordaan S, Chetty S, Mungra N, Koopmans I, van Bommel PE, Helfrich W, Barth S (2017) CSPG4: a target for selective delivery of human cytolytic fusion proteins and TRAIL. Biomedicines 5(3):E37. https://doi.org/10.3390/biomedicines5030037

    Article  CAS  PubMed  Google Scholar 

  133. Ilieva KM, Cheung A, Mele S, Chiaruttini G, Crescioli S, Griffin M, Nakamura M, Spicer JF, Tsoka S, Lacy KE, Tutt ANJ, Karagiannis SN (2018) Chondroitin sulfate proteoglycan 4 and its potential as an antibody immunotherapy target across different tumor types. Front Immunol 8:1911. https://doi.org/10.3389/fimmu.2017.01911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rodriguez A, Brown C, Badie B (2017) Chimeric antigen receptor T-cell therapy for glioblastoma. Transl Res 187:93–102. https://doi.org/10.1016/j.trsl.2017.07.003

    Article  CAS  PubMed  Google Scholar 

  135. Rivera Z, Ferrone S, Wang X, Jube S, Yang H, Pass HI, Kanodia S, Gaudino G, Carbone M (2012) CSPG4 as a target of antibody-based immunotherapy for malignant mesothelioma. Clin Cancer Res 18(19):5352–5363. https://doi.org/10.1158/1078-0432.CCR-12-0628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Gao Q, Lu J, Huo Y, Baby N, Ling EA, Dheen ST (2010) NG2, a member of chondroitin sulfate proteoglycans family mediates the inflammatory response of activated microglia. Neuroscience 165(2):386–394. https://doi.org/10.1016/j.neuroscience.2009.10.022

    Article  CAS  PubMed  Google Scholar 

  137. Pituch KC, Miska J, Krenciute G, Panek WK, Li G, Rodriguez-Cruz T, Wu M, Han Y, Lesniak MS, Gottschalk S, Balyasnikova IV (2018) Adoptive transfer of IL13Rα2-specific chimeric antigen receptor T cells creates a pro-inflammatory environment in glioblastoma. Mol Ther 26(4):986–995. https://doi.org/10.1016/j.ymthe.2018.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Finocchiaro G, Pellegatta S (2019) NG2/CSPG4 in glioblastoma: about flexibility. Neuro-Oncology 21(6):697–698. https://doi.org/10.1093/neuonc/noz055

    Article  PubMed  PubMed Central  Google Scholar 

  139. Hide T, Komohara Y, Miyasato Y, Nakamura H, Makino K, Takeya M, Kuratsu JI, Mukasa A, Yano S (2018) Oligodendrocyte progenitor cells and macrophages/microglia produce glioma stem cell niches at the tumor border. EBioMedicine 30:94–104. https://doi.org/10.1016/j.ebiom.2018.02.024

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by Fondazione Compagnia di San Paolo (Turin, Italy) (Grant No. 2016.AAI2705.U3302) and Fondazione Edo ed Elvo Tempia Valenta – ONLUS (Biella, Italy).

Author information

Authors and Affiliations

  1. Centro di Ricerca Traslazionale sulle Malattie Autoimmuni e Allergiche (CAAD), Università del Piemonte Orientale (UPO), Novara, Italy

    Marta Mellai

  2. Dipartimento di Scienze della Salute, Scuola di Medicina, Università del Piemonte Orientale (UPO), Novara, Italy

    Marta Mellai & Renzo Boldorini

  3. Fondazione Edo ed Elvo Tempia Valenta – ONLUS, Biella, Italy

    Marta Mellai

  4. Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, Torino, Italy

    Cristina Casalone, Cristiano Corona, Paola Crociara & Alessandra Favole

  5. Dipartimento di Scienze Mediche, Università di Torino/Città della Salute e della Scienza, Torino, Italy

    Paola Cassoni

  6. Ex Centro Ricerche/Fondazione Policlinico di Monza, Vercelli, Italy

    Davide Schiffer

Authors
  1. Marta Mellai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Casalone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristiano Corona
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paola Crociara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alessandra Favole
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paola Cassoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Davide Schiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Renzo Boldorini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marta Mellai .

Editor information

Editors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2020 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mellai, M. et al. (2020). Chondroitin Sulphate Proteoglycans in the Tumour Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment . Advances in Experimental Medicine and Biology, vol 1272. Springer, Cham. https://doi.org/10.1007/978-3-030-48457-6_5

Download citation

Publish with us

Policies and ethics

Search

Navigation