• 1
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW & Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114, 97109.
  • 2
    Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, Haas-Kogan D, James CD, Oakes SA, Debnath J et al. (2010) Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 3, ra81.
  • 3
    Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318, 287290.
  • 4
    Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA et al. (2011) Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810817.
  • 5
    Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S et al. (2012) Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA 109, 30413046.
  • 6
    Fuster MM & Esko JD (2005) The sweet and sour of cancer: glycans as novel therapeutic targets. Nat Rev Cancer 5, 526542.
  • 7
    Iozzo RV & Schaefer L (2010) Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. FEBS J 277, 38643875.
  • 8
    Rosen SD & Lemjabbar-Alaoui H (2010) Sulf-2: an extracellular modulator of cell signaling and a cancer target candidate. Expert Opin Ther Targets 14, 935949.
  • 9
    Phillips JJ (2012) Novel therapeutic targets in the brain tumor microenvironment. Oncotarget 3, 568575.
  • 10
    10 Cecchi F, Pajalunga D, Fowler CA, Uren A, Rabe DC, Peruzzi B, Macdonald NJ, Blackman DK, Stahl SJ, Byrd RA et al. (2012) Targeted disruption of heparan sulfate interaction with hepatocyte and vascular endothelial growth factors blocks normal and oncogenic signaling. Cancer Cell 22, 250262.
  • 11
    Phillips JJ, Huillard E, Robinson AE, Ward A, Lum DH, Polley MY, Rosen SD, Rowitch DH & Werb Z (2012) Heparan sulfate sulfatase SULF2 regulates PDGFRalpha signaling and growth in human and mouse malignant glioma. J Clin Invest 122, 911922.
  • 12
    Sugiarto S, Persson AI, Munoz EG, Waldhuber M, Lamagna C, Andor N, Hanecker P, Ayers-Ringler J, Phillips J, Siu J et al. (2011) Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 20, 328340.
  • 13
    Svendsen A, Verhoeff JJ, Immervoll H, Brogger JC, Kmiecik J, Poli A, Netland IA, Prestegarden L, Planaguma J, Torsvik A et al. (2011) Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. Acta Neuropathol 122, 495510.
  • 14
    Chekenya M, Krakstad C, Svendsen A, Netland IA, Staalesen V, Tysnes BB, Selheim F, Wang J, Sakariassen PO, Sandal T et al. (2008) The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling. Oncogene 27, 51825194.
  • 15
    Stallcup WB & Huang FJ (2008) A role for the NG2 proteoglycan in glioma progression. Cell Adh Migr 2, 192201.
  • 16
    Su G, Meyer K, Nandini CD, Qiao D, Salamat S & Friedl A (2006) Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells. Am J Pathol 168, 20142026.
  • 17
    Viapiano MS, Matthews RT & Hockfield S (2003) A novel membrane-associated glycovariant of BEHAB/brevican is up-regulated during rat brain development and in a rat model of invasive glioma. J Biol Chem 278, 3323933247.
  • 18
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al. (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98110.
  • 19
    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, e7752.
  • 20
    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L et al. (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157173.
  • 21
    Zimmermann DR & Dours-Zimmermann MT (2008) Extracellular matrix of the central nervous system: from neglect to challenge. Histochem Cell Biol 130, 635653.
  • 22
    Maeda N, Ishii M, Nishimura K & Kamimura K (2011) Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem Res 36, 12281240.
  • 23
    Abaskharoun M, Bellemare M, Lau E & Margolis RU (2010) Glypican-1, phosphacan/receptor protein-tyrosine phosphatase-zeta/beta and its ligand, tenascin-C, are expressed by neural stem cells and neural cells derived from embryonic stem cells. ASN Neuro 2, e00039.
  • 24
    Esko JD & Lindahl U (2001) Molecular diversity of heparan sulfate. J Clin Invest 108, 169173.
  • 25
    Kwok JC, Warren P & Fawcett JW (2012) Chondroitin sulfate: a key molecule in the brain matrix. Int J Biochem Cell Biol 44, 582586.
  • 26
    Greene DK, Tumova S, Couchman JR & Woods A (2003) Syndecan-4 associates with alpha-actinin. J Biol Chem 278, 76177623.
  • 27
    Longley RL, Woods A, Fleetwood A, Cowling GJ, Gallagher JT & Couchman JR (1999) Control of morphology, cytoskeleton and migration by syndecan-4. J Cell Sci 112, 34213431.
  • 28
    Echtermeyer F, Baciu PC, Saoncella S, Ge Y & Goetinck PF (1999) Syndecan-4 core protein is sufficient for the assembly of focal adhesions and actin stress fibers. J Cell Sci 112, 34333441.
  • 29
    Beauvais DM & Rapraeger AC (2010) Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation. J Cell Sci 123, 37963807.
  • 30
    Shipp EL & Hsieh-Wilson LC (2007) Profiling the sulfation specificities of glycosaminoglycan interactions with growth factors and chemotactic proteins using microarrays. Chem Biol 14, 195208.
  • 31
    Bespalov MM, Sidorova YA, Tumova S, Ahonen-Bishopp A, Magalhaes AC, Kulesskiy E, Paveliev M, Rivera C, Rauvala H & Saarma M (2011) Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin. J Cell Biol 192, 153169.
  • 32
    Ashikari-Hada S, Habuchi H, Kariya Y, Itoh N, Reddi AH & Kimata K (2004) Characterization of growth factor-binding structures in heparin/heparan sulfate using an octasaccharide library. J Biol Chem 279, 1234612354.
  • 33
    Han C, Belenkaya TY, Khodoun M, Tauchi M, Lin X & Lin X (2004) Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation. Development 131, 15631575.
  • 34
    Han C, Yan D, Belenkaya TY & Lin X (2005) Drosophila glypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc. Development 132, 667679.
  • 35
    Rapraeger AC, Krufka A & Olwin BB (1991) Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science 252, 17051708.
  • 36
    Yayon A, Klagsbrun M, Esko JD, Leder P & Ornitz DM (1991) Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64, 841848.
  • 37
    Kreuger J, Salmivirta M, Sturiale L, Gimenez-Gallego G & Lindahl U (2001) Sequence analysis of heparan sulfate epitopes with graded affinities for fibroblast growth factors 1 and 2. J Biol Chem 276, 3074430752.
  • 38
    Ford-Perriss M, Guimond SE, Greferath U, Kita M, Grobe K, Habuchi H, Kimata K, Esko JD, Murphy M & Turnbull JE (2002) Variant heparan sulfates synthesized in developing mouse brain differentially regulate FGF signaling. Glycobiology 12, 721727.
  • 39
    Goodger SJ, Robinson CJ, Murphy KJ, Gasiunas N, Harmer NJ, Blundell TL, Pye DA & Gallagher JT (2008) Evidence that heparin saccharides promote FGF2 mitogenesis through two distinct mechanisms. J Biol Chem 283, 1300113008.
  • 40
    Chuang CY, Lord MS, Melrose J, Rees MD, Knox SM, Freeman C, Iozzo RV & Whitelock JM (2010) Heparan sulfate-dependent signaling of fibroblast growth factor 18 by chondrocyte-derived perlecan. Biochemistry 49, 55245532.
  • 41
    Sarrazin S, Lamanna WC & Esko JD (2011) Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol in press, doi:10.1101/cshperspect.a004952.
  • 42
    Haubst N, Georges-Labouesse E, De Arcangelis A, Mayer U & Gotz M (2006) Basement membrane attachment is dispensable for radial glial cell fate and for proliferation, but affects positioning of neuronal subtypes. Development 133, 32453254.
  • 43
    Giros A, Morante J, Gil-Sanz C, Fairen A & Costell M (2007) Perlecan controls neurogenesis in the developing telencephalon. BMC Dev Biol 7, 29.
  • 44
    Costell M, Gustafsson E, Aszodi A, Morgelin M, Bloch W, Hunziker E, Addicks K, Timpl R & Fassler R (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147, 11091122.
  • 45
    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, 241247.
  • 46
    Kucharova K & Stallcup WB (2010) The NG2 proteoglycan promotes oligodendrocyte progenitor proliferation and developmental myelination. Neuroscience 166, 185194.
  • 47
    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, e30637.
  • 48
    Habuchi H, Habuchi O & Kimata K (2004) Sulfation pattern in glycosaminoglycan: does it have a code? Glycoconj J 21, 4752.
  • 49
    Bink RJ, Habuchi H, Lele Z, Dolk E, Joore J, Rauch GJ, Geisler R, Wilson SW, den Hertog J, Kimata K et al. (2003) Heparan sulfate 6-o-sulfotransferase is essential for muscle development in zebrafish. J Biol Chem 278, 3111831127.
  • 50
    Bulow HE & Hobert O (2004) Differential sulfations and epimerization define heparan sulfate specificity in nervous system development. Neuron 41, 723736.
  • 51
    Kamimura K, Fujise M, Villa F, Izumi S, Habuchi H, Kimata K & Nakato H (2001) Drosophila heparan sulfate 6-O-sulfotransferase (dHS6ST) gene. Structure, expression, and function in the formation of the tracheal system. J Biol Chem 276, 1701417021.
  • 52
    Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S & Rosen SD (2002) Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem 277, 4917549185.
  • 53
    Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM & Emerson CP Jr (2001) Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 293, 16631666.
  • 54
    Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U & Emerson CP Jr (2003) QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol 162, 341351.
  • 55
    Ai X, Kitazawa T, Do AT, Kusche-Gullberg M, Labosky PA & Emerson CP Jr (2007) SULF1 and SULF2 regulate heparan sulfate-mediated GDNF signaling for esophageal innervation. Development 134, 33273338.
  • 56
    Dai Y, Yang Y, MacLeod V, Yue X, Rapraeger AC, Shriver Z, Venkataraman G, Sasisekharan R & Sanderson RD (2005) HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo. J Biol Chem 280, 4006640073.
  • 57
    Viviano BL, Paine-Saunders S, Gasiunas N, Gallagher J & Saunders S (2004) Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin. J Biol Chem 279, 56045611.
  • 58
    Danesin C, Agius E, Escalas N, Ai X, Emerson C, Cochard P & Soula C (2006) Ventral neural progenitors switch toward an oligodendroglial fate in response to increased Sonic hedgehog (Shh) activity: involvement of Sulfatase 1 in modulating Shh signaling in the ventral spinal cord. J Neurosci 26, 50375048.
  • 59
    Freeman SD, Moore WM, Guiral EC, Holme AD, Turnbull JE & Pownall ME (2008) Extracellular regulation of developmental cell signaling by XtSulf1. Dev Biol 320, 436445.
  • 60
    Lamanna WC, Frese MA, Balleininger M & Dierks T (2008) Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling. J Biol Chem 283, 2772427735.
  • 61
    Fujita K, Takechi E, Sakamoto N, Sumiyoshi N, Izumi S, Miyamoto T, Matsuura S, Tsurugaya T, Akasaka K & Yamamoto T (2010) HpSulf, a heparan sulfate 6-O-endosulfatase, is involved in the regulation of VEGF signaling during sea urchin development. Mech Dev 127, 235245.
  • 62
    Uchimura K, Morimoto-Tomita M, Bistrup A, Li J, Lyon M, Gallagher J, Werb Z & Rosen SD (2006) HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1. BMC Biochem 7, 2.
  • 63
    Habuchi H, Nagai N, Sugaya N, Atsumi F, Stevens RL & Kimata K (2007) Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality. J Biol Chem 282, 1557815588.
  • 64
    Sugaya N, Habuchi H, Nagai N, Ashikari-Hada S & Kimata K (2008) 6-O-sulfation of heparan sulfate differentially regulates various fibroblast growth factor-dependent signalings in culture. J Biol Chem 283, 1036610376.
  • 65
    Hayano S, Kurosaka H, Yanagita T, Kalus I, Milz F, Ishihara Y, Islam MN, Kawanabe N, Saito M, Kamioka H et al. (2012) Roles of heparan sulfate sulfation in dentinogenesis. J Biol Chem 287, 1221712229.
  • 66
    Kalus I, Salmen B, Viebahn C, von Figura K, Schmitz D, D'Hooge R & Dierks T (2009) Differential involvement of the extracellular 6-O-endosulfatases Sulf1 and Sulf2 in brain development and neuronal and behavioural plasticity. J Cell Mol Med 13, 45054521.
  • 67
    Ratzka A, Kalus I, Moser M, Dierks T, Mundlos S & Vortkamp A (2008) Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. Dev Dyn 237, 339353.
  • 68
    Ida M, Shuo T, Hirano K, Tokita Y, Nakanishi K, Matsui F, Aono S, Fujita H, Fujiwara Y, Kaji T et al. (2006) Identification and functions of chondroitin sulfate in the milieu of neural stem cells. J Biol Chem 281, 59825991.
  • 69
    Mercier F & Arikawa-Hirasawa E (2012) Heparan sulfate niche for cell proliferation in the adult brain. Neurosci Lett 510, 6772.
  • 70
    Wang Q, Yang L, Alexander C & Temple S (2012) The niche factor syndecan-1 regulates the maintenance and proliferation of neural progenitor cells during mammalian cortical development. PLoS One 7, e42883.
  • 71
    Sirko S, von Holst A, Weber A, Wizenmann A, Theocharidis U, Gotz 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, 775787.
  • 72
    Trotter J, Karram K & Nishiyama A (2010) NG2 cells: Properties, progeny and origin. Brain Res Rev 63, 7282.
  • 73
    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, 1683116837.
  • 74
    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, 35803590.
  • 75
    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, 315330.
  • 76
    Cattaruzza S, Ozerdem U, Denzel M, Ranscht B, Bulian P, Cavallaro U, Zanocco D, Colombatti A, Stallcup WB & Perris R (2012) Multivalent proteoglycan modulation of FGF mitogenic responses in perivascular cells. Angiogenesis. in press, doi:10.1007/s10456-012-9316-7.
  • 77
    Burg MA, Tillet E, Timpl R & Stallcup WB (1996) Binding of the NG2 proteoglycan to type VI collagen and other extracellular matrix molecules. J Biol Chem 271, 2611026116.
  • 78
    Wen Y, Makagiansar IT, Fukushi J, Liu FT, Fukuda MN & Stallcup WB (2006) Molecular basis of interaction between NG2 proteoglycan and galectin-3. J Cell Biochem 98, 115127.
  • 79
    Nishiyama A, Komitova M, Suzuki R & Zhu X (2009) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci 10, 922.
  • 80
    Barritt DS, Pearn MT, Zisch AH, Lee SS, Javier RT, Pasquale EB & Stallcup WB (2000) The multi-PDZ domain protein MUPP1 is a cytoplasmic ligand for the membrane-spanning proteoglycan NG2. J Cell Biochem 79, 213224.
  • 81
    Chatterjee N, Stegmuller J, Schatzle P, Karram K, Koroll M, Werner HB, Nave KA & Trotter J (2008) Interaction of syntenin-1 and the NG2 proteoglycan in migratory oligodendrocyte precursor cells. J Biol Chem 283, 83108317.
  • 82
    Stegmuller J, Werner H, Nave KA & Trotter J (2003) The proteoglycan NG2 is complexed with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by the PDZ glutamate receptor interaction protein (GRIP) in glial progenitor cells. Implications for glial-neuronal signaling. J Biol Chem 278, 35903598.
  • 83
    Makagiansar IT, Williams S, Dahlin-Huppe K, Fukushi J, Mustelin T & Stallcup WB (2004) Phosphorylation of NG2 proteoglycan by protein kinase C-alpha regulates polarized membrane distribution and cell motility. J Biol Chem 279, 5526255270.
  • 84
    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, 155165.
  • 85
    Forsberg M, Holmborn K, Kundu S, Dagalv A, Kjellen L & Forsberg-Nilsson K (2012) Undersulfation of heparan sulfate restricts differentiation potential of mouse embryonic stem cells. J Biol Chem 287, 1085310862.
  • 86
    Braquart-Varnier C, Danesin C, Clouscard-Martinato C, Agius E, Escalas N, Benazeraf B, Ai X, Emerson C, Cochard P & Soula C (2004) A subtractive approach to characterize genes with regionalized expression in the gliogenic ventral neuroepithelium: identification of chick sulfatase 1 as a new oligodendrocyte lineage gene. Mol Cell Neurosci 25, 612628.
  • 87
    Touahri Y, Escalas N, Benazeraf B, Cochard P, Danesin C & Soula C (2012) Sulfatase 1 promotes the motor neuron-to-oligodendrocyte fate switch by activating Shh signaling in Olig2 progenitors of the embryonic ventral spinal cord. J Neurosci 32, 1801818034.
  • 88
    Ishii M & Maeda N (2008) Oversulfated chondroitin sulfate plays critical roles in the neuronal migration in the cerebral cortex. J Biol Chem 283, 3261032620.
  • 89
    Asher RA, Morgenstern DA, Shearer MC, Adcock KH, Pesheva P & Fawcett JW (2002) Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells. J Neurosci 22, 22252236.
  • 90
    Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Doring A, Sloka S, Stirling DP, Rivest S & Yong VW (2012) Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol 72, 419432.
  • 91
    Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW & McMahon SB (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636640.
  • 92
    Sato Y, Nakanishi K, Tokita Y, Kakizawa H, Ida M, Maeda H, Matsui F, Aono S, Saito A, Kuroda Y et al. (2008) A highly sulfated chondroitin sulfate preparation. CS-E, prevents excitatory amino acid-induced neuronal cell death. J Neurochem 104, 15651576.
  • 93
    Kucharova K, Chang Y, Boor A, Yong VW & Stallcup WB (2011) Reduced inflammation accompanies diminished myelin damage and repair in the NG2 null mouse spinal cord. J Neuroinflammation 8, 158.
  • 94
    Higginson JR, Thompson SM, Santos-Silva A, Guimond SE, Turnbull JE & Barnett SC (2012) Differential sulfation remodelling of heparan sulfate by extracellular 6-o-sulfatases regulates fibroblast growth factor-induced boundary formation by glial cells: implications for glial cell transplantation. J Neurosci 32, 1590215912.
  • 95
    Iozzo RV & Sanderson RD (2011) Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med 15, 10131031.
  • 96
    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, 39043923.
  • 97
    Aikawa T, Whipple CA, Lopez ME, Gunn J, Young A, Lander AD & Korc M (2008) Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells. J Clin Invest 118, 8999.
  • 98
    Kleeff J, Ishiwata T, Kumbasar A, Friess H, Buchler MW, Lander AD & Korc M (1998) The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J Clin Invest 102, 16621673.
  • 99
    Whipple CA, Young AL & Korc M (2011) A Kras(G12D)-driven genetic mouse model of pancreatic cancer requires glypican-1 for efficient proliferation and angiogenesis. Oncogene 31, 25352544.
  • 100
    Vlodavsky I, Beckhove P, Lerner I, Pisano C, Meirovitz A, Ilan N & Elkin M (2012) Significance of heparanase in cancer and inflammation. Cancer Microenviron 5, 115132.
  • 101
    Ramani VC, Yang Y, Ren Y, Nan L & Sanderson RD (2011) Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity. J Biol Chem 286, 64906499.
  • 102
    Purushothaman A, Uyama T, Kobayashi F, Yamada S, Sugahara K, Rapraeger AC & Sanderson RD (2010) Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis. Blood 115, 24492457.
  • 103
    Purushothaman A, Babitz SK & Sanderson RD (2012) Heparanase enhances the insulin receptor signaling pathway to activate ERK in multiple myeloma. J Biol Chem 287, 4128841296.
  • 104
    Yang Y, Macleod V, Miao HQ, Theus A, Zhan F, Shaughnessy JD Jr, Sawyer J, Li JP, Zcharia E, Vlodavsky I et al. (2007) Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem 282, 1332613333.
  • 105
    Morimoto-Tomita M, Uchimura K, Bistrup A, Lum DH, Egeblad M, Boudreau N, Werb Z & Rosen SD (2005) Sulf-2, a proangiogenic heparan sulfate endosulfatase, is upregulated in breast cancer. Neoplasia 7, 10011010.
  • 106
    Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang YQ, Tsay D, He B, Jablons DM & Rosen SD (2010) Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis. Oncogene 29, 635646.
  • 107
    Lai J, Chien J, Staub J, Avula R, Greene EL, Matthews TA, Smith DI, Kaufmann SH, Roberts LR & Shridhar V (2003) Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. J Biol Chem 278, 2310723117.
  • 108
    Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M & Rosen SD (2007) Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2, e392.
  • 109
    Hur K, Han TS, Jung EJ, Yu J, Lee HJ, Kim WH, Goel A & Yang HK (2012) Up-regulated expression of sulfatases (SULF1 and SULF2) as prognostic and metastasis predictive markers in human gastric cancer. J Pathol 228, 8898.
  • 110
    Yang JD, Sun Z, Hu C, Lai J, Dove R, Nakamura I, Lee JS, Thorgeirsson SS, Kang KJ, Chu IS et al. (2011) Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival. Genes Chromosom Cancer 50, 122135.
  • 111
    Johansson FK, Brodd J, Eklof C, Ferletta M, Hesselager G, Tiger CF, Uhrbom L & Westermark B (2004) Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging. Proc Natl Acad Sci USA 101, 1133411337.
  • 112
    Fuster MM, Wang L, Castagnola J, Sikora L, Reddi K, Lee PH, Radek KA, Schuksz M, Bishop JR, Gallo RL et al. (2007) Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis. J Cell Biol 177, 539549.
  • 113
    Ferreras C, Rushton G, Cole CL, Babur M, Telfer BA, van Kuppevelt TH, Gardiner JM, Williams KJ, Jayson GC & Avizienyte E (2012) Endothelial heparan sulfate 6-o-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor. J Biol Chem 287, 3613236146.
  • 114
    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, 10351046.
  • 115
    Parish CR (2006) The role of heparan sulphate in inflammation. Nat Rev Immunol 6, 633643.
  • 116
    Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL & Karin M (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102106.
  • 117
    Lerner I, Hermano E, Zcharia E, Rodkin D, Bulvik R, Doviner V, Rubinstein AM, Ishai-Michaeli R, Atzmon R, Sherman Y et al. (2011) Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice. J Clin Invest 121, 17091721.
  • 118
    Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A, Popoff S, Nutt CL, Louis DN, Cairncross JG et al. (2010) A multigene predictor of outcome in glioblastoma. Neuro Oncol 12, 4957.
  • 119
    Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G, Seligson D, Kremen TJ, Palotie A, Liau LM et al. (2003) Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 22, 23612373.
  • 120
    Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tonjes M, Sill M, Bender S et al. (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425437.
  • 121
    Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH et al. (2011) The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25, 25942609.
  • 122
    The Cancer Genome Atlas (TCGA) Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 10611068.
  • 123
    Datta MW, Hernandez AM, Schlicht MJ, Kahler AJ, DeGueme AM, Dhir R, Shah RB, Farach-Carson C, Barrett A & Datta S (2006) Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway. Mol Cancer 5, 9.
  • 124
    Jijiwa M, Demir H, Gupta S, Leung C, Joshi K, Orozco N, Huang T, Yildiz VO, Shibahara I, de Jesus JA et al. (2011) CD44v6 regulates growth of brain tumor stem cells partially through the AKT-mediated pathway. PLoS One 6, e24217.
  • 125
    Zhou Z, Wang J, Cao R, Morita H, Soininen R, Chan KM, Liu B, Cao Y & Tryggvason K (2004) Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res 64, 46994702.
  • 126
    Foehr ED, Lorente G, Kuo J, Ram R, Nikolich K & Urfer R (2006) Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model. Cancer Res 66, 22712278.
  • 127
    Arslan F, Bosserhoff AK, Nickl-Jockschat T, Doerfelt A, Bogdahn U & Hau P (2007) The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-beta2. Br J Cancer 96, 15601568.
  • 128
    Khotskaya YB, Dai Y, Ritchie JP, MacLeod V, Yang Y, Zinn K & Sanderson RD (2009) Syndecan-1 is required for robust growth, vascularization, and metastasis of myeloma tumors in vivo. J Biol Chem 284, 2608526095.
  • 129
    Berman B, Ostrovsky O, Shlissel M, Lang T, Regan D, Vlodavsky I, Ishai-Michaeli R & Ron D (1999) Similarities and differences between the effects of heparin and glypican-1 on the bioactivity of acidic fibroblast growth factor and the keratinocyte growth factor. J Biol Chem 274, 3613236138.
  • 130
    Gengrinovitch S, Berman B, David G, Witte L, Neufeld G & Ron D (1999) Glypican-1 is a VEGF165 binding proteoglycan that acts as an extracellular chaperone for VEGF165. J Biol Chem 274, 1081610822.
  • 131
    Qiao D, Meyer K, Mundhenke C, Drew SA & Friedl A (2003) Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 signaling in brain endothelial cells. Specific role for glypican-1 in glioma angiogenesis. J Biol Chem 278, 1604516053.
  • 132
    Wang J, Svendsen A, Kmiecik J, Immervoll H, Skaftnesmo KO, Planaguma J, Reed RK, Bjerkvig R, Miletic H, Enger PO et al. (2011) Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma. PLoS One 6, e23062.
  • 133
    Ulbricht U, Eckerich C, Fillbrandt R, Westphal M & Lamszus K (2006) RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo. J Neurochem 98, 14971506.
  • 134
    McClain CR, Sim FJ & Goldman SA (2012) pleiotrophin suppression of receptor protein tyrosine phosphatase-beta/zeta maintains the self-renewal competence of fetal human oligodendrocyte progenitor cells. J Neurosci 32, 1506615075.
  • 135
    Hernandez D, Miquel-Serra L, Docampo MJ, Marco-Ramell A, Cabrera J, Fabra A & Bassols A (2011) V3 versican isoform alters the behavior of human melanoma cells by interfering with CD44/ErbB-dependent signaling. J Biol Chem 286, 14751485.
  • 136
    Leygue E, Snell L, Dotzlaw H, Troup S, Hiller-Hitchcock T, Murphy LC, Roughley PJ & Watson PH (2000) Lumican and decorin are differentially expressed in human breast carcinoma. J Pathol 192, 313320.
  • 137
    Theocharis AD (2002) Human colon adenocarcinoma is associated with specific post-translational modifications of versican and decorin. Biochim Biophys Acta 1588, 165172.
  • 138
    Li Y, Sheu CC, Ye Y, de Andrade M, Wang L, Chang SC, Aubry MC, Aakre JA, Allen MS, Chen F et al. (2010) Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol 11, 321330.
  • 139
    Porsch H, Bernert B, Mehic M, Theocharis AD, Heldin CH & Heldin P (2012) Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. Oncogene in press, doi:10.1038/onc.2012.475.
  • 140
    Misra S, Toole BP & Ghatak S (2006) Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells. J Biol Chem 281, 3493634941.
  • 141
    Itano N, Sawai T, Atsumi F, Miyaishi O, Taniguchi S, Kannagi R, Hamaguchi M & Kimata K (2004) Selective expression and functional characteristics of three mammalian hyaluronan synthases in oncogenic malignant transformation. J Biol Chem 279, 1867918687.
  • 142
    Itano N, Zhuo L & Kimata K (2008) Impact of the hyaluronan-rich tumor microenvironment on cancer initiation and progression. Cancer Sci 99, 17201725.
  • 143
    Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B & Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52, 32133219.
  • 144
    Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y et al. (2010) PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24, 22052218.
  • 145
    Engler JR, Robinson AE, Smirnov I, Hodgson JG, Berger MS, Gupta N, James CD, Molinaro A & Phillips JJ (2012) Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. PLoS One 7, e43339.
  • 146
    Watanabe A, Mabuchi T, Satoh E, Furuya K, Zhang L, Maeda S & Naganuma H (2006) Expression of syndecans, a heparan sulfate proteoglycan, in malignant gliomas: participation of nuclear factor-kappaB in upregulation of syndecan-1 expression. J Neurooncol 77, 2532.
  • 147
    Beauvais DM, Burbach BJ & Rapraeger AC (2004) The syndecan-1 ectodomain regulates alphavbeta3 integrin activity in human mammary carcinoma cells. J Cell Biol 167, 171181.
  • 148
    Beauvais DM, Ell BJ, McWhorter AR & Rapraeger AC (2009) Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor. J Exp Med 206, 691705.
  • 149
    Kharabi Masouleh B, Ten Dam GB, Wild MK, Seelige R, van der Vlag J, Rops AL, Echtermeyer FG, Vestweber D, van Kuppevelt TH, Kiesel L et al. (2009) Role of the heparan sulfate proteoglycan syndecan-1 (CD138) in delayed-type hypersensitivity. J Immunol 182, 49854993.
  • 150
    Xu J, Park PW, Kheradmand F & Corry DB (2005) Endogenous attenuation of allergic lung inflammation by syndecan-1. J Immunol 174, 57585765.
  • 151
    Hayashida K, Parks WC & Park PW (2009) Syndecan-1 shedding facilitates the resolution of neutrophilic inflammation by removing sequestered CXC chemokines. Blood 114, 30333043.
  • 152
    Nishiyama A, Lin XH, Giese N, Heldin CH & Stallcup WB (1996) Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain. J Neurosci Res 43, 299314.
  • 153
    Giamanco KA & Matthews RT (2012) Deconstructing the perineuronal net: cellular contributions and molecular composition of the neuronal extracellular matrix. Neuroscience 218, 367384.
  • 154
    Giamanco KA, Morawski M & Matthews RT (2010) Perineuronal net formation and structure in aggrecan knockout mice. Neuroscience 170, 13141327.
  • 155
    Hu B, Kong LL, Matthews RT & Viapiano MS (2008) The proteoglycan brevican binds to fibronectin after proteolytic cleavage and promotes glioma cell motility. J Biol Chem 283, 2484824859.
  • 156
    Jaworski DM, Kelly GM, Piepmeier JM & Hockfield S (1996) BEHAB (brain enriched hyaluronan binding) is expressed in surgical samples of glioma and in intracranial grafts of invasive glioma cell lines. Cancer Res 56, 22932298.
  • 157
    Zhang H, Kelly G, Zerillo C, Jaworski DM & Hockfield S (1998) Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion In vivo. J Neurosci 18, 23702376.
  • 158
    Matthews RT, Gary SC, Zerillo C, Pratta M, Solomon K, Arner EC & Hockfield S (2000) Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member. J Biol Chem 275, 2269522703.
  • 159
    Viapiano MS, Hockfield S & Matthews RT (2008) BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion. J Neurooncol 88, 261272.
  • 160
    Lum DH, Tan J, Rosen SD & Werb Z (2007) Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase gene, Sulf2. Mol Cell Biol 27, 678688.
  • 161
    Gill RB, Day A, Barstow A, Zaman G, Chenu C & Dhoot GK (2012) Mammalian Sulf1 RNA alternative splicing and its significance to tumour growth regulation. Tumour Biol 33, 16691680.
  • 162
    Giannini C, Sarkaria JN, Saito A, Uhm JH, Galanis E, Carlson BL, Schroeder MA & James CD (2005) Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol 7, 164176.
  • 163
    Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R et al. (2002) Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1, 269277.
  • 164
    Dredge K, Hammond E, Handley P, Gonda TJ, Smith MT, Vincent C, Brandt R, Ferro V & Bytheway I (2011) PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models. Br J Cancer 104, 635642.
  • 165
    Hossain MM, Hosono-Fukao T, Tang R, Sugaya N, van Kuppevelt TH, Jenniskens GJ, Kimata K, Rosen SD & Uchimura K (2010) Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88. Glycobiology 20, 175186.
  • 166
    Johnstone KD, Karoli T, Liu L, Dredge K, Copeman E, Li CP, Davis K, Hammond E, Bytheway I, Kostewicz E et al. (2010) Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth. J Med Chem 53, 16861699.
  • 167
    Joyce JA, Freeman C, Meyer-Morse N, Parish CR & Hanahan D (2005) A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene 24, 40374051.
  • 168
    Zhou H, Roy S, Cochran E, Zouaoui R, Chu CL, Duffner J, Zhao G, Smith S, Galcheva-Gargova Z, Karlgren J et al. (2011) M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis. PLoS One 6, e21106.
  • 169
    Liu CJ, Lee PH, Lin DY, Wu CC, Jeng LB, Lin PW, Mok KT, Lee WC, Yeh HZ, Ho MC et al. (2009) Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol 50, 958968.
  • 170
    Yang I, Han SJ, Kaur G, Crane C & Parsa AT (2010) The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17, 610.
  • 171
    Thorne RG, Lakkaraju A, Rodriguez-Boulan E & Nicholson C (2008) In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate. Proc Natl Acad Sci USA 105, 84168421.
  • 172
    Dmitrieva N, Yu L, Viapiano M, Cripe TP, Chiocca EA, Glorioso JC & Kaur B (2011) Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy. Clin Cancer Res 17, 13621372.
  • 173
    Christianson HC, van Kuppevelt TH & Belting M (2012) ScFv anti-heparan sulfate antibodies unexpectedly activate endothelial and cancer cells through p38 MAPK: implications for antibody-based targeting of heparan sulfate proteoglycans in cancer. PLoS One 7, e49092.
  • 174
    Joensuu H, Anttonen A, Eriksson M, Makitaro R, Alfthan H, Kinnula V & Leppa S (2002) Soluble syndecan-1 and serum basic fibroblast growth factor are new prognostic factors in lung cancer. Cancer Res 62, 52105217.
  • 175
    Taguchi A, Politi K, Pitteri SJ, Lockwood WW, Faca VM, Kelly-Spratt K, Wong CH, Zhang Q, Chin A, Park KS et al. (2011) Lung cancer signatures in plasma based on proteome profiling of mouse tumor models. Cancer Cell 20, 289299.
  • 176
    Esko JD, Kimata K & Lindahl U (2009) Proteoglycans and sulfated glycosaminoglycans. In Essentials of Glycobiology (Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW & Etzler ME, eds), Chapter 16. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.