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TGF-beta in neural stem cells and in tumors of the central nervous system

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Abstract

Mechanisms that regulate neural stem cell activity in the adult brain are tightly coordinated. They provide new neurons and glia in regions associated with high cellular and functional plasticity, after injury, or during neurodegeneration. Because of the proliferative and plastic potential of neural stem cells, they are currently thought to escape their physiological control mechanisms and transform to cancer stem cells. Signals provided by proteins of the transforming growth factor (TGF)-beta family might represent a system by which neural stem cells are controlled under physiological conditions but released from this control after transformation to cancer stem cells. TGF-beta is a multifunctional cytokine involved in various physiological and patho-physiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegeneration when it modulates and dampens inflammatory responses. After injury, although TGF-beta is neuroprotective, it may limit the self-repair of the brain by inhibiting neural stem cell proliferation. Similar to its effect on neural stem cells, TGF-beta reveals anti-proliferative control on most cell types; however, paradoxically, many brain tumors escape from TGF-beta control. Moreover, brain tumors develop mechanisms that change the anti-proliferative influence of TGF-beta into oncogenic cues, mainly by orchestrating a multitude of TGF-beta-mediated effects upon matrix, migration and invasion, angiogenesis, and, most importantly, immune escape mechanisms. Thus, TGF-beta is involved in tumor progression. This review focuses on TGF-beta and its role in the regulation and control of neural and of brain-cancer stem cells.

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References

  1. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 97:12846–12851

  2. Ackman JB, Siddiqi F, Walikonis RS, LoTurco JJ (2006) Fusion of microglia with pyramidal neurons after retroviral infection. J Neurosci 26:11413–11422

  3. Alexson TO, Hitoshi S, Coles BL, Bernstein A, Kooy D van der (2006) Notch signaling is required to maintain all neural stem cell populations—irrespective of spatial or temporal niche. Dev Neurosci 28:34–48

  4. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973

  5. Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116:217–224

  6. 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 96:1560–1568

  7. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970

  8. Ata KA, Lennmyr F, Funa K, Olsson Y, Terent A (1999) Expression of transforming growth factor-beta1, 2, 3 isoforms and type I and II receptors in acute focal cerebral ischemia: an immunohistochemical study in rat after transient and permanent occlusion of middle cerebral artery. Acta Neuropathol (Berl) 97:447–455

  9. Baghdassarian D, Toru-Delbauffe D, Gavaret JM, Pierre M (1993) Effects of transforming growth factor-beta 1 on the extracellular matrix and cytoskeleton of cultured astrocytes. Glia 7:193–202

  10. Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner P, Aigner L, Brawanski A, Bogdahn U, Beier C (2007) CD133+ and CD133- glioblastoma derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67:4010–4015

  11. Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA (2001) Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J Neurosci 21:6718–6731

  12. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL (2001) Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 12:27–36

  13. Bhowmick NA, Ghiassi M, Aakre M, Brown K, Singh V, Moses HL (2003) TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proc Natl Acad Sci USA 100:15548–15553

  14. Bierie B, Moses HL (2006) Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6:506–520

  15. Bitzer M, Gersdorff G von, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M, Bottinger EP (2000) A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev 14:187–197

  16. Boche D, Cunningham C, Docagne F, Scott H, Perry VH (2006) TGFbeta1 regulates the inflammatory response during chronic neurodegeneration. Neurobiol Dis 22:638–650

  17. Border WA, Noble NA (1997) TGF-beta in kidney fibrosis: a target for gene therapy. Kidney Int 51:1388–1396

  18. Bottner M, Unsicker K, Suter-Crazzolara C (1996) Expression of TGF-beta type II receptor mRNA in the CNS. Neuroreport 7:2903–2907

  19. Bottner M, Krieglstein K, Unsicker K (2000) The transforming growth factor-betas: structure, signaling, and roles in nervous system development and functions. J Neurochem 75:2227–2240

  20. Breier G, Blum S, Peli J, Groot M, Wild C, Risau W, Reichmann E (2002) Transforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis. Int J Cancer 97:142–148

  21. Brionne TC, Tesseur I, Masliah E, Wyss-Coray T (2003) Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 40:1133–1145

  22. Bruna A, Darken RS, Rojo F, Ocana A, Penuelas S, Arias A, Paris R, Tortosa A, Mora J, Baselga J, Seoane J (2007) High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11:147–160

  23. Buckwalter MS, Yamane M, Coleman BS, Ormerod BK, Chin JT, Palmer T, Wyss-Coray T (2006) Chronically increased transforming growth factor-beta1 strongly inhibits hippocampal neurogenesis in aged mice. Am J Pathol 169:154–164

  24. Bye N, Zieba M, Wreford NG, Nichols NR (2001) Resistance of the dentate gyrus to induced apoptosis during ageing is associated with increases in transforming growth factor-beta1 messenger RNA. Neuroscience 105:853–862

  25. Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255:197–200

  26. Cairns J (2006) Cancer and the immortal strand hypothesis. Genetics 174:1069–1072

  27. Carlson ME, Conboy IM (2007) Regulating the Notch pathway in embryonic, adult and old stem cells. Curr Opin Pharmacol 7:303–309

  28. Cayouette M, Raff M (2002) Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals. Nat Neurosci 5:1265–1269

  29. Cayouette M, Whitmore AV, Jeffery G, Raff M (2001) Asymmetric segregation of Numb in retinal development and the influence of the pigmented epithelium. J Neurosci 21:5643–5651

  30. Close JL, Gumuscu B, Reh TA (2005) Retinal neurons regulate proliferation of postnatal progenitors and Muller glia in the rat retina via TGF{beta} signaling. Development 132:3015–3026

  31. Conboy MJ, Karasov AO, Rando TA (2007) High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol 5:e102

  32. Constam DB, Philipp J, Malipiero UV, Dijke P ten, Schachner M, Fontana A (1992) Differential expression of transforming growth factor-beta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia. J Immunol 148:1404–1410

  33. Constam DB, Schmid P, Aguzzi A, Schachner M, Fontana A (1994) Transient production of TGF-beta 2 by postnatal cerebellar neurons and its effect on neuroblast proliferation. Eur J Neurosci 6:766–778

  34. Cordenonsi M, Montagner M, Adorno M, Zacchigna L, Martello G, Mamidi A, Soligo S, Dupont S, Piccolo S (2007) Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation. Science 315:840–843

  35. Couillard-Despres S, Uyanik G, Ploetz S, Karl C, Koch H, Winkler J, Aigner L (2004) Mitotic impairment by doublecortin is diminished by doublecortin mutations found in patients. Neurogenetics 5:83–93

  36. D’Abronzo FH, Swearingen B, Klibanski A, Alexander JM (1999) Mutational analysis of activin/transforming growth factor-beta type I and type II receptor kinases in human pituitary tumors. J Clin Endocrinol Metab 84:1716–1721

  37. Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913–1925

  38. de Caestecker MP, Parks WT, Frank CJ, Castagnino P, Bottaro DP, Roberts AB, Lechleider RJ (1998) Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev 12:1587–1592

  39. De Groot CJ, Montagne L, Barten AD, Sminia P, Van Der Valk P (1999) Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 isoforms and TGF-beta type I and type II receptors in multiple sclerosis lesions and human adult astrocyte cultures. J Neuropathol Exp Neurol 58:174–187

  40. de Sampaio e Spohr TC, Martinez R, Silva EF da, Neto VM, Gomes FC (2002) Neuro-glia interaction effects on GFAP gene: a novel role for transforming growth factor-beta1. Eur J Neurosci 16:2059–2069

  41. Dennler S, Goumans MJ, Dijke P ten (2002) Transforming growth factor beta signal transduction. J Leukoc Biol 71:731–740

  42. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584

  43. Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringman TS, Berger WH (1987) Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res 47:707–712

  44. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29:117–129

  45. Diebold RJ, Eis MJ, Yin M, Ormsby I, Boivin GP, Darrow BJ, Saffitz JE, Doetschman T (1995) Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA 92:12215–12219

  46. Engel ME, Datta PK, Moses HL (1998) RhoB is stabilized by transforming growth factor beta and antagonizes transcriptional activation. J Biol Chem 273:9921–9926

  47. Engel ME, McDonnell MA, Law BK, Moses HL (1999) Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem 274:37413–37420

  48. Fan X, Salford LG, Widegren B (2007) Glioma stem cells: evidence and limitation. Semin Cancer Biol 17:214–218

  49. Farkas LM, Dunker N, Roussa E, Unsicker K, Krieglstein K (2003) Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J Neurosci 23:5178–5186

  50. Faulkner NE, Dujardin DL, Tai CY, Vaughan KT, O’Connell CB, Wang Y, Vallee RB (2000) A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nat Cell Biol 2:784–791

  51. Feng XH, Derynck R (2005) Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 21:659–693

  52. Flanders KC, Ludecke G, Engels S, Cissel DS, Roberts AB, Kondaiah P, Lafyatis R, Sporn MB, Unsicker K (1991) Localization and actions of transforming growth factor-betas in the embryonic nervous system. Development 113:183–191

  53. Flanders KC, Ren RF, Lippa CF (1998) Transforming growth factor-betas in neurodegenerative disease. Prog Neurobiol 54:71–85

  54. Fontana A, Bodmer S, Frei K, Malipiero U, Siepl C (1991) Expression of TGF-beta 2 in human glioblastoma: a role in resistance to immune rejection? Ciba Found Symp 157:232–241

  55. Friese MA, Wischhusen J, Wick W, Weiler M, Eisele G, Steinle A, Weller M (2004) RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 64:7596–7603

  56. Fujiwara K, Ikeda H, Yoshimoto T (1998) Abnormalities in expression of genes, mRNA, and proteins of transforming growth factor-beta receptor type I and type II in human pituitary adenomas. Clin Neuropathol 17:19–26

  57. Funaba M, Zimmerman CM, Mathews LS (2002) Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J Biol Chem 277:41361–41368

  58. Gaiano N, Nye JS, Fishell G (2000) Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26:395–404

  59. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021

  60. Galter D, Bottner M, Unsicker K (1999) Developmental regulation of the serotonergic transmitter phenotype in rostral and caudal raphe neurons by transforming growth factor-betas. J Neurosci Res 56:531–538

  61. Gil-Perotin S, Marin-Husstege M, Li J, Soriano-Navarro M, Zindy F, Roussel MF, Garcia-Verdugo JM, Casaccia-Bonnefil P (2006) Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors. J Neurosci 26:1107–1116

  62. Gomes FC, Sousa Vde O, Romao L (2005) Emerging roles for TGF-beta1 in nervous system development. Int J Dev Neurosci 23:413–424

  63. Gotz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6:777–788

  64. Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K, Pandolfi PP (2005) Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437:147–153

  65. Guo M, Jan LY, Jan YN (1996) Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron 17:27–41

  66. Hau P, Kunz-Schughart LA, Rummele P, Arslan F, Dorfelt A, Koch H, Lohmeier A, Hirschmann B, Muller A, Bogdahn U, Bosserhoff AK (2006) Tenascin-C protein is induced by transforming growth factor-beta1 but does not correlate with time to tumor progression in high-grade gliomas. J Neurooncol 77:1–7

  67. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Gotz M (2002) Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 5:308–315

  68. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183

  69. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57

  70. Hunter KE, Sporn MB, Davies AM (1993) Transforming growth factor-betas inhibit mitogen-stimulated proliferation of astrocytes. Glia 7:203–211

  71. Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206

  72. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K (1997) Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389:622–626

  73. Izumoto S, Arita N, Ohnishi T, Hiraga S, Taki T, Tomita N, Ohue M, Hayakawa T (1997) Microsatellite instability and mutated type II transforming growth factor-beta receptor gene in gliomas. Cancer Lett 112:251–256

  74. Jachimczak P, Bogdahn U, Schneider J, Behl C, Meixensberger J, Apfel R, Dorries R, Schlingensiepen KH, Brysch W (1993) The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J Neurosurg 78:944–951

  75. Jachimczak P, Fabel-Schulte K, Hessdorfer B, Brysch W, Schlingensiepen KH, Blesch A, Bogdahn U (1995) Transforming growth factor-beta-mediated regulation of human peripheral blood mononuclear cell proliferation as detected with phosphorothioate antisense oligodeoxynucleotides. Cell Immunol 165:125–133

  76. Jachimczak P, Hessdorfer B, Fabel-Schulte K, Wismeth C, Brysch W, Schlingensiepen KH, Bauer A, Blesch A, Bogdahn U (1996) Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides. Int J Cancer 65:332–337

  77. Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, Alvarez-Buylla A (2006) PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51:187–199

  78. Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, Shen J, Mao Y, Banwait S, Greenberg DA (2006) Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci USA 103:13198–13202

  79. Johns LD, Babcock G, Green D, Freedman M, Sriram S, Ransohoff RM (1992) Transforming growth factor-beta 1 differentially regulates proliferation and MHC class-II antigen expression in forebrain and brainstem astrocyte primary cultures. Brain Res 585:229–236

  80. Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355:1253–1261

  81. Karl C, Couillard-Despres S, Prang P, Munding M, Kilb W, Brigadski T, Ploetz S, Mages W, Luhmann H, Winkler J, Bogdahn U, Aigner L (2005) Neuronal presursor specific activity of a human doublecortin regulatory sequence. J Neurochem 92:264–282

  82. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T (2000) BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 275:17647–17652

  83. Kjellman C, Olofsson SP, Hansson O, Von Schantz T, Lindvall M, Nilsson I, Salford LG, Sjogren HO, Widegren B (2000) Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer 89:251–258

  84. Kluppel M, Wrana JL (2005) Turning it up a Notch: cross-talk between TGF beta and Notch signaling. Bioessays 27:115–118

  85. Kondo T, Raff M (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289:1754–1757

  86. Koochekpour S, Merzak A, Pilkington GJ (1996) Vascular endothelial growth factor production is stimulated by gangliosides and TGF-beta isoforms in human glioma cells in vitro. Cancer Lett 102:209–215

  87. Kretzschmar M, Doody J, Timokhina I, Massague J (1999) A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev 13:804–816

  88. Krieglstein K, Farkas L, Unsicker K (1998a) TGF-beta regulates the survival of ciliary ganglionic neurons synergistically with ciliary neurotrophic factor and neurotrophins. J Neurobiol 37:563–572

  89. Krieglstein K, Reuss B, Maysinger D, Unsicker K (1998b) Short communication: transforming growth factor-beta mediates the neurotrophic effect of fibroblast growth factor-2 on midbrain dopaminergic neurons. Eur J Neurosci 10:2746–2750

  90. Krieglstein K, Henheik P, Farkas L, Jaszai J, Galter D, Krohn K, Unsicker K (1998c) Glial cell line-derived neurotrophic factor requires transforming growth factor-beta for exerting its full neurotrophic potential on peripheral and CNS neurons. J Neurosci 18:9822–9834

  91. Krieglstein K, Strelau J, Schober A, Sullivan A, Unsicker K (2002) TGF-beta and the regulation of neuron survival and death. J Physiol (Paris) 96:25–30

  92. Labbe E, Letamendia A, Attisano L (2000) Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and Wnt pathways. Proc Natl Acad Sci USA 97:8358–8363

  93. Lehrmann E, Kiefer R, Christensen T, Toyka KV, Zimmer J, Diemer NH, Hartung HP, Finsen B (1998) Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. Glia 24:437–448

  94. Letamendia A, Labbe E, Attisano L (2001) Transcriptional regulation by Smads: crosstalk between the TGF-beta and Wnt pathways. J Bone Joint Surg Am 83-A (Suppl 1):S31–S39

  95. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146

  96. Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:1370–1375

  97. Lin AH, Luo J, Mondshein LH, Dijke P ten, Vivien D, Contag CH, Wyss-Coray T (2005) Global analysis of Smad2/3-dependent TGF-beta signaling in living mice reveals prominent tissue-specific responses to injury. J Immunol 175:547–554

  98. Lindholm D, Castren E, Kiefer R, Zafra F, Thoenen H (1992) Transforming growth factor-beta 1 in the rat brain: increase after injury and inhibition of astrocyte proliferation. J Cell Biol 117:395–400

  99. Machein MR, Plate KH (2004) Role of VEGF in developmental angiogenesis and in tumor angiogenesis in the brain. Cancer Treat Res 117:191–218

  100. Malatesta P, Hack MA, Hartfuss E, Kettenmann H, Klinkert W, Kirchhoff F, Gotz M (2003) Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37:751–764

  101. Marino S (2005) Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 11:17–22

  102. Massague J (1990) The transforming growth factor-beta family. Annu Rev Cell Biol 6:597–641

  103. Massague J (1992) Receptors for the TGF-beta family. Cell 69:1067–1070

  104. Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791

  105. Massague J (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1:169–178

  106. Massague J, Chen YG (2000) Controlling TGF-beta signaling. Genes Dev 14:627–644

  107. Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309

  108. Mazars A, Lallemand F, Prunier C, Marais J, Ferrand N, Pessah M, Cherqui G, Atfi A (2001) Evidence for a role of the JNK cascade in Smad7-mediated apoptosis. J Biol Chem 276:36797–36803

  109. McKinnon RD, Piras G, Ida JA Jr, Dubois-Dalcq M (1993) A role for TGF-beta in oligodendrocyte differentiation. J Cell Biol 121:1397–1407

  110. Mendelsohn ML (1960) The growth fraction: a new concept applied to neoplasia. Science 132:1496

  111. Merok JR, Lansita JA, Tunstead JR, Sherley JL (2002) Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics. Cancer Res 62:6791–6795

  112. Merzak A, McCrea S, Koocheckpour S, Pilkington GJ (1994) Control of human glioma cell growth, migration and invasion in vitro by transforming growth factor beta 1. Br J Cancer 70:199–203

  113. Miller MW (2003) Expression of transforming growth factor-beta in developing rat cerebral cortex: effects of prenatal exposure to ethanol. J Comp Neurol 460:410–424

  114. Miller MW, Luo J (2002) Effects of ethanol and transforming growth factor beta (TGF beta) on neuronal proliferation and nCAM expression. Alcohol Clin Exp Res 26:1281–1285

  115. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

  116. Mittaud P, Labourdette G, Zingg H, Guenot-Di Scala D (2002) Neurons modulate oxytocin receptor expression in rat cultured astrocytes: involvement of TGF-beta and membrane components. Glia 37:169–177

  117. Miyake K, Kimura S, Nakanishi M, Hisada A, Hasegawa M, Nagao S, Abe Y (2000) Transforming growth factor-beta1 stimulates contraction of human glioblastoma cell-mediated collagen lattice through enhanced alpha2 integrin expression. J Neuropathol Exp Neurol 59:18–28

  118. Modena P, Lualdi E, Facchinetti F, Veltman J, Reid JF, Minardi S, Janssen I, Giangaspero F, Forni M, Finocchiaro G, Genitori L, Giordano F, Riccardi R, Schoenmakers EF, Massimino M, Sozzi G (2006) Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol 24:5223–5233

  119. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967

  120. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765

  121. Morganti-Kossmann MC, Kossmann T, Brandes ME, Mergenhagen SE, Wahl SM (1992) Autocrine and paracrine regulation of astrocyte function by transforming growth factor-beta. J Neuroimmunol 39:163–173

  122. Morita N, Takumi T, Kiyama H (1996) Distinct localization of two serine-threonine kinase receptors for activin and TGF-beta in the rat brain and down-regulation of type I activin receptor during peripheral nerve regeneration. Brain Res Mol Brain Res 42:263–271

  123. Moses HL, Branum EL, Proper JA, Robinson RA (1981) Transforming growth factor production by chemically transformed cells. Cancer Res 41:2842–2848

  124. Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118:3573–3584

  125. Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, Zent R, Arteaga CL (2006) Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 25:3408–3423

  126. Nakao A, Roijer E, Imamura T, Souchelnytskyi S, Stenman G, Heldin CH, Dijke P ten (1997) Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway. J Biol Chem 272:2896–2900

  127. Nickl-Jockschat T, Arslan F, Doerfelt A, Bogdahn U, Bosserhoff A, Hau P (2007) An imbalance between Smad and MAPK pathways is responsible for TGF-beta tumor promoting effects in high-grade gliomas. Int J Oncol 30:499–507

  128. Nicolis SK (2007) Cancer stem cells and "stemness" genes in neuro-oncology. Neurobiol Dis 25:217–229

  129. Niimi H, Pardali K, Vanlandewijck M, Heldin CH, Moustakas A (2007) Notch signaling is necessary for epithelial growth arrest by TGF-beta. J Cell Biol 176:695–707

  130. Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G, 2nd, Jiang L, Kang J, Nedergaard M, Goldman SA (2003) Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 9:439–447

  131. Ohgaki H, Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol (Berl) 109:93–108

  132. Palmer TD, Markakis EA, Willhoite AR, Safar F, Gage FH (1999) Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 19:8487–8497

  133. Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813

  134. Paulus W, Baur I, Huettner C, Schmausser B, Roggendorf W, Schlingensiepen KH, Brysch W (1995) Effects of transforming growth factor-beta 1 on collagen synthesis, integrin expression, adhesion and invasion of glioma cells. J Neuropathol Exp Neurol 54:236–244

  135. Pelton RW, Saxena B, Jones M, Moses HL, Gold LI (1991) Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol 115:1091–1105

  136. Pessah M, Marais J, Prunier C, Ferrand N, Lallemand F, Mauviel A, Atfi A (2002) c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity. J Biol Chem 277:29094–29100

  137. Petersen PH, Zou K, Hwang JK, Jan YN, Zhong W (2002) Progenitor cell maintenance requires Numb and Numblike during mouse neurogenesis. Nature 419:929–934

  138. Petersen PH, Zou K, Krauss S, Zhong W (2004) Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis. Nat Neurosci 7:803–811

  139. Petritsch C, Beug H, Balmain A, Oft M (2000) TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest. Genes Dev 14:3093–3101

  140. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765

  141. Platten M, Wick W, Wild-Bode C, Aulwurm S, Dichgans J, Weller M (2000) Transforming growth factors beta(1) (TGF-beta(1)) and TGF-beta(2) promote glioma cell migration via up-regulation of alpha(V)beta(3) integrin expression. Biochem Biophys Res Commun 268:607–611

  142. Platten M, Wick W, Weller M (2001) Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52:401–410

  143. Poulsen KT, Armanini MP, Klein RD, Hynes MA, Phillips HS, Rosenthal A (1994) TGF beta 2 and TGF beta 3 are potent survival factors for midbrain dopaminergic neurons. Neuron 13:1245–1252

  144. Rambhatla L, Ram-Mohan S, Cheng JJ, Sherley JL (2005) Immortal DNA strand cosegregation requires p53/IMPDH-dependent asymmetric self-renewal associated with adult stem cells. Cancer Res 65:3155–3161

  145. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

  146. Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF (1999) Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem 274:35053–35058

  147. Roberts AB (1998) Molecular and cell biology of TGF-beta. Miner Electrolyte Metab 24:111–119

  148. Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 100:8621–8623

  149. Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB (1981) New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci USA 78:5339–5343

  150. Rooprai HK, Rucklidge GJ, Panou C, Pilkington GJ (2000) The effects of exogenous growth factors on matrix metalloproteinase secretion by human brain tumour cells. Br J Cancer 82:52–55

  151. Roussa E, Krieglstein K (2004) Induction and specification of midbrain dopaminergic cells: focus on SHH, FGF8, and TGF-beta. Cell Tissue Res 318:23–33

  152. Roussa E, Farkas LM, Krieglstein K (2004) TGF-beta promotes survival on mesencephalic dopaminergic neurons in cooperation with SHH and FGF-8. Neurobiol Dis 16:300–310

  153. Samuels V, Barrett JM, Bockman S, Pantazis CG, Allen MB Jr (1989) Immunocytochemical study of transforming growth factor expression in benign and malignant gliomas. Am J Pathol 134:894–902

  154. Santra M, Zhang X, Santra S, Jiang F, Chopp M (2006) Ectopic doublecortin gene expression suppresses the malignant phenotype in glioblastoma cells. Cancer Res 66:11726–11735

  155. Savarese TM, Jang T, Low HP, Salmonsen R, Litofsky NS, Matuasevic Z, Ross AH, Recht LD (2005) Isolation of immortalized, INK4a/ARF-deficient cells from the subventricular zone after in utero N-ethyl-N-nitrosourea exposure. J Neurosurg 102:98–108

  156. Schlingensiepen R, Goldbrunner M, Szyrach MN, Stauder G, Jachimczak P, Bogdahn U, Schulmeyer F, Hau P, Schlingensiepen KH (2005) Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 15:94–104

  157. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B, Jachimczak P (2006) Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine Growth Factor Rev 17:129–139

  158. Seoane J (2006) Escaping from the TGFbeta anti-proliferative control. Carcinogenesis 27:2148–2156

  159. Shen Q, Zhong W, Jan YN, Temple S (2002) Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 129:4843–4853

  160. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700

  161. Shi Y, Wang YF, Jayaraman L, Yang H, Massague J, Pavletich NP (1998) Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94:585–594

  162. Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S (2006) Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol 8:677–687

  163. Siegel PM, Massague J (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3:807–821

  164. Siegenthaler JA, Miller MW (2004) Transforming growth factor beta1 modulates cell migration in rat cortex: effects of ethanol. Cereb Cortex 14:791–802

  165. Siepl C, Bodmer S, Frei K, MacDonald HR, De Martin R, Hofer E, Fontana A (1988) The glioblastoma-derived T cell suppressor factor/transforming growth factor-beta 2 inhibits T cell growth without affecting the interaction of interleukin 2 with its receptor. Eur J Immunol 18:593–600

  166. Siller KH, Serr M, Steward R, Hays TS, Doe CQ (2005) Live imaging of Drosophila brain neuroblasts reveals a role for Lis1/dynactin in spindle assembly and mitotic checkpoint control. Mol Biol Cell 16:5127–5140

  167. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

  168. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

  169. Souchelnytskyi S, Tamaki K, Engstrom U, Wernstedt C, Dijke P ten, Heldin CH (1997) Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem 272:28107–28115

  170. Sousa Vde O, Romao L, Neto VM, Gomes FC (2004) Glial fibrillary acidic protein gene promoter is differently modulated by transforming growth factor-beta 1 in astrocytes from distinct brain regions. Eur J Neurosci 19:1721–1730

  171. Sousa Vde O, Almeida JC, Eller CM, Gomes FC (2006) Characterization of TGF-beta1 type II receptor expression in cultured cortical astrocytes. In Vitro Cell Dev Biol Anim 42:171–175

  172. Stiles JD, Ostrow PT, Balos LL, Greenberg SJ, Plunkett R, Grand W, Heffner RR Jr (1997) Correlation of endothelin-1 and transforming growth factor beta 1 with malignancy and vascularity in human gliomas. J Neuropathol Exp Neurol 56:435–439

  173. Suzumura A, Sawada M, Yamamoto H, Marunouchi T (1993) Transforming growth factor-beta suppresses activation and proliferation of microglia in vitro. J Immunol 151:2150–2158

  174. Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson RJ (2005) Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8:323–335

  175. Thomas DA, Massague J (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8:369–380

  176. Toyo-Oka K, Sasaki S, Yano Y, Mori D, Kobayashi T, Toyoshima YY, Tokuoka SM, Ishii S, Shimizu T, Muramatsu M, Hiraiwa N, Yoshiki A, Wynshaw-Boris A, Hirotsune S (2005) Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration. Hum Mol Genet 14:3113–3128

  177. Tysnes BB, Bjerkvig R (2007) Cancer initiation and progression: Involvement of stem cells and the microenvironment. Biochim Biophys Acta 1775:283–297

  178. Uhm JH, Gladson CL, Rao JS (1999a) The role of integrins in the malignant phenotype of gliomas. Front Biosci 4:D188–D199

  179. Uhm JH, Dooley NP, Kyritsis AP, Rao JS, Gladson CL (1999b) Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res 5:1587–1594

  180. Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC (2002) Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res 62:5551–5558

  181. Ulloa L, Doody J, Massague J (1999) Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397:710–713

  182. Unsicker K, Krieglstein K (2002) TGF-betas and their roles in the regulation of neuron survival. Adv Exp Med Biol 513:353–374

  183. Unsicker K, Strelau J (2000) Functions of transforming growth factor-beta isoforms in the nervous system. Cues based on localization and experimental in vitro and in vivo evidence. Eur J Biochem 267:6972–6975

  184. Unsicker K, Flanders KC, Cissel DS, Lafyatis R, Sporn MB (1991) Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system. Neuroscience 44:613–625

  185. Vallieres L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22:486–492

  186. Vergeli M, Mazzanti B, Ballerini C, Gran B, Amaducci L, Massacesi L (1995) Transforming growth factor-beta 1 inhibits the proliferation of rat astrocytes induced by serum and growth factors. J Neurosci Res 40:127–133

  187. Vivien D, Bernaudin M, Buisson A, Divoux D, MacKenzie ET, Nouvelot A (1998) Evidence of type I and type II transforming growth factor-beta receptors in central nervous tissues: changes induced by focal cerebral ischemia. J Neurochem 70:2296–2304

  188. Vroemen M, Aigner L, Winkler J, Weidner N (2003) Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci 18:743–751

  189. Wachs FP, Winner B, Couillard-Despres S, Schiller T, Aigner R, Winkler J, Bogdahn U, Aigner L (2006) Transforming growth factor-beta1 is a negative modulator of adult neurogenesis. J Neuropathol Exp Neurol 65:358–370

  190. Wakefield LM, Roberts AB (2002) TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12:22–29

  191. Weber RG, Bridger JM, Benner A, Weisenberger D, Ehemann V, Reifenberger G, Lichter P (1998) Centrosome amplification as a possible mechanism for numerical chromosome aberrations in cerebral primitive neuroectodermal tumors with TP53 mutations. Cytogenet Cell Genet 83:266–269

  192. Wick W, Platten M, Weller M (2001) Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta. J Neurooncol 53:177–185

  193. Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR 3rd, Nusse R (2003) Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423:448–452

  194. Winner B, Lie DC, Rockenstein E, Aigner R, Aigner L, Masliah E, Kuhn HG, Winkler J (2004) Human wild-type alpha-synuclein impairs neurogenesis. J Neuropathol Exp Neurol 63:1155–1166

  195. Winner B, Rockenstein E, Lie DC, Aigner R, Mante M, Bogdahn U, Couillard-Depres S, Masliah E, Winkler J (2007) Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis. Neurobiol Aging Jan 30 [Epub ahead of print] PMID:17275140

  196. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370:341–347

  197. Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35:419–432

  198. Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K (1999) XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J 18:179–187

  199. Yamashita H, ten Dijke P, Franzen P, Miyazono K, Heldin CH (1994) Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta. J Biol Chem 269:20172–20178

  200. Yamashita YM, Jones DL, Fuller MT (2003) Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301:1547–1550

  201. Yamashita YM, Mahowald AP, Perlin JR, Fuller MT (2007) Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315:518–521

  202. Yi JY, Shin I, Arteaga CL (2005) Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase. J Biol Chem 280:10870–10876

  203. Yu L, Hebert MC, Zhang YE (2002) TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 21:3749–3759

  204. Yue J, Mulder KM (2000) Requirement of Ras/MAPK pathway activation by transforming growth factor beta for transforming growth factor beta 1 production in a Smad-dependent pathway. J Biol Chem 275:35656

  205. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23:1155–1165

  206. Zhu Y, Roth-Eichhorn S, Braun N, Culmsee C, Rami A, Krieglstein J (2000) The expression of transforming growth factor-beta1 (TGF-beta1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat. Brain Res 866:286–298

  207. Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF (2005) Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8:119–130

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Acknowledgements

The authors thank Peter Hau for his input on TGF-beta and brain tumors, and Claudia Karl for editorial assistance.

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Correspondence to Ludwig Aigner.

Additional information

This work was supported by the German Federal Ministry of Education and Research (BMBF no. 01GA0510 and no. 0312134) and by the Bavarian State Ministry of Sciences, Research and the Arts, "Forneurocell grant".

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Aigner, L., Bogdahn, U. TGF-beta in neural stem cells and in tumors of the central nervous system. Cell Tissue Res 331, 225–241 (2008). https://doi.org/10.1007/s00441-007-0466-7

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Keywords

  • Neurogenesis
  • Smad signaling
  • Cancer
  • Stem cells
  • Immune system
  • Brain