Biological Horizons for Targeting Brain Malignancy

  • Samuel A. Hughes
  • Pragathi Achanta
  • Allen L. Ho
  • Vincent J. Duenas
  • Alfredo Quiñones-Hinojosa
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 671)


Though currently available clinical treatments and therapies have clearly extended the survival of patients with brain tumors, many of these advances are short lived, particularly with respect to high grade gliomas such as glioblastoma multiforme. The missing link to an efficacious treatment of high grade gliomas is a more complete understanding of the basic molecular and cellular origin of brain tumors. However, new discoveries of stem cell and developmental neurobiology have now borne the cancer stem cell hypothesis, drawing off of intriguing similarities between benign and malignant cells within the central nervous system. Investigation of cancer stem cell hypothesis and brain tumor propagation is the current frontier of stem cell and cancer biology. Neurosurgery is also watching closely this promising new area of focus. “Molecular neurosurgery”, glioma treatments involving biologics using neural stem cells to target the cancer at the level of individual migratory cell, is a rapidly evolving field. This coming progression of applied cancer stem cell research, coupled with current modalities, promises more comprehensive brain cancer interventions.


Stem Cell Vascular Endothelial Growth Factor Brain Tumor Glioma Cell Cancer Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10):987–96.PubMedCrossRefGoogle Scholar
  2. 2.
    CBTRUS. CBTRUS Primary Brain Tumors in the United States. Central Brain Tumor Registry of the United States; 2005-2006.Google Scholar
  3. 3.
    Louis DN, Ohgaki H, Wiestler OD et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl) 2007; 114(2):97–109.CrossRefGoogle Scholar
  4. 4.
    Laws ER, Parney IF, Huang W et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 2003; 99(3):467–73.PubMedCrossRefGoogle Scholar
  5. 5.
    Chang SM, Parney IF, Huang W et al. Patterns of care for adults with newly diagnosed malignant glioma. JAMA 2005; 293(5):557–64.PubMedCrossRefGoogle Scholar
  6. 6.
    DeAngelis LM. Brain tumors. N Engl J Med 2001; 344(2):114–23.PubMedCrossRefGoogle Scholar
  7. 7.
    McGirt MJ, Chaichana KL, Attenello FJ et al. Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neurosurgery 2008; 63(4):700–7; author reply 7–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965; 124(3):319–35.CrossRefGoogle Scholar
  9. 9.
    Altman J, Das GD. Autoradiographic and histological studies of postnatal neurogenesis. I. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions. J Comp Neurol 1966; 126(3):337–89.PubMedCrossRefGoogle Scholar
  10. 10.
    Gage FH, Kempermann G, Palmer TD et al. Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol 1998; 36(2):249–66.PubMedCrossRefGoogle Scholar
  11. 11.
    Quinones-Hinojosa A, Chaichana K. The human subventricular zone: a source of new cells and a potential source of brain tumors. Exp Neurol 2007; 205(2):313–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Quinones-Hinojosa A, Sanai N, Soriano-Navarro M et al. Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol 2006; 494(3):415–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Aboody KS, Brown A, Rainov NG et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 2000; 97(23):12846–51.PubMedCrossRefGoogle Scholar
  14. 14.
    Hemmati HD, Nakano I, Lazareff JA et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 2003; 100(25):15178–83.PubMedCrossRefGoogle Scholar
  15. 15.
    Galli R, Binda E, Orfanelli U et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004; 64(19):7011–21.PubMedCrossRefGoogle Scholar
  16. 16.
    Singh SK, Clarke ID, Terasaki M et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63(18):5821–8.PubMedGoogle Scholar
  17. 17.
    Singh SK, Hawkins C, Clarke ID et al. Identification of human brain tumour initiating cells. Nature 2004; 432(7015):396–401.PubMedCrossRefGoogle Scholar
  18. 18.
    Yuan X, Curtin J, Xiong Y et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 2004; 23(58):9392–400.PubMedCrossRefGoogle Scholar
  19. 19.
    Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med 2005; 353(8):811–22.PubMedCrossRefGoogle Scholar
  20. 20.
    Bachoo RM, Maher EA, Ligon KL et al. Epidermal growth factor receptor and Ink4α/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 2002; 1(3):269–77.PubMedCrossRefGoogle Scholar
  21. 21.
    Clarke MF. Neurobiology: at the root of brain cancer. Nature 2004; 432(7015):281–2.PubMedCrossRefGoogle Scholar
  22. 22.
    Berger F, Gay E, Pelletier L et al. Development of gliomas: potential role of asymmetrical cell division of neural stem cells. Lancet Oncol 2004; 5(8):511–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhu Y, Parada LF. The molecular and genetic basis of neurological tumours. Nat Rev Cancer 2002; 2(8):616–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Romer JT, Kimura H, Magdaleno S et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 2004; 6(3):229–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Nelson SJ, Cha S. Imaging glioblastoma multiforme. Cancer J 2003; 9(2):134–45.PubMedCrossRefGoogle Scholar
  26. 26.
    Benedetti S, Bruzzone MG, Pollo B et al. Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene. Cancer Res 1999; 59(3):645–52.PubMedGoogle Scholar
  27. 27.
    Ehtesham M, Kabos P, Kabosova A et al. The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 2002; 62(20):5657–63.PubMedGoogle Scholar
  28. 28.
    Laywell ED, Steindler DA, Silver DJ. Astrocytic stem cells in the adult brain. Neurosurg Clin N Am 2007; 18(1):21–30, viii.PubMedCrossRefGoogle Scholar
  29. 29.
    Campbell K, Olsson M, Bjorklund A. Regional incorporation and site-specific differentiation of striatal precursors transplanted to the embryonic forebrain ventricle. Neuron 1995; 15(6):1259–73.PubMedCrossRefGoogle Scholar
  30. 30.
    Sidman RL, Miale IL, Feder N. Cell proliferation and migration in the primitive ependymal zone: an autoradiographic study of histogenesis in the nervous system. Exp Neurol 1959; 1:322–33.PubMedCrossRefGoogle Scholar
  31. 31.
    Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992; 255(5052):1707–10.PubMedCrossRefGoogle Scholar
  32. 32.
    Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 1992; 12(11):4565–74.PubMedGoogle Scholar
  33. 33.
    Reubinoff BE, Pera MF, Vajta G et al. Effective cryopreservation of human embryonic stem cells by the open pulled straw vitrification method. Hum Reprod 2001; 16(10):2187–94.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang ZG, Jiang Q, Zhang R et al. Magnetic resonance imaging and neurosphere therapy of stroke in rat. Ann Neurol 2003; 53(2):259–63.PubMedCrossRefGoogle Scholar
  35. 35.
    Snyder EY, Deitcher DL, Walsh C et al. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 1992; 68(1):33–51.PubMedCrossRefGoogle Scholar
  36. 36.
    Palmer TD, Schwartz PH, Taupin P et al. Cell culture. Progenitor cells from human brain after death. Nature 2001; 411(6833):42–3PubMedCrossRefGoogle Scholar
  37. 37.
    Rosario CM, Yandava BD, Kosaras B et al. Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action. Development 1997; 124(21):4213–24.PubMedGoogle Scholar
  38. 38.
    Snyder EY, Yoon C, Flax JD et al. Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc Natl Acad Sci USA 1997; 94(21):11663–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Zlomanczuk P, Mrugala M, de la Iglesia HO et al. Transplanted clonal neural stem-like cells respond to remote photic stimulation following incorporation within the suprachiasmatic nucleus. Exp Neurol 2002; 174(2):162–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Park KI, Liu S, Flax JD et al. Transplantation of neural progenitor and stem cells: developmental insights may suggest new therapies for spinal cord and other CNS dysfunction. J Neurotrauma 1999; 16(8):675–87.PubMedCrossRefGoogle Scholar
  41. 41.
    Flax JD, Aurora S, Yang C et al. Engraftable human neural stem cells respond to developmental cues, replace neurons and express foreign genes. Nat Biotechnol 1998; 16(11):1033–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Yip S, Sabetrasekh R, Sidman RL et al. Neural stem cells as novel cancer therapeutic vehicles. Eur J Cancer 2006; 42(9):1298–308.PubMedCrossRefGoogle Scholar
  43. 43.
    Snyder EY, Loring JF. A role for stem cell biology in the physiological and pathological aspects of aging. J Am Geriatr Soc 2005; 53(9 Suppl):S287–91.CrossRefGoogle Scholar
  44. 44.
    Kosztowski T, Zaidi HA, Quinones-Hinojosa A. Applications of neural and mesenchymal stem cells in the treatment of gliomas. Expert Rev Anticancer Ther 2009; 9(5):597–612.PubMedCrossRefGoogle Scholar
  45. 45.
    Zaidi HA DMF, Quinones-Hinojosa A. Brain Tumor Stem Cells. In: Youman, ed. Textbook of Neurological Surgery. 6th ed, 2008.Google Scholar
  46. 46.
    Chaichana KL, McGirt MJ, Laterra J et al. Recurrence and malignant degeneration after resection of adult hemispheric low-grade gliomas. J Neurosurg 2009.Google Scholar
  47. 47.
    Benedetti S, Pirola B, Pollo B et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000; 6(4):447–50.PubMedCrossRefGoogle Scholar
  48. 48.
    Ehtesham M, Kabos P, Gutierrez MA et al. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 2002; 62(24):7170–4.PubMedGoogle Scholar
  49. 49.
    Barresi V, Belluardo N, Sipione S et al. Transplantation of prodrug-converting neural progenitor cells for brain tumor therapy. Cancer Gene Ther 2003; 10(5):396–402.PubMedCrossRefGoogle Scholar
  50. 50.
    Uhl M, Weiler M, Wick W et al. Migratory neural stem cells for improved thymidine kinase-based gene therapy of malignant gliomas. Biochem Biophys Res Commun 2005; 328(1):125–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Li S, Tokuyama T, Yamamoto J et al. Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther 2005; 12(7):600–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Darsalia V, Heldmann U, Lindvall O et al. Stroke-induced neurogenesis in aged brain. Stroke 2005; 36(8):1790–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Liu YP, Lang BT, Baskaya MK et al. The potential of neural stem cells to repair stroke-induced brain damage. Acta Neuropathol 2009.Google Scholar
  54. 54.
    Snethen H, Love S, Scolding N. disease-responsive neural precursor cells are present in multiple sclerosis lesions. Regen Med 2008; 3(6):835–47.PubMedCrossRefGoogle Scholar
  55. 55.
    Kendall SE, Najbauer J, Johnston HF et al. Neural stem cell targeting of glioma is dependent on phosphoinositide 3-kinase signaling. Stem Cells 2008; 26(6):1575–86.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhao D, Najbauer J, Garcia E et al. Neural stem cell tropism to glioma: critical role of tumor hypoxia. Mol Cancer Res 2008; 6(12):1819–29.PubMedCrossRefGoogle Scholar
  57. 57.
    Glass R, Synowitz M, Kronenberg G et al. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 2005; 25(10):2637–46.PubMedCrossRefGoogle Scholar
  58. 58.
    Fomchenko EI, Holland EC. Stem cells and brain cancer. Exp Cell Res 2005; 306(2):323–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Walzlein JH, Synowitz M, Engels B et al. The antitumorigenic response of neural precursors depends on subventricular proliferation and age. Stem Cells 2008; 26(11):2945–54.PubMedCrossRefGoogle Scholar
  60. 60.
    Klassen H. Recruitment of endogenous neural progenitor cells by malignant neoplasms of the central nervous system. Curr Stem Cell Res Ther 2007; 2(2):113–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Doetsch F, Petreanu L, Caille I et al. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 2002; 36(6):1021–34.PubMedCrossRefGoogle Scholar
  62. 62.
    Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000; 425(4):479–94.PubMedCrossRefGoogle Scholar
  63. 63.
    Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat Rev Cancer 2006; 6(6):425–36.PubMedCrossRefGoogle Scholar
  64. 64.
    Lim DA, Cha S, Mayo MC et al. Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 2007; 9(4):424–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Mineo JF, Bordron A, Baroncini M et al. Prognosis factors of survival time in patients with glioblastoma multiforme: a multivariate analysis of 340 patients. Acta Neurochir (Wien) 2007; 149(3):245–53.CrossRefGoogle Scholar
  66. 66.
    Chaichana KL, McGirt MJ, Frazier J et al. Relationship of glioblastoma multiforme to the lateral ventricles predicts survival following tumor resection. J Neurooncol 2008.Google Scholar
  67. 67.
    Snyder EY, Taylor RM, Wolfe JH. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 1995; 374(6520):367–70.PubMedCrossRefGoogle Scholar
  68. 68.
    Yandava BD, Billinghurst LL, Snyder EY. “Global” cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Proc Natl Acad Sci USA 1999; 96(12):7029–34.PubMedCrossRefGoogle Scholar
  69. 69.
    Lacorazza HD, Flax JD, Snyder EY et al. Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat Med 1996; 2(4):424–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Snyder EY, Park KI, Flax JD et al. Potential of neural “stem-like” cells for gene therapy and repair of the degenerating central nervous system. Adv Neurol 1997; 72:121–32.PubMedGoogle Scholar
  71. 71.
    Riess P, Zhang C, Saatman KE et al. Transplanted neural stem cells survive, differentiate and improve neurological motor function after experimental traumatic brain injury. Neurosurgery 2002; 51(4):1043–52; discussion 52-4.PubMedCrossRefGoogle Scholar
  72. 72.
    Yip S, Aboody KS, Burns M et al. Neural stem cell biology may be well suited for improving brain tumor therapies. Cancer J 2003; 9(3):189–204.PubMedCrossRefGoogle Scholar
  73. 73.
    Yip SS Rl, Snyder EY. Stem cells for targeting CNS malignancy. Principles of molecular neurosurgery: Basel: Karger Publishers, 2005;624–44.CrossRefGoogle Scholar
  74. 74.
    Erlandsson A, Larsson J, Forsberg-Nilsson K. Stem cell factor is a chemoattractant and a survival factor for CNS stem cells. Exp Cell Res 2004; 301(2):201–10.PubMedCrossRefGoogle Scholar
  75. 75.
    Widera D, Holtkamp W, Entschladen F et al. MCP-1 induces migration of adult neural stem cells. Eur J Cell Biol 2004; 83(8):381–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Sun L, Lee J, Fine HA. Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J Clin Invest 2004; 113(9):1364–74.PubMedGoogle Scholar
  77. 77.
    Serfozo P, Schlarman MS, Pierret C et al. Selective migration of neuralized embryonic stem cells to stem cell factor and media conditioned by glioma cell lines. Cancer Cell Int 2006; 6:1.PubMedCrossRefGoogle Scholar
  78. 78.
    Werbowetski T, Bjerkvig R, Del Maestro RF. Evidence for a secreted chemorepellent that directs glioma cell invasion. J Neurobiol 2004; 60(1):71–88.PubMedCrossRefGoogle Scholar
  79. 79.
    Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001; 2(2):108–15.PubMedCrossRefGoogle Scholar
  80. 80.
    Zagzag D, Esencay M, Mendez O et al. Hypoxia-and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer’s structures. Am J Pathol 2008; 173(2):545–60.PubMedCrossRefGoogle Scholar
  81. 81.
    Itoh T, Satou T, Ishida H et al. The relationship between SDF-1alpha/CXCR4 and neural stem cells appearing in damaged area after traumatic brain injury in rats. Neurol Res 2009; 31(1):90–102.PubMedCrossRefGoogle Scholar
  82. 82.
    Imitola J, Raddassi K, Park KI et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci USA 2004; 101(52):18117–22.PubMedCrossRefGoogle Scholar
  83. 83.
    Lazarini F, Tham TN, Casanova P et al. Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia 2003; 42(2):139–48.PubMedCrossRefGoogle Scholar
  84. 84.
    Rempel SA, Dudas S, Ge S et al. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 2000; 6(1):102–11.PubMedGoogle Scholar
  85. 85.
    Zhou Y, Larsen PH, Hao C et al. CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem 2002; 277(51):49481–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Rubin JB, Kung AL, Klein RS et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 2003; 100(23):13513–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Allport JR, Shinde Patil VR, Weissleder R. Murine neuronal progenitor cells are preferentially recruited to tumor vasculature via alpha4-integrin and SDF-1alpha-dependent mechanisms. Cancer Biol Ther 2004; 3(9):838–44.PubMedCrossRefGoogle Scholar
  88. 88.
    Fears CY, Sontheimer HW, Bullard DC et al. Could labeled neuronal progenitor cells be used to target glioma tumor endothelium? Cancer Biol Ther 2004; 3(9):845–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Ehtesham M, Yuan X, Kabos P et al. Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 2004; 6(3):287–93.PubMedCrossRefGoogle Scholar
  90. 90.
    Tabatabai G, Bahr O, Mohle R et al. Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells. Brain 2005; 128(Pt 9):2200–11.PubMedCrossRefGoogle Scholar
  91. 91.
    Pluchino S, Zanotti L, Rossi B et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005; 436(7048):266–71.PubMedCrossRefGoogle Scholar
  92. 92.
    Lee BC, Lee TH, Avraham S et al. Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res 2004; 2(6):327–38.PubMedGoogle Scholar
  93. 93.
    Liang Z, Wu T, Lou H et al. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res 2004; 64(12):4302–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Schmidt NO, Przylecki W, Yang W et al. Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 2005; 7(6):623–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Kaur B, Tan C, Brat DJ et al. Genetic and hypoxic regulation of angiogenesis in gliomas. J Neurooncol 2004; 70(2):229–43.PubMedCrossRefGoogle Scholar
  96. 96.
    Lambrechts D, Carmeliet P. VEGF at the neurovascular interface: therapeutic implications for motor neuron disease. Biochim Biophys Acta 2006; 1762(11–12):1109–21.PubMedGoogle Scholar
  97. 97.
    Cross MJ, Dixelius J, Matsumoto T et al. VEGF-receptor signal transduction. Trends Biochem Sci 2003; 28(9):488–94.PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang H, Vutskits L, Pepper MS et al. VEGF is a chemoattractant for FGF-2-stimulated neural progenitors. J Cell Biol 2003; 163(6):1375–84.PubMedCrossRefGoogle Scholar
  99. 99.
    Schmidt NO, Koeder D, Messing M et al. Vascular endothelial growth factor-stimulated cerebral microvascular endothelial cells mediate the recruitment of neural stem cells to the neurovascular niche. Brain Res 2009.Google Scholar
  100. 100.
    Feldkamp MM, Lau N, Guha A. Signal transduction pathways and their relevance in human astrocytomas. J Neurooncol 1997; 35(3):223–48.PubMedCrossRefGoogle Scholar
  101. 101.
    Dunn IF, Heese O, Black PM. Growth factors in glioma angiogenesis: FGFs, PDGF, EGF and TGFs. J Neurooncol 2000; 50(1–2):121–37.PubMedCrossRefGoogle Scholar
  102. 102.
    Chicoine MR, Silbergeld DL. Mitogens as motogens. J Neurooncol 1997; 35(3):249–57.PubMedCrossRefGoogle Scholar
  103. 103.
    Boockvar JA, Kapitonov D, Kapoor G et al. Constitutive EGFR signaling confers a motile phenotype to neural stem cells. Mol Cell Neurosci 2003; 24(4):1116–30.PubMedCrossRefGoogle Scholar
  104. 104.
    Mellinghoff IK, Wang MY, Vivanco I et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005; 353(19):2012–24.PubMedCrossRefGoogle Scholar
  105. 105.
    Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 2005; 23(10):2411–22.PubMedCrossRefGoogle Scholar
  106. 106.
    Tatenhorst L, Puttmann S, Senner V et al. Genes associated with fast glioma cell migration in vitro and in vivo. Brain Pathol 2005; 15(1):46–54.PubMedCrossRefGoogle Scholar
  107. 107.
    Ma HI, Lin SZ, Chiang YH et al. Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adeno-associated viral (AAV) vector. Gene Ther 2002; 9(1):2–11.PubMedCrossRefGoogle Scholar
  108. 108.
    Gomez-Manzano C, Yung WK, Alemany R et al. Genetically modified adenoviruses against gliomas: from bench to bedside. Neurology 2004; 63(3):418–26.PubMedGoogle Scholar
  109. 109.
    Li S, Gao Y, Tokuyama T et al. Genetically engineered neural stem cells migrate and suppress glioma cell growth at distant intracranial sites. Cancer Lett 2007; 251(2):220–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Herrlinger U, Woiciechowski C, Sena-Esteves M et al. Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas. Mol Ther 2000; 1(4):347–57.PubMedCrossRefGoogle Scholar
  111. 111.
    Eklund JW, Kuzel TM. A review of recent findings involving interleukin-2-based cancer therapy. Curr Opin Oncol 2004; 16(6):542–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Smyth MJ, Cretney E, Kershaw MH et al. Cytokines in cancer immunity and immunotherapy. Immunol Rev 2004; 202:275–93.PubMedCrossRefGoogle Scholar
  113. 113.
    Jean WC, Spellman SR, Wallenfriedman MA et al. Interleukin-12-based immunotherapy against rat 9L glioma. Neurosurgery 1998; 42(4):850–6; discussion 6–7.PubMedCrossRefGoogle Scholar
  114. 114.
    Ehtesham M, Samoto K, Kabos P et al. Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer. Cancer Gene Ther 2002; 9(11):925–34.PubMedCrossRefGoogle Scholar
  115. 115.
    Rhines LD, Sampath P, DiMeco F et al. Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma. Neurosurgery 2003; 52(4):872–9; discussion 9–80.PubMedCrossRefGoogle Scholar
  116. 116.
    Yang SY, Liu H, Zhang JN. Gene therapy of rat malignant gliomas using neural stem cells expressing IL-12. DNA Cell Biol 2004; 23(6):381–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Kim SK, Cargioli TG, Machluf M et al. PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin Cancer Res 2005; 11(16):5965–70.PubMedCrossRefGoogle Scholar
  118. 118.
    Zhang Z, Jiang Q, Jiang F et al. In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. Neuroimage 2004; 23(1):281–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Daldrup-Link HE, Rudelius M, Piontek G et al. Migration of iron oxide-labeled human hematopoietic progenitor cells in a mouse model: in vivo monitoring with 1.5-T MR imaging equipment. Radiology 2005; 234(1):197–205.PubMedCrossRefGoogle Scholar
  120. 120.
    Stroh M, Zimmer JP, Duda DG et al. Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nat Med 2005; 11(6):678–82.PubMedCrossRefGoogle Scholar
  121. 121.
    Nakamizo A, Marini F, Amano T et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65(8):3307–18.PubMedGoogle Scholar
  122. 122.
    Chiocca EA, Aghi M, Fulci G. Viral therapy for glioblastoma. Cancer J 2003; 9(3):167–79.PubMedCrossRefGoogle Scholar
  123. 123.
    Chiocca EA, Broaddus WC, Gillies GT et al. Neurosurgical delivery of chemotherapeutics, targeted toxins, genetic viral therapies in neuro-oncology. J Neurooncol 2004; 69(1–3):101–17.PubMedCrossRefGoogle Scholar
  124. 124.
    Kew Y, Levin VA. Advances in gene therapy and immunotherapy for brain tumors. Curr Opin Neurol 2003; 16(6):665–70.PubMedCrossRefGoogle Scholar
  125. 125.
    Kurihara H, Zama A, Tamura M et al. Glioma/glioblastoma-specific adenoviral gene expression using the nestin gene regulator. Gene Ther 2000; 7(8):686–93.PubMedCrossRefGoogle Scholar
  126. 126.
    Fueyo J, Alemany R, Gomez-Manzano C et al. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J Natl Cancer Inst 2003; 95(9):652–60.PubMedCrossRefGoogle Scholar
  127. 127.
    Stojdl DF, Lichty BD, tenOever BR et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 2003; 4:263–75.PubMedCrossRefGoogle Scholar
  128. 128.
    Manome Y, Wen PY, Dong Y et al. Viral vector transduction of the human deoxycytidine kinase cDNA sensitizes glioma cells to the cytotoxic effects of cytosine arabinoside in vitro and in vivo. Nat Med 1996; 2(5):567–73.PubMedCrossRefGoogle Scholar
  129. 129.
    Lynch WP, Sharpe AH, Snyder EY. Neural stem cells as engraftable packaging lines can mediate gene delivery to microglia: evidence from studying retroviral env-related neurodegeneration. J Virol 1999; 73(8):6841–51.PubMedGoogle Scholar
  130. 130.
    Arnhold S, Hilgers M, Lenartz D et al. Neural precursor cells as carriers for a gene therapeutical approach in tumor therapy. Cell Transplant 2003; 12(8):827–37.PubMedGoogle Scholar
  131. 131.
    Ehtesham M, Samoto K, Kabos P et al. Treatment of intracranial glioma with in situ interferon-gamma and necrosis factor-alpha gene transfer. Cancer Gene Ther 2002; 9(11):925–34.PubMedCrossRefGoogle Scholar
  132. 132.
    Walczak H, Miller RE, Ariail K et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-ligand in vivo. Nat Med 1999; 5(2):157–63.PubMedCrossRefGoogle Scholar
  133. 133.
    Kim I, Kim H, Im S et al. Induction of intracranial glioblastoma apoptosis by transplantation of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) expressing human neural stem cells (NSCs). In: Annual meeting of society of neuroscience. San Diego; 2004.Google Scholar
  134. 134.
    Lewin M, Carlesso N, Tung CH et al. Tat peptide-derivatized magnetic nanoparticles allow in recovery of progenitor cells. Nat Biotechnol 2000; 18(4):410–4.PubMedCrossRefGoogle Scholar
  135. 135.
    Anderson SA, Glod J, Arbab AS et al. Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 2005; 105(1):420–5.PubMedCrossRefGoogle Scholar
  136. 136.
    Jaiswal JK, Simon SM. Potentials and pitfalls of fluorescent quantum dots for biological imaging. Trends Cell Biol 2004; 14(9):497–504.PubMedCrossRefGoogle Scholar
  137. 137.
    Gao X, Cui Y, Levenson RM et al. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 2004; 22(8):969–76.PubMedCrossRefGoogle Scholar
  138. 138.
    Loo C, Lowery A, Halas N et al. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Lett 2005; 5(4):709–11.PubMedCrossRefGoogle Scholar
  139. 139.
    Hirsch LR, Stafford RJ, Bankson JA et al. Nanoshell-mediated near-infrared thermal therapy of tumors undermagnetic resonance guidance. Proc Natl Acad Sci USA 2003; 100(23):13549–54.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Samuel A. Hughes
    • 1
  • Pragathi Achanta
    • 2
  • Allen L. Ho
    • 3
  • Vincent J. Duenas
    • 4
  • Alfredo Quiñones-Hinojosa
    • 5
  1. 1.Department of Neurological SurgeryOregon Health and Sciences UniversityPortlandUSA
  2. 2.Department of NeurosurgeryJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.Del E. Webb Neuroscience, Aging and Stem Cell Research CenterBurnham Institute for Regenerative MedicineLa JollaUSA
  5. 5.Department of NeurosurgeryNeuroscience and Cellular and Molecular Medicine, Johns Hopkins UniversityBaltimoreUSA

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