Journal of Neuro-Oncology

, Volume 85, Issue 2, pp 133–148 | Cite as

Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression

  • Marianela Candolfi
  • James F. Curtin
  • W. Stephen Nichols
  • AKM. G. Muhammad
  • Gwendalyn D. King
  • G. Elizabeth Pluhar
  • Elizabeth A. McNiel
  • John R. Ohlfest
  • Andrew B. Freese
  • Peter F. Moore
  • Jonathan Lerner
  • Pedro R. Lowenstein
  • Maria G. Castro
Lab Investigation-Human/Animal Tissue


Although rodent glioblastoma (GBM) models have been used for over 30 years, the extent to which they recapitulate the characteristics encountered in human GBMs remains controversial. We studied the histopathological features of dog GBM and human xenograft GBM models in immune-deficient mice (U251 and U87 GBM in nude Balb/c), and syngeneic GBMs in immune-competent rodents (GL26 cells in C57BL/6 mice, CNS-1 cells in Lewis rats). All GBMs studied exhibited neovascularization, pleomorphism, vimentin immunoreactivity, and infiltration of T-cells and macrophages. All the tumors showed necrosis and hemorrhages, except the U87 human xenograft, in which the most salient feature was its profuse neovascularization. The tumors differed in the expression of astrocytic intermediate filaments: human and dog GBMs, as well as U251 xenografts expressed glial fibrillary acidic protein (GFAP) and vimentin, while the U87 xenograft and the syngeneic rodent GBMs were GFAP and vimentin+. Also, only dog GBMs exhibited endothelial proliferation, a key feature that was absent in the murine models. In all spontaneous and implanted GBMs we found histopathological features compatible with tumor invasion into the non-neoplastic brain parenchyma. Our data indicate that murine models of GBM appear to recapitulate several of the human GBM histopathological features and, considering their reproducibility and availability, they constitute a valuable in vivo system for preclinical studies. Importantly, our results indicate that dog GBM emerges as an attractive animal model for testing novel therapies in a spontaneous tumor in the context of a larger brain.


Glioma Dog U251 U87 CNS-1 GL26 



This work is supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) Grant 1R01 NS44556.01, Minority Supplement NS445561; 1R21-NSO54143.01; 1UO1 NS052465.01; NIH/NINDS 1 RO3 TW006273-01 to M.G.C.; NIH/NINDS Grants 1 RO1 NS 054193.01; RO1 NS 42893.01; U54 NS045309-01, and 1R21 NS047298-01 to P.R.L. The Bram and Elaine Goldsmith and the Medallions Group Endowed Chairs in Gene Therapeutics to PRL and MGC, respectively, The Linda Tallen and David Paul Kane Foundation Annual Fellowship and the Board of Governors at CSMC. M.C and GDK are supported by NIH/NINDS 1F32 NS058156.01 and 1F32 NS0503034.01.


  1. 1.
    Castro MG, Cowen R, Williamson IK, David A, Jimenez-Dalmaroni MJ, Yuan X, Bigliari A Williams JC, Hu J, Lowenstein PR (2003) Current and future strategies for the treatment of malignant brain tumors. Pharmacol Ther 98:71–108PubMedCrossRefGoogle Scholar
  2. 2.
    Chiocca EA (2002) Oncolytic viruses. Nat Rev Cancer 2:938–950PubMedCrossRefGoogle Scholar
  3. 3.
    Curtin JF, King GD, Candolfi M, Greeno RB, Kroeger KM, Lowenstein PR, Castro MG (2005) Combining cytotoxic and immune-mediated gene therapy to treat brain tumors. Curr Top Med Chem 5:1151–1170PubMedCrossRefGoogle Scholar
  4. 4.
    Gomez-Manzano C, Yung WK, Alemany R, Fueyo J (2004) Genetically modified adenoviruses against gliomas: from bench to bedside. Neurology 63:418–426PubMedGoogle Scholar
  5. 5.
    King GD, Curtin JF, Candolfi M, Kroeger K, Lowenstein PR, Castro MG (2005) Gene therapy and targeted toxins for glioma. Curr Gene Ther 5:535–557PubMedCrossRefGoogle Scholar
  6. 6.
    Prados MD, Levin V (2000) Biology and treatment of malignant glioma. Semin Oncol 27:1–10PubMedGoogle Scholar
  7. 7.
    Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15:1311–1333PubMedCrossRefGoogle Scholar
  8. 8.
    Kleihues P, Zulch KJ, Matsumoto S, Radke U (1970) Morphology of malignant gliomas induced in rabbits by systemic application of N-methyl-N-nitrosourea. Z Neurol 198:65–78PubMedCrossRefGoogle Scholar
  9. 9.
    Ding H, Nagy A, Gutmann DH, Guha A (2000) A review of astrocytoma models. Neurosurg Focus 8:1–8Google Scholar
  10. 10.
    Castro MG, Curtin J, King GD, Candolfi M, Czer P, Sciascia S, Kroeger K, Fakhouri T, Honig S, Kuoy W, Kang T, Johnson S, Lowenstein PR (2006) Novel gene therapeutic approaches to brain cancer. In: Castro MG, Lowenstein PR (eds) Gene therapy for neurological disorders. Taylor and Francis Group, New York, pp 229–264Google Scholar
  11. 11.
    Fecci PE, Mitchell DA, Archer GE, Morse MA, Lyerly HK, Bigner DD, Sampson JH (2003) The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors. J Neurooncol 64:161–176PubMedGoogle Scholar
  12. 12.
    Rainov NG, Ren H (2003) Gene therapy for human malignant brain tumors. Cancer J 9:180–188PubMedGoogle Scholar
  13. 13.
    Ali S, Curtin JF, Zirger JM, Xiong W, King GD, Barcia C, Liu C, Puntel M, Goverdhana S, Lowenstein PR, Castro MG (2004) Inflammatory and anti-glioma effects of an adenovirus expressing human soluble Fms-like tyrosine kinase 3 ligand (hsFlt3L): treatment with hsFlt3L inhibits intracranial glioma progression. Mol Ther 10:1071–1084PubMedCrossRefGoogle Scholar
  14. 14.
    Ali S, King GD, Curtin JF, Candolfi M, Xiong W, Liu C, Puntel M, Cheng Q, Prieto J, Ribas A, Kupiec-Weglinski J, van Rooijen N, Lassmann H, Lowenstein PR, Castro MG (2005) Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model. Cancer Res 65:7194–7204PubMedCrossRefGoogle Scholar
  15. 15.
    Kruse CA, Molleston MC, Parks EP, Schiltz PM, Kleinschmidt-DeMasters BK, Hickey WF (1994) A rat glioma model, CNS-1, with invasive characteristics similar to those of human gliomas: a comparison to 9L gliosarcoma. J Neurooncol 22:191–200PubMedCrossRefGoogle Scholar
  16. 16.
    Albright L, Madigan JC, Gaston MR, Houchens DP (1975) Therapy in an intracerebral murine glioma model, using Bacillus Calmette-Guerin, neuraminidase-treated tumor cells, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Cancer Res 35:658–665PubMedGoogle Scholar
  17. 17.
    Curtin J, King GD, Xiong W, Liu C, Lowenstein PR, Castro MG (2005) Stimulation of the immune system using gene therapy is an effective approach for treating brain tumors in mouse and rat models. American society of gene therapy 8th annual meeting. Mol Ther 11:S106Google Scholar
  18. 18.
    Owens GC, Orr EA, DeMasters BK, Muschel RJ, Berens ME, Kruse CA (1998) Overexpression of a transmembrane isoform of neural cell adhesion molecule alters the invasiveness of rat CNS-1 glioma. Cancer Res 58:2020–2028PubMedGoogle Scholar
  19. 19.
    Kim CH, Hong MJ, Park SD, Kim CK, Park MY, Sohn HJ, Cho HI, Kim TG, Hong YK (2006) Enhancement of anti-tumor immunity specific to murine glioma by vaccination with tumor cell lysate-pulsed dendritic cells engineered to produce interleukin-12. Cancer Immunol Immunother 55:1309–1319PubMedCrossRefGoogle Scholar
  20. 20.
    Heidner GL, Kornegay JN, Page RL, Dodge RK, Thrall DE (1991) Analysis of survival in a retrospective study of 86 dogs with brain tumors. J Vet Intern Med 5:219–226PubMedCrossRefGoogle Scholar
  21. 21.
    Foster ES, Carrillo JM, Patnaik AK (1988) Clinical signs of tumors affecting the rostral cerebrum in 43 dogs. J Vet Intern Med 2:71–74PubMedCrossRefGoogle Scholar
  22. 22.
    LeCouteur RA (1999) Current concepts in the diagnosis and treatment of brain tumours in dogs and cats. J Small Anim Pract 40:411–416PubMedGoogle Scholar
  23. 23.
    Stonehewer J, Mackin AJ, Tasker S, Simpson JW, Mayhew IG (2000) Idiopathic phenobarbital-responsive hypersialosis in the dog: an unusual form of limbic epilepsy? J Small Anim Pract 41:416–421PubMedGoogle Scholar
  24. 24.
    Stoica G, Kim HT, Hall DG, Coates JR (2004) Morphology, immunohistochemistry, and genetic alterations in dog astrocytomas. Vet Pathol 41:10–19PubMedCrossRefGoogle Scholar
  25. 25.
    Lipsitz D, Higgins RJ, Kortz GD, Dickinson PJ, Bollen AW, Naydan DK, LeCouteur RA (2003) Glioblastoma multiforme: clinical findings, magnetic resonance imaging, and pathology in five dogs. Vet Pathol 40:659–669PubMedCrossRefGoogle Scholar
  26. 26.
    Orrison WW Jr, Rose DF, Hart BL, Maclin EL, Sanders JA, Willis BK, Marchand EP, Wood CC, Davis LE (1992) Noninvasive preoperative cortical localization by magnetic source imaging. AJNR Am J Neuroradiol 13:1124–1128PubMedGoogle Scholar
  27. 27.
    Aghi M, Rabkin S, Martuza RL (2006) Effect of chemotherapy-induced DNA repair on oncolytic herpes simplex viral replication. J Natl Cancer Inst 98:38–50PubMedCrossRefGoogle Scholar
  28. 28.
    Conrad C, Miller CR, Ji Y, Gomez-Manzano C, Bharara S, McMurray JS, Lang FF, Wong F, Sawaya R, Yung WK, Fueyo J (2005) Delta24-hyCD adenovirus suppresses glioma growth in vivo by combining oncolysis and chemosensitization. Cancer Gene Ther 12:284–294PubMedCrossRefGoogle Scholar
  29. 29.
    Jiang H, Gomez-Manzano C, Alemany R, Medrano D, Alonso M, Bekele BN, Lin E, Conrad CC, Yung WK, Fueyo J (2005) Comparative effect of oncolytic adenoviruses with E1A-55 kDa or E1B-55 kDa deletions in malignant gliomas. Neoplasia 7:48–56PubMedCrossRefGoogle Scholar
  30. 30.
    Samoto K, Ehtesham M, Perng GC, Hashizume K, Wechsler SL, Nesburn AB, Black KL, Yu JS (2002) A herpes simplex virus type 1 mutant with gamma 34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice. Neurosurgery 50:599–605 discussion 605–606PubMedCrossRefGoogle Scholar
  31. 31.
    Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM (1998) Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58:4654–4659PubMedGoogle Scholar
  32. 32.
    Lund EL, Bastholm L, Kristjansen PE (2000) Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. Clin Cancer Res 6:971–978PubMedGoogle Scholar
  33. 33.
    Schmidt NO, Ziu M, Carrabba G, Giussani C, Bello L, Sun Y, Schmidt K, Albert M, Black PM, Carroll RS (2004) Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model. Clin Cancer Res 10:1255–1262PubMedCrossRefGoogle Scholar
  34. 34.
    Ausman JI, Shapiro WR, Rall DP (1970) Studies on the chemotherapy of experimental brain tumors: development of an experimental model. Cancer Res 30:2394–2400PubMedGoogle Scholar
  35. 35.
    Kosugi I, Kawasaki H, Arai Y, Tsutsui Y (2002) Innate immune responses to cytomegalovirus infection in the developing mouse brain and their evasion by virus-infected neurons. Am J Pathol 161:919–928PubMedGoogle Scholar
  36. 36.
    Chen SC, Leach MW, Chen Y, Cai XY, Sullivan L, Wiekowski M, Dovey-Hartman BJ, Zlotnik A, Lira SA (2002) Central nervous system inflammation and neurological disease in transgenic mice expressing the CC chemokine CCL21 in oligodendrocytes. J Immunol 168:1009–1017PubMedGoogle Scholar
  37. 37.
    Stein VM, Czub M, Schreiner N, Moore PF, Vandevelde M, Zurbriggen A, Tipold A (2004) Microglial cell activation in demyelinating canine distemper lesions. J Neuroimmunol 153:122–131PubMedCrossRefGoogle Scholar
  38. 38.
    Curtin JF, King GD, Barcia C, Liu C, Hubert FX, Guillonneau C, Josien R, Anegon I, Lowenstein PR, Castro MG (2006) Fms-like tyrosine kinase 3 ligand recruits plasmacytoid dendritic cells to the brain. J Immunol 176:3566–3577PubMedGoogle Scholar
  39. 39.
    Brat DJ, Castellano-Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, Devi SN, Kaur B, Van Meir EG (2004) Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 64:920–927PubMedCrossRefGoogle Scholar
  40. 40.
    Dong S, Nutt CL, Betensky RA, Stemmer-Rachamimov AO, Denko NC, Ligon KL, Rowitch DH, Louis DN (2005) Histology-based expression profiling yields novel prognostic markers in human glioblastoma. J Neuropathol Exp Neurol 64:948–955PubMedGoogle Scholar
  41. 41.
    Rong Y, Durden DL, Van Meir EG, Brat DJ (2006) ‘Pseudopalisading’ necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65:529–539PubMedGoogle Scholar
  42. 42.
    Maher E, McKee A (2003) Neoplasms of the central nervous system. In: Skarin A III (ed) Atlas of diagnostic oncology. Elsevier, AmsterdamGoogle Scholar
  43. 43.
    Frosch M, Anthony D, Girolami D (2005) The central nervous system. In: Kumar V, Abbas A, Fausto N (eds) Robbins and cotran pathologic basis of disease. Elsevier, AmsterdamGoogle Scholar
  44. 44.
    Fine H, Barker F, Market J, Loeffer J (2005) Neoplasms of the central nervous system. In: Vita VD VII, Rosenberg S, Hellman S (eds) Cancer principles and practice of oncology. Lippincott, PhiladelphiaGoogle Scholar
  45. 45.
    Trojanoski J (2005) The nervous system. In: Rubin E IV et al (ed) Rubin’s pathology. Clinopathologic foundations of medicine. Lippincott, PhiladelphiaGoogle Scholar
  46. 46.
    Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D (2005) Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 15:297–310PubMedCrossRefGoogle Scholar
  47. 47.
    Zagzag D, Friedlander DR, Margolis B, Grumet M, Semenza GL, Zhong H, Simons JW, Holash J, Wiegand SJ, Yancopoulos GD (2000) Molecular events implicated in brain tumor angiogenesis and invasion. Pediatr Neurosurg 33:49–55PubMedCrossRefGoogle Scholar
  48. 48.
    Schnitzer J, Franke WW, Schachner M (1981) Immunocytochemical demonstration of vimentin in astrocytes and ependymal cells of developing and adult mouse nervous system. J Cell Biol 90:435–447PubMedCrossRefGoogle Scholar
  49. 49.
    Jones TR, Bigner SH, Schold SC Jr, Eng LF, Bigner DD (1981) Anaplastic human gliomas grown in athymic mice. Morphology and glial fibrillary acidic protein expression. Am J Pathol 105:316–327Google Scholar
  50. 50.
    Elison D, Love S, Chimelli L, Lowe K, Roberts GW, Vinters HV (1998) Astrocytic neoplasms. In: Ellison D, Love S (eds) Neuropathology. Mosby International Ltd., Barcelona, Spain, pp. 35.1–35.10Google Scholar
  51. 51.
    Kleihues P, Burger P, Collins V (2000) Glioblastoma. In: Kleihues P II, Cavenee WK (eds) Pathology and genetics of the nervous system. International Agency for Research on Cancer, Lyon, France, pp 29–39Google Scholar
  52. 52.
    Leung SY, Wong MP, Chung LP, Chan AS, Yuen ST (1997) Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol (Berl) 93:518–527CrossRefGoogle Scholar
  53. 53.
    Horten BC, Basler GA, Shapiro WR (1981) Xenograft of human malignant glial tumors into brains of nude mice. A histopatholgical study. J Neuropathol Exp Neurol 40:493–511Google Scholar
  54. 54.
    Jones NR, Rossi ML, Gregoriou M, Hughes JT (1990) Investigation of the expression of epidermal growth factor receptor and blood group A antigen in 110 human gliomas. Neuropathol Appl Neurobiol 16:185–192PubMedGoogle Scholar
  55. 55.
    Benveniste P, Chadwick BS, Miller RG, Reimann J (1990) Characterization of cells with T cell markers in athymic nude bone marrow and of their in vitro-derived clonal progeny. Comparison with euthymic bone marrow. J Immunol 144:411–419Google Scholar
  56. 56.
    Palacios R, Samaridis J (1991) Rearrangement patterns of T-cell receptor genes in the spleen of athymic (nu/nu) young mice. Immunogenetics 33:90–95PubMedCrossRefGoogle Scholar
  57. 57.
    Takigawa M, Hanaoka M (1978) In vivo maturation of B cells in the spleen of nude mice following administration of bacterial lipopolysaccharide. Int Arch Allergy Appl Immunol 56:115–122PubMedGoogle Scholar
  58. 58.
    Payer E, Strohal R, Kutil R, Elbe A, Stingl G (1992) Demonstration of a CD3+ lymphocyte subset in the epidermis of athymic nude mice. Evidence for T cell receptor diversity. J Immunol 149:413–420PubMedGoogle Scholar
  59. 59.
    Shiohara T, Moriya N, Hayakawa J, Arahari K, Yagita H, Nagashima M, Ishikawa H (1993) Bone marrow-derived dendritic epidermal T cells express T cell receptor-alpha beta/CD3 and CD8. Evidence for their extrathymic maturation. J Immunol 150:4323–4330PubMedGoogle Scholar
  60. 60.
    Kennedy JD, Pierce CW, Lake JP (1992) Extrathymic T cell maturation. Phenotypic analysis of T cell subsets in nude mice as a function of age. J Immunol 148:1620–1629PubMedGoogle Scholar
  61. 61.
    Bandeira A, Itohara S, Bonneville M, Burlen-Defranoux O, Mota-Santos T, Coutinho A, Tonegawa S (1991) Extrathymic origin of intestinal intraepithelial lymphocytes bearing T-cell antigen receptor gamma delta. Proc Natl Acad Sci USA 88:43–47PubMedCrossRefGoogle Scholar
  62. 62.
    Kirk SJ, Regan MC, Wasserkrug HL, Sodeyama M, Barbul A (1992) Arginine enhances T-cell responses in athymic nude mice. JPEN J Parenter Enteral Nutr 16:429–432PubMedCrossRefGoogle Scholar
  63. 63.
    Bello L, Lucini V, Giussani C, Carrabba G, Pluderi M, Scaglione F, Tomei G, Villani R, Black PM, Bikfalvi A, Carroll RS (2003) IS20I, a specific alphavbeta3 integrin inhibitor, reduces glioma growth in vivo. Neurosurgery 52:177–185 discussion 185–186PubMedCrossRefGoogle Scholar
  64. 64.
    Ke LD, Shi YX, Im SA, Chen X, Yung WK (2000) The relevance of cell proliferation, vascular endothelial growth factor, and basic fibroblast growth factor production to angiogenesis and tumorigenicity in human glioma cell lines. Clin Cancer Res 6:2562–2572PubMedGoogle Scholar
  65. 65.
    Hornebeck W, Emonard H, Monboisse JC, Bellon G (2002) Matrix-directed regulation of pericellular proteolysis and tumor progression. Semin Cancer Biol 12:231–241PubMedCrossRefGoogle Scholar
  66. 66.
    Taipale J, Saharinen J, Keski-Oja J (1998) Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. Adv Cancer Res 75:87–134PubMedGoogle Scholar
  67. 67.
    Wickstrom SA, Alitalo K, Keski-Oja J (2005) Endostatin signaling and regulation of endothelial cell-matrix interactions. Adv Cancer Res 94:197–229PubMedCrossRefGoogle Scholar
  68. 68.
    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 7:164–176PubMedCrossRefGoogle Scholar
  69. 69.
    Sarkaria JN, Carlson BL, Schroeder MA, Grogan P, Brown PD, Giannini C, Ballman KV, Kitange GJ, Guha A, Pandita A, James CD (2006) Use of an orthotopic xenograft model for assessing the effect of epidermal growth factor receptor amplification on glioblastoma radiation response. Clin Cancer Res 12:2264–2271PubMedCrossRefGoogle Scholar
  70. 70.
    Cho SY, Ravasi L, Szajek LP, Seidel J, Green MV, Fine HA, Eckelman WC (2005) Evaluation of (76)Br-FBAU as a PET reporter probe for HSV1-tk gene expression imaging using mouse models of human glioma. J Nucl Med 46:1923–1930PubMedGoogle Scholar
  71. 71.
    Tentori L, Leonetti C, Scarsella M, D’Amati G, Vergati M, Portarena I, Xu W, Kalish V, Zupi G, Zhang J, Graziani G (2003) Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin Cancer Res 9:5370–5379PubMedGoogle Scholar
  72. 72.
    Shen S, Khazaeli MB, Gillespie GY, Alvarez VL (2005) Radiation dosimetry of 131I-chlorotoxin for targeted radiotherapy in glioma-bearing mice. J Neurooncol 71:113–119PubMedCrossRefGoogle Scholar
  73. 73.
    Kawakami K, Kawakami M, Kioi M, Husain SR, Puri RK (2004) Distribution kinetics of targeted cytotoxin in glioma by bolus or convection-enhanced delivery in a murine model. J Neurosurg 101:1004–1011PubMedGoogle Scholar
  74. 74.
    Cirielli C, Inyaku K, Capogrossi MC, Yuan X, Williams JA (1999) Adenovirus-mediated wild-type p53 expression induces apoptosis and suppresses tumorigenesis of experimental intracranial human malignant glioma. J Neurooncol 43:99–108PubMedCrossRefGoogle Scholar
  75. 75.
    Lamfers ML, Gianni D, Tung CH, Idema S, Schagen FH, Carette JE, Quax PH, Van Beusechem VW, Vandertop WP, Dirven CM, Chiocca EA, Gerritsen WR (2005) Tissue inhibitor of metalloproteinase-3 expression from an oncolytic adenovirus inhibits matrix metalloproteinase activity in vivo without affecting antitumor efficacy in malignant glioma. Cancer Res 65:9398–9405PubMedCrossRefGoogle Scholar
  76. 76.
    Dewey RA, Morrissey G, Cowsill CM, Stone D, Bolognani F, Dodd NJ, Southgate TD, Klatzmann D, Lassmann H, Castro MG, Lowenstein PR (1999) Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials. Nat Med 5:1256–1263PubMedCrossRefGoogle Scholar
  77. 77.
    Candolfi M, Curtin JF, Xiong W, Kroeger KM, Liu C, Rentsendorj A, Agadjanian H, Medina-Kauwe L, Palmer D, Ng P, Lowenstein PR, Castro MG (2006) Effective high capacity gutless adenoviral vectors mediated transgene expression in human glioma cells. Mol Ther 14:371–381PubMedCrossRefGoogle Scholar
  78. 78.
    Maleniak TC, Darling JL, Lowenstein PR, Castro MG (2001) Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU. Cancer Gene Ther 8:589–598PubMedCrossRefGoogle Scholar
  79. 79.
    Albert FK, Forsting M, Sartor K, Adams HP, Kunze S (1994) Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34:45–60 discussion 60–61PubMedCrossRefGoogle Scholar
  80. 80.
    Choucair AK, Levin VA, Gutin PH, Davis RL, Silver P, Edwards MS, Wilson CB (1986) Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg 65:654–658PubMedGoogle Scholar
  81. 81.
    Assanah M, Lochhead R, Ogden A, Bruce J, Goldman J, Canoll P (2006) Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci 26:6781–6790PubMedCrossRefGoogle Scholar
  82. 82.
    Pena L, Perez-Alenza MD, Rodriguez-Bertos A, Nieto A (2003) Canine inflammatory mammary carcinoma: histopathology, immunohistochemistry and clinical implications of 21 cases. Breast Cancer Res Treat 78:141–148PubMedCrossRefGoogle Scholar
  83. 83.
    Mahapokai W, Van Sluijs FJ, Schalken JA (2000) Models for studying benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 3:28–33PubMedCrossRefGoogle Scholar
  84. 84.
    Ahrar K, Madoff DC, Gupta S, Wallace MJ, Price RE, Wright KC (2002) Development of a large animal model for lung tumors. J Vasc Interv Radiol 13:923–928PubMedCrossRefGoogle Scholar
  85. 85.
    Dickerson EB, Fosmire S, Padilla ML, Modiano JF, Helfand SC (2002) Potential to target dysregulated interleukin-2 receptor expression in canine lymphoid and hematopoietic malignancies as a model for human cancer. J Immunother 25:36–45PubMedCrossRefGoogle Scholar
  86. 86.
    Vail DM, MacEwen EG (2000) Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest 18:781–792PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Marianela Candolfi
    • 1
    • 2
  • James F. Curtin
    • 1
    • 2
  • W. Stephen Nichols
    • 6
  • AKM. G. Muhammad
    • 1
  • Gwendalyn D. King
    • 1
    • 2
  • G. Elizabeth Pluhar
    • 3
  • Elizabeth A. McNiel
    • 3
  • John R. Ohlfest
    • 4
  • Andrew B. Freese
    • 4
  • Peter F. Moore
    • 5
  • Jonathan Lerner
    • 1
    • 2
  • Pedro R. Lowenstein
    • 1
    • 2
  • Maria G. Castro
    • 1
    • 2
  1. 1.Departments of Molecular and Medical Pharmacology and Medicine, David Geffen School of MedicineUCLALos AngelesUSA
  2. 2.Board of Governors’ Gene Therapeutics Research InstituteCedars-Sinai Medical CenterLos AngelesUSA
  3. 3.Department of Veterinary Clinical SciencesUniversity of MinnesotaSaint PaulUSA
  4. 4.Department of NeurosurgeryUniversity of MinnesotaMinneapolisUSA
  5. 5.Department of Veterinary, Pathology, Microbiology, and Immunology, School of Veterinary MedicineUniversity of CaliforniaDavisUSA
  6. 6.Department of Pathology and Laboratory MedicineCedars-Sinai Medical CenterLos AngelesUSA

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