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Disease relevance of Glioblastoma


High impact information on Glioblastoma

  • Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice [5].
  • The neu oncogene, which is frequently activated in neuro- and glioblastomas of BDIX rats, was originally identified in the NIH 3T3 focus-forming assay. cDNA clones of the normal and transforming alleles of neu have been isolated [6].
  • Radiation plus metronidazole for glioblastoma [7].
  • Retrovirus-mediated transfer of the gene for interleukin-4 is an effective treatment for rat brain glioblastomas [8].
  • Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant [9].

Chemical compound and disease context of Glioblastoma


Biological context of Glioblastoma

  • The c-erb-B-2 gene is conserved in vertebrates and it has been suggested that the neu gene, detected in a series of rat neuro/glioblastomas, is, in fact, the rat c-erb-B-2 gene [21].
  • This downregulation may significantly contribute to glioblastoma development, since we show that an increase in TSP-1 expression is sufficient to strongly suppress glioblastoma cell tumorigenicity in vivo [22].
  • RESULTS: Mutation of PTEN, amplification of EGFR, and loss of the q arm of chromosome 10 were statistically significantly less common in anaplastic astrocytoma than in glioblastoma multiforme (P =.033, P =.001, and P<.001, respectively), and mutation of p53 was statistically significantly more common (P<.001) [23].
  • These results were subsequently confirmed with fresh brain tumor and nonneoplastic brain tissue biopsy samples; increased expression of the N-ras proto-oncogene was observed in five of five glioblastomas, all of which also showed EGFr gene overexpression, but not in well-differentiated gliomas or in nonneoplastic brain tissue specimens [24].
  • The results of the present study indicate that multidrug-resistant human glioblastoma multiforme cells retain their increased sensitivity to the antiproliferative activity of the combination of IFN-beta plus IFN-gamma, and differences in antigenic phenotype are apparent in independent multidrug-resistant glioblastoma multiforme clones [25].

Anatomical context of Glioblastoma

  • In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells [26].
  • Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth [27].
  • Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes [28].
  • Urokinase-type plasminogen activator (uPA) receptor (uPAR) is expressed on the surface of glioblastoma and some other tumor cells and endothelial cells [29].
  • RESULTS: In vitro, DTAT was highly potent and selective in killing uPAR-expressing glioblastoma cells (U118MG, U373MG, and U87MG) and human umbilical vein endothelial cells [29].

Gene context of Glioblastoma

  • Multivariate classification and regression-tree analysis of all 174 patients identified EGFR amplification as an independent predictor of prolonged survival in patients with glioblastoma multiforme who were older than 60 years of age [23].
  • RNA transfer blot analysis of biopsies from glioblastoma multiforme showed transcripts for PDGF A and B chains and the PDGF receptor [30].
  • Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells [31].
  • Expression and rearrangement of the ROS1 gene in human glioblastoma cells [32].
  • Thus, mTor is required for neuronal hypertrophy downstream of Pten deficiency, but is not required for maintenance of normal neuronal soma size. mTOR inhibitors may be useful therapeutic agents for diseases in brain resulting from PTEN deficiency such as Lhermitte-Duclos disease or glioblastoma multiforme [33].
  • We show that ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma [34].
  • All responsive tumors were derived from glioblastomas exhibiting EGFR amplification and expression of the truncated EGFRvIII variant, which were maintained in the xenografts [35].
  • Glioblastomas with IDH1 mutation diagnosed as primary had clinical and genetic profiles similar to those of secondary glioblastomas, suggesting that they may have rapidly progressed from a less malignant precursor lesion that escaped clinical diagnosis and were thus misclassified as primary [36].
  • Enhancing BRGs (EBRG) exhibited MRI enhancement, a long-established criterion for glioblastoma progression, and expressed mitogen-activated protein kinases, neural cell adhesion molecule-1 (NCAM-1), and aquaporin 4 [37].

Analytical, diagnostic and therapeutic context of Glioblastoma


  1. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Reilly, K.M., Loisel, D.A., Bronson, R.T., McLaughlin, M.E., Jacks, T. Nat. Genet. (2000) [Pubmed]
  2. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Seoane, J., Le, H.V., Shen, L., Anderson, S.A., Massagué, J. Cell (2004) [Pubmed]
  3. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Kwon, C.H., Zhu, X., Zhang, J., Knoop, L.L., Tharp, R., Smeyne, R.J., Eberhart, C.G., Burger, P.C., Baker, S.J. Nat. Genet. (2001) [Pubmed]
  4. Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Van Nostrand, W.E., Wagner, S.L., Suzuki, M., Choi, B.H., Farrow, J.S., Geddes, J.W., Cotman, C.W., Cunningham, D.D. Nature (1989) [Pubmed]
  5. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Holland, E.C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R.E., Fuller, G.N. Nat. Genet. (2000) [Pubmed]
  6. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Bargmann, C.I., Hung, M.C., Weinberg, R.A. Cell (1986) [Pubmed]
  7. Radiation plus metronidazole for glioblastoma. Urtasun, R.C., Band, P.R., Chapman, J.D., Feldstein, M.L. N. Engl. J. Med. (1977) [Pubmed]
  8. Gene therapy of experimental brain tumors using neural progenitor cells. Benedetti, S., Pirola, B., Pollo, B., Magrassi, L., Bruzzone, M.G., Rigamonti, D., Galli, R., Selleri, S., Di Meco, F., De Fraja, C., Vescovi, A., Cattaneo, E., Finocchiaro, G. Nat. Med. (2000) [Pubmed]
  9. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Millauer, B., Shawver, L.K., Plate, K.H., Risau, W., Ullrich, A. Nature (1994) [Pubmed]
  10. Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Van Meir, E.G., Polverini, P.J., Chazin, V.R., Su Huang, H.J., de Tribolet, N., Cavenee, W.K. Nat. Genet. (1994) [Pubmed]
  11. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Lee, J.O., Yang, H., Georgescu, M.M., Di Cristofano, A., Maehama, T., Shi, Y., Dixon, J.E., Pandolfi, P., Pavletich, N.P. Cell (1999) [Pubmed]
  12. The neu oncogene encodes an epidermal growth factor receptor-related protein. Bargmann, C.I., Hung, M.C., Weinberg, R.A. Nature (1986) [Pubmed]
  13. Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA. Trojan, J., Johnson, T.R., Rudin, S.D., Ilan, J., Tykocinski, M.L., Ilan, J. Science (1993) [Pubmed]
  14. Quality and duration of survival in glioblastoma multiforme. Combined surgical, radiation, and lomustine therapy. Hochberg, F.H., Linggood, R., Wolfson, L., Baker, W.H., Kornblith, P. JAMA (1979) [Pubmed]
  15. Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Eoli, M., Menghi, F., Bruzzone, M.G., De Simone, T., Valletta, L., Pollo, B., Bissola, L., Silvani, A., Bianchessi, D., D'Incerti, L., Filippini, G., Broggi, G., Boiardi, A., Finocchiaro, G. Clin. Cancer Res. (2007) [Pubmed]
  16. Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma. Miyashita, K., Kawakami, K., Nakada, M., Mai, W., Shakoori, A., Fujisawa, H., Hayashi, Y., Hamada, J., Minamoto, T. Clin. Cancer Res. (2009) [Pubmed]
  17. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Grossman, S.A., Ye, X., Piantadosi, S., Desideri, S., Nabors, L.B., Rosenfeld, M., Fisher, J. Clin. Cancer Res. (2010) [Pubmed]
  18. Bortezomib Primes Glioblastoma, Including Glioblastoma Stem Cells, for TRAIL by Increasing tBid Stability and Mitochondrial Apoptosis. Unterkircher, T., Cristofanon, S., Vellanki, S.H., Nonnenmacher, L., Karpel-Massler, G., Wirtz, C.R., Debatin, K.M., Fulda, S. Clin. Cancer Res. (2011) [Pubmed]
  19. The mTOR kinase inhibitors, CC214-1 and CC214-2, preferentially block the growth of EGFRvIII-activated glioblastomas. Gini, B., Zanca, C., Guo, D., Matsutani, T., Masui, K., Ikegami, S., Yang, H., Nathanson, D., Villa, G.R., Shackelford, D., Zhu, S., Tanaka, K., Babic, I., Akhavan, D., Lin, K., Assuncao, A., Gu, Y., Bonetti, B., Mortensen, D.S., Xu, S., Raymon, H.K., Cavenee, W.K., Furnari, F.B., James, C.D., Kroemer, G., Heath, J.R., Hege, K., Chopra, R., Cloughesy, T.F., Mischel, P.S. Clin. Cancer Res. (2013) [Pubmed]
  20. Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth. Karkare, S., Chhipa, R.R., Anderson, J., Liu, X., Henry, H., Gasilina, A., Nassar, N., Roychoudhury, J., Clark, J.P., Kumar, A., Pauletti, G.M., Ghosh, P.K., Dasgupta, B. Clin. Cancer Res. (2014) [Pubmed]
  21. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Yamamoto, T., Ikawa, S., Akiyama, T., Semba, K., Nomura, N., Miyajima, N., Saito, T., Toyoshima, K. Nature (1986) [Pubmed]
  22. Thrombospondin-1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. Tenan, M., Fulci, G., Albertoni, M., Diserens, A.C., Hamou, M.F., El Atifi-Borel, M., Feige, J.J., Pepper, M.S., Van Meir, E.G. J. Exp. Med. (2000) [Pubmed]
  23. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. Smith, J.S., Tachibana, I., Passe, S.M., Huntley, B.K., Borell, T.J., Iturria, N., O'Fallon, J.R., Schaefer, P.L., Scheithauer, B.W., James, C.D., Buckner, J.C., Jenkins, R.B. J. Natl. Cancer Inst. (2001) [Pubmed]
  24. Overexpression of N-ras oncogene and epidermal growth factor receptor gene in human glioblastomas. Gerosa, M.A., Talarico, D., Fognani, C., Raimondi, E., Colombatti, M., Tridente, G., De Carli, L., Della Valle, G. J. Natl. Cancer Inst. (1989) [Pubmed]
  25. Effect of recombinant fibroblast interferon and recombinant immune interferon on growth and the antigenic phenotype of multidrug-resistant human glioblastoma multiforme cells. Reddy, P.G., Graham, G.M., Datta, S., Guarini, L., Moulton, T.A., Jiang, H.P., Gottesman, M.M., Ferrone, S., Fisher, P.B. J. Natl. Cancer Inst. (1991) [Pubmed]
  26. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Shweiki, D., Itin, A., Soffer, D., Keshet, E. Nature (1992) [Pubmed]
  27. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Gao, T., Furnari, F., Newton, A.C. Mol. Cell (2005) [Pubmed]
  28. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Rajasekhar, V.K., Viale, A., Socci, N.D., Wiedmann, M., Hu, X., Holland, E.C. Mol. Cell (2003) [Pubmed]
  29. Targeting urokinase-type plasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT. Vallera, D.A., Li, C., Jin, N., Panoskaltsis-Mortari, A., Hall, W.A. J. Natl. Cancer Inst. (2002) [Pubmed]
  30. Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Hermansson, M., Nistér, M., Betsholtz, C., Heldin, C.H., Westermark, B., Funa, K. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  31. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Rubin, J.B., Kung, A.L., Klein, R.S., Chan, J.A., Sun, Y., Schmidt, K., Kieran, M.W., Luster, A.D., Segal, R.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  32. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Birchmeier, C., Sharma, S., Wigler, M. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  33. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Kwon, C.H., Zhu, X., Zhang, J., Baker, S.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  34. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Horvath, S., Zhang, B., Carlson, M., Lu, K.V., Zhu, S., Felciano, R.M., Laurance, M.F., Zhao, W., Qi, S., Chen, Z., Lee, Y., Scheck, A.C., Liau, L.M., Wu, H., Geschwind, D.H., Febbo, P.G., Kornblum, H.I., Cloughesy, T.F., Nelson, S.F., Mischel, P.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  35. Inhibition of glioblastoma growth in a highly invasive nude mouse model can be achieved by targeting epidermal growth factor receptor but not vascular endothelial growth factor receptor-2. Martens, T., Laabs, Y., Günther, H.S., Kemming, D., Zhu, Z., Witte, L., Hagel, C., Westphal, M., Lamszus, K. Clin. Cancer Res. (2008) [Pubmed]
  36. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Nobusawa, S., Watanabe, T., Kleihues, P., Ohgaki, H. Clin. Cancer Res. (2009) [Pubmed]
  37. Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy. Delay, M., Jahangiri, A., Carbonell, W.S., Hu, Y.L., Tsao, S., Tom, M.W., Paquette, J., Tokuyasu, T.A., Aghi, M.K. Clin. Cancer Res. (2012) [Pubmed]
  38. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Jacobs, A., Voges, J., Reszka, R., Lercher, M., Gossmann, A., Kracht, L., Kaestle, C., Wagner, R., Wienhard, K., Heiss, W.D. Lancet (2001) [Pubmed]
  39. Decrease in telomerase activity in U-87MG human glioblastomas after treatment with an antagonist of growth hormone-releasing hormone. Kiaris, H., Schally, A.V. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  40. Synthesis and secretion of proteins resembling platelet-derived growth factor by human glioblastoma and fibrosarcoma cells in culture. Pantazis, P., Pelicci, P.G., Dalla-Favera, R., Antoniades, H.N. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  41. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Krieg, M., Marti, H.H., Plate, K.H. Blood (1998) [Pubmed]
  42. First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia. Brandes, A.A., Basso, U., Reni, M., Vastola, F., Tosoni, A., Cavallo, G., Scopece, L., Ferreri, A.J., Panucci, M.G., Monfardini, S., Ermani, M. J. Clin. Oncol. (2004) [Pubmed]
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