Disease relevance of Glioblastoma

• The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo) [1].
• We suggest that the activity of this network confers resistance to TGF-beta-mediated cytostasis during the development of the telencephalic neuroepithelium and in glioblastoma brain tumor cells [2].
• Somatic inactivation of PTEN occurs in different human tumors including glioblastoma, endometrial carcinoma and prostate carcinoma [3].
• Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas [1].
• A monoclonal antibody against PN-II (designated mAbP2-1) recognized PN-II in immunoblots of serum-free culture medium from human glioblastoma cells and neuroblastoma cells, as well as in homogenates of normal and Alzheimer's disease brains [4].

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

• Here, we tested the role of p53 in the angiogenic process by introducing a tetracycline-regulated wild type p53 gene into null glioblastoma cells [10].
• The PTEN C2 domain binds phospholipid membranes in vitro, and mutation of basic residues that could mediate this reduces PTEN's membrane affinity and its ability to suppress the growth of glioblastoma tumor cells [11].
• The neu oncogene is repeatedly activated in neuro- and glioblastomas derived by transplacental mutagenesis of the BDIX strain of rat with ethylnitrosourea [12].
• Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA [13].
• Quality and duration of survival in glioblastoma multiforme. Combined surgical, radiation, and lomustine therapy [14].

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 [15].
• 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 [16].
• 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) [17].
• 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 [18].
• 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 [19].

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 [20].
• Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth [21].
• Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes [22].
• Urokinase-type plasminogen activator (uPA) receptor (uPAR) is expressed on the surface of glioblastoma and some other tumor cells and endothelial cells [23].
• 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 [23].

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 [17].
• RNA transfer blot analysis of biopsies from glioblastoma multiforme showed transcripts for PDGF A and B chains and the PDGF receptor [24].
• 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 [25].
• Expression and rearrangement of the ROS1 gene in human glioblastoma cells [26].
• 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 [27].

Analytical, diagnostic and therapeutic context of Glioblastoma

• In clinical gene-therapy trials for recurrent glioblastomas, transduction of the herpes simplex virus type-1 thymidine kinase (HSV-1-tk) gene with subsequent prodrug activation by ganciclovir was found to be safe, but clinical response was poor [28].
• Nude mice bearing xenografts of U-87MG human glioblastomas were treated with GH-RH antagonist MZ-5-156 [29].
• Immunoprecipitation of proteins extracted from metabolically labeled human glioblastoma and fibrosarcoma cells with antiserum to platelet-derived growth factor (PDGF) showed that these cells express and secrete proteins that are recognized specifically by the antiserum [30].
• Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas [31].
• First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia [32].

References