Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma is the most malignant and frequent primary brain tumour in adults. Current treatment remains insufficient as these tumours display a diffuse infiltrative growth pattern and tend to recur despite extensive debulking surgery followed by radio- and chemotherapy. The alkylating agents carmustine (1,3-bis-(2-chloroethyl)-1-nitrosourea, or BCNU) and temozolomide (TMZ) are the drugs of choice for adjuvant glioma chemotherapy. However, several independent DNA repair mechanisms can restore the integrity of alkylated DNA bases, and thus contribute to drug resistance and subsequent therapy failure. Recent work suggests that glioblastomas develop as cellular and functional hierarchies through small subpopulations of stem cell-like cancer cells that are responsible for tumour initiation and maintenance. Such cells also appear to possess enhanced DNA repair capacity compared to other cells within the tumours. Challenges in glioblastoma therapy are to determine (1) whether the cancer stem-like cell subpopulations represent a clinically novel target for therapy, and (2) which additional treatment strategies should be applied to improve quality of life and prolong survival of glioblastoma patients. This review addresses clinically relevant mechanisms which contribute to glioma resistance towards current alkylating agent-based chemotherapy, and discusses related mechanisms and treatment strategies in the light of the cancer stem cell hypothesis.
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PMID:DNA repair and cancer stem-like cells--potential partners in glioma drug resistance? 1850 20

Glioblastoma (GBM) is the most common type of primary brain cancer and carries a dismal prognosis primarily due to the emergence of resistance towards extant radiation, conventional and targeted chemotherapies. Although GBM resists therapy-induced apoptosis, tumors show a seemingly paradoxical propensity for florid intratumoral necrogenesis. This necrosis manifests pathologically as microscopic foci or confluent expanses of necrotic tumor. While it is now well recognized that necrosis is an active cell death process and that apoptosis and necrosis death modalities are intertwined on multiple levels, the precise molecular mechanisms and genetic elements underlying these forms of cell death in GBM remain areas of active investigation. In recent oncogenomic studies, we identified a novel GBM oncoprotein, Bcl2-Like 12 (Bcl2L12), which is significantly expressed in the majority of primary GBM tumor specimens and distantly related to canonical Bcl-2 proteins. Due to its distinctive impact on cell death signaling, Bcl2L12 phenocopies pro-necrotic and anti-apoptotic propensities of high grade glioma: Mechanistically, we determined that unlike prototypic Bcl-2 family members, Bcl2L12 does not safeguard mitochondrial membrane integrity, but instead potently inhibits apoptosis at the level of post-mitochondrial effector caspase-3/7 activation. A combination of enforced expression, RNAi-mediated extinction, co-localization and protein interaction studies revealed that Bcl2L12 inhibits caspases 3 and 7 via distinct mechanisms. Direct physical interaction underlies Bcl2L12's inhibition of caspase-7 processing, whereas Bcl2L12-induced transcriptional upregulation of the small heat shock protein alpha B-crystallin is instrumental to neutralization of caspase-3 activation. Mirroring the cellular phenotype elicited by energy depletion, genetic or pharmacologic inhibition of post-mitochondrial apoptosis signaling molecules, Bcl2L12 promotes necrogenesis in glial cells in the context of a proapoptotic stimulus establishing that it represents a novel regulator of the balance between apoptosis and necrosis in GBM.
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PMID:What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator. 1876 59

Glioblastoma is the most common high-grade glioma characterized by strikingly poor therapeutic outcome with survival time of about a year. This makes a search for new therapeutic approaches to glioblastoma treatment an area of great clinical importance. The present study aims to explore the potential of targeted delivery of 125I-radiolabeled antibodies, specific to glial fibrillary acidic protein (GFAP) and AMVB1 (antigen of abluminal membrane of endotheliocytes predominantly expressed in glioblastoma microvessels) as a strategy for in vivo tumor targeting. Rat C6 glioma model was used to test this hypothesis. Tumor bearing animals, injected with radiolabeled monoclonal antibodies to GFAP or AMVB1, were compared to control group, which received nonspecific mouse IgG. Radioactivity of blood, brain hemispheres, and some other tissues was measured 6, 24, 48, 72, and 96 h posttreatment. Our results demonstrate accumulation of both types of antibodies in tumors. Concentrations of both antibodies were significantly increased in tumor-bearing hemisphere compared to intact hemisphere. Antibodies to GFAP specifically accumulated in brain and bound tumor tissue with the high affinity. In contrast, increased accumulation of anti-AMVB1 antibody was detected in antigen-expressing organs, such as spleen and kidney. Based on results presented, we propose that the monoclonal antibodies to GFAP can be used as vectors for the delivery of diagnostic and pharmacological agents to high-grade gliomas. Development of this strategy would open new clinical perspectives for glioblastoma diagnostics and therapy.
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PMID:Targeted transport of 125I-labeled antibody to GFAP and AMVB1 in an experimental rat model of C6 glioma. 1877 45

Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.
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PMID:p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. 1894 56

Glioblastoma tumour cells release microvesicles (exosomes) containing mRNA, miRNA and angiogenic proteins. These microvesicles are taken up by normal host cells, such as brain microvascular endothelial cells. By incorporating an mRNA for a reporter protein into these microvesicles, we demonstrate that messages delivered by microvesicles are translated by recipient cells. These microvesicles are also enriched in angiogenic proteins and stimulate tubule formation by endothelial cells. Tumour-derived microvesicles therefore serve as a means of delivering genetic information and proteins to recipient cells in the tumour environment. Glioblastoma microvesicles also stimulated proliferation of a human glioma cell line, indicating a self-promoting aspect. Messenger RNA mutant/variants and miRNAs characteristic of gliomas could be detected in serum microvesicles of glioblastoma patients. The tumour-specific EGFRvIII was detected in serum microvesicles from 7 out of 25 glioblastoma patients. Thus, tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test.
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PMID:Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. 2041 3

The present study aims to assess the feasibility and the effectiveness of a second-line Fotemustine chemotherapy in patients with recurrent Glioblastoma after standard primary treatment. Between 2005 and 2007, 50 patients with relapsed malignant glioma (median age=56.8 years; median KPS=90) underwent a second-line chemotherapy with Fotemustine. Selected patients were previously treated with a standard 60 Gy Radiotherapy course and Temozolomide Chemotherapy. Patients were stratified into classes according to the prognostic Recursive Partition Analysis. Endpoints of the study were Progression Free Survival at 6 months, duration of Objective Response and Stabilization, Overall Survival and toxicity. At analysis, 36 patients were dead and 14 were alive. Median follow-up from primary diagnosis was 26.6 months. The Efficacy control of the disease was 62%. PFS was 6.1 months; PFS-6 was 52% and median overall survival from primary diagnosis was 24.5 months, with few manageable haematological toxicities. Fotemustine was safe and effective as second-line chemotherapy in recurrent glioblastoma.
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PMID:A multi-institutional phase II study on second-line Fotemustine chemotherapy in recurrent glioblastoma. 1901 76

Glioblastoma is a severe type of primary brain tumor, and its highly invasive character is considered to be a major therapeutic obstacle. Phospholipase D (PLD) isozyme is overexpressed in various human tumor tissues and involved in tumorigenesis. However, the molecular mechanisms by which PLD enhances glioma invasion are unknown. In this study, we demonstrate that the increased expression of PLD and its enzymatic activity in the glioma stimulate the secretion and expression of matrix metalloproteinase (MMP)-2 and induce the invasiveness of glioma cells. The upregulation of MMP-2 induced by phosphatidic acid (PA), the product of PLD, was mediated by protein kinase C (PKC), protein kinase A (PKA), nuclear factor-kappaB (NF-kappaB) and Sp1 and it enhanced glioma cell invasion. PA activated PKC and PKA and induced the nuclear translocation and transactivation of NF-kappaB. PA also increased the binding of NF-kappaB and Sp1 to the MMP-2 promoter. Mutation of the NF-kappaB- or Sp1-binding sites significantly attenuated MMP-2 promoter activity. This is the first report to show that NF-kappaB and Sp1 are essential transcriptional factors linking PLD to MMP-2 upregulation, providing evidence that PLD contributes to glioma progression by enhancing MMP-2 expression and tumor cell invasion via PKC/PKA/NF-kappaB/Sp1-mediated signaling pathways.
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PMID:Overexpression of phospholipase D enhances matrix metalloproteinase-2 expression and glioma cell invasion via protein kinase C and protein kinase A/NF-kappaB/Sp1-mediated signaling pathways. 1912 47

Glioblastoma stem cells are able to reform original glioblastoma and express the neural stem cell marker CD133 and Nestin. They can self-renew and proliferate in tumor sphere medium containing EGF, bFGF and LIF that is known to be permissive for stem cell proliferation. In this study, we found that neurosphere-like colonies appeared after the human primary glioblastoma cells had been switched into pure DMEM/F12 medium. We investigated whether tumor spheres formed in pure DMEM/F12 medium possess the characteristics of glioblastoma stem cells. We identified that the tumor sphere cells were cancer stem cells of glioblastoma and they can self-renew and proliferate in pure DMEM/F12 medium. Glioblastoma cells can secrete several factors that result in autocrine motility signaling and stimulate glioma invasion. We hypothesized that an essential autocrine signal promotes the self-renewal and proliferation of human glioblastoma stem cells in pure DMEM/F12 medium. Then, expression of EGF and bFGF in glioblastoma stem cells were analyzed. Both the mRNA and protein of EGF and bFGF were detected in three human glioblastoma stem cells. Our findings suggest that autocrine of EGF and bFGF may sustain the self-renewal of glioblastoma stem cells.
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PMID:Autocrine factors sustain glioblastoma stem cell self-renewal. 1914 17

Glioblastoma (GBM) is a highly lethal primary brain cancer with hallmark features of diffuse invasion, intense apoptosis resistance and florid necrosis, robust angiogenesis, and an immature profile with developmental plasticity. In the course of assessing the developmental consequences of central nervous system (CNS)-specific deletion of p53 and Pten, we observed a penetrant acute-onset malignant glioma phenotype with striking clinical, pathological, and molecular resemblance to primary GBM in humans. This primary, as opposed to secondary, GBM presentation in the mouse prompted genetic analysis of human primary GBM samples that revealed combined p53 and Pten mutations as the most common tumor suppressor defects in primary GBM. On the mechanistic level, the "multiforme" histopathological presentation and immature differentiation marker profile of the murine tumors motivated transcriptomic promoter-binding element and functional studies of neural stem cells (NSCs), which revealed that dual, but not singular, inactivation of p53 and Pten promotes cellular c-Myc activation. This increased c-Myc activity is associated not only with impaired differentiation, enhanced self-renewal capacity of NSCs, and tumor-initiating cells (TICs), but also with maintenance of TIC tumorigenic potential. Together, these murine studies have provided a highly faithful model of primary GBM, revealed a common tumor suppressor mutational pattern in human disease, and established c-Myc as a key component of p53 and Pten cooperative actions in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal, and tumorigenic potential.
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PMID:Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. 1915 Sep 64

Glioblastoma is defined by its aggressive invasion, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and epidermal growth factor receptor by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phospho-SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. Reduction of invasive potential was observed in vitro at concentrations well below the IC(50) of dasatinib, which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in focal adhesion kinase autophosphorylation. Cell cycle analysis revealed minimal G(1) arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in light chain 3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death. Dasatinib in combination with temozolomide more effectively increased the therapeutic efficacy of temozolomide than when dasatinib was combined with carboplatin or irinotecan. These results strongly support the clinical use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide.
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PMID:Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. 1919 Jan 19


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