Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma (GBM) remains a highly lethal neoplasm, refractory to current therapies. The molecular genetic aberrations most closely related to clinical aggressiveness in GBM have been difficult to identify, perhaps due in part to the short survival range observed in cohorts of GBM patients. To address this, we characterized 39 tumors from rare patients (2-5% of all GBM cases) who experienced long-term survival (>3 years) using comparative genomic hybridization as a genome-wide screen. We then compared the frequency and type of aberrations with those in tumors from 24 typical or short-term survivors [STSs (<1.5 years)]. Losses of 9p and 10 and simple gains of chromosome 7 showed at least trends toward increased frequency in the STS group. Additional aberrations, including loss of 6q and gains of 19q and 20q, were significantly more frequent in the STS group. The presence of 19q loss was exclusive to the long-term survivor (LTS) group. Multivariate analyses indicated that 6q loss, 10q loss, and 19q gain were associated with short-term survival (all P < 0.01). The combination of any two of these three aberrations was seen in 16 of 24 STSs but only 1 of 39 LTSs. This comparison of rare LTSs with STSs (typical GBM survivors) identified 6q loss, 10q loss, and 19q gain, particularly when two or more of these were present, as most closely associated with aggressive clinical behavior in GBM. Loss of 19q may be a marker of long-term survival.
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PMID:Genetic aberrations defined by comparative genomic hybridization distinguish long-term from typical survivors of glioblastoma. 1241 48

Advances in the immunohistochemical detection of neuron-specific and neuronal-associated antigens have resulted in the discovery of neuronal elements in certain primary human brain tumors. The results have been not only to expand what neuropathologists commonly recognize as gangliogliomas, including the tumors now known as glioneurocytic tumor with neuropil rosettes and papillary ganglioneuroma, but also to expand the spectrum of tumor types to now include tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma. These discoveries have helped us to better understand the biology of these tumors and to refine our classification of them. Distinctions among these tumors include sites of predilection, such as the temporal lobe with the dysembryoplastic neuroepithelial tumors, and a spectrum of clinical aggressiveness that spans indolent "quasi-hamartomatous" lesions, such as the dysembryoplastic neuroepithelial tumor, to high-grade, highly aggressive tumors, such as the supratentorial primitive neuroectodermal tumor (World Health Organization Grade IV). Many of these tumors also commonly exhibit a glial component, as determined by both their histologic appearance and their immunoreactivity for glial fibrillary acidic protein. This review covers these recently described lesions, including the desmoplastic infantile ganglioglioma, the dysembryoplastic neuroepithelial tumor, the papillary glioneuronal tumor, the glioneuronal tumor with neuropil rosettes, and the mixed glioblastoma-cerebral neuroblastoma (supratentorial primitive neuroectodermal tumor), as well as the known tumors, ganglioglioma, medulloepithelioma, and medulloblastoma. For pathologists confronted by this growing array of tumors and subtypes, it is appropriate to focus on them and understand the differential diagnosis to be considered when confronted by them.
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PMID:Glioneuronal tumors of the central nervous system. 1262 33

Effects of ionising radiation on extracellular matrix (ECM)-modulated cell survival and on adhesion and invasion are not well understood. In particular, the aggressiveness of glioblastoma multiforme has been associated with tumour cell invasion into adjacent normal brain tissue. To examine these effects in more depth, four human glioblastoma cell lines (A-172, U-138, LN-229 and LN-18) were irradiated on fibronectin (FN), Matrigel, BSA or polystyrene. Major findings of this study include a significantly increased survival of irradiated A-172 but not of irradiated U-138, LN-229, and LN-18 cells on FN or Matrigel compared to cells irradiated on polystyrene or BSA. Irradiation induced a dose-dependent increase in functional beta 1- and beta 3-integrins in all four glioma cell lines. This integrin induction caused improved cell adhesion to FN or Matrigel. In contrast to U-138, LN-229 and LN-18 cells, irradiation strongly impaired A-172 cell invasion. Invasion of all cell lines was inhibited by anti-integrin antibodies, the disintegrin echistatin and the MMP-2/-9 inhibitor III. Additionally, beta 1- and beta 3-integrins modulated basal and radiation-altered gelatinolytic activity of MMP-2. Tested glioblastoma cell lines showed a differential cellular susceptibility to FN or Matrigel which affected the cellular radiosensitivity. Three out of four glioma cell lines demonstrated a combination of a substratum-independent survival after irradiation and an invasive potential which was not affected by irradiation. beta 1- and beta 3-integrins were identified to play a substantial, regulatory role in survival, adhesion, invasion and MMP-2 activity. Detailed insights into radioresistance and invasion processes might offer new therapeutic strategies to enhance cell killing of lethal high-grade astrocytoma.
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PMID:Irradiation differentially affects substratum-dependent survival, adhesion, and invasion of glioblastoma cell lines. 1464 48

Historically, in vivo imaging methods have largely relied on imaging gross anatomy. More recently it has become possible to depict biological processes at the cellular and molecular level. These new research methods use magnetic resonance imaging (MRI), positron emission tomography (PET), near-infrared optical imaging, scintigraphy, and autoradiography in vivo and in vitro. Of primary interest is the development of methods using MRI and PET with which the progress of gene therapy in glioblastoma (herpes simplex virus-thymidine kinase) and Parkinson's disease can be monitored and graphically displayed. The distribution of serotonin receptors in the human brain and the duration of serotonin-receptor antagonist binding can be assessed by PET. With PET, it is possible to localize neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. MR tracking of transplanted oligodendrocyte progenitors is feasible for determining the extent of remyelinization in myelin-deficient rats. Stroke therapy in adult rats with subventricular zone cells can be monitored by MRI. Transgene expression (beta-galactosidase, tyrosinase, engineered transferrin receptor) can also be visualized using MRI. Macrophages can be marked with certain iron-containing contrast agents which, through accumulation at the margins of glioblastomas, ameliorate the visual demarcation in MRI. The use of near-infrared optical imaging techniques to visualize matrix-metalloproteinases and cathepsin B can improve the assessment of tumor aggressiveness and angiogenesis-inhibitory therapy. Apoptosis could be detected using near-infrared optical imaging representation of caspase 3 activity and annexin B. This review demonstrates the need for neurohistological research if further progress is to be made in the emerging but burgeoning field of molecular imaging.
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PMID:Molecular imaging: Bridging the gap between neuroradiology and neurohistology. 1502 22

Astrocytic tumors' aggressiveness results from an imbalance between cell proliferation and cell death favoring growth, but also from the propensity of tumor cells to detach from the primary tumor site, migrate, and invade the surrounding parenchyma. Astrocytic tumor progression is known to be associated with an increased expression of galectin-3. We investigated in cell culture how galectin-3 expression affects astrocytoma cell motility. Galectin-3 deficient cells were obtained by stable transfection of the U373 glioblastoma cell line with a specific expression antisense plasmid. Cultured galectin-3 deficient glioblastoma cells showed increased motility potential on laminin and modifications in the cytoskeleton reorganization. In addition, c-DNA microarrays and quantitative immunofluorescence analysis showed that galectin-3 deficient U373 cells have an increased expression of integrins-alpha6 and -beta1, proteins known to be implicated in the regulation of cell adhesion.
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PMID:Multifaceted role of galectin-3 on human glioblastoma cell motility. 1555 81

The matrix metalloproteinase (MMP) family members catalyze extracellular proteolysis. Recent reports have suggested that expression of MMP-2 and -9 might play a critical role in neoplastic tissue invasion or metastasis. In this study, the relationship between the expression of MMP-2 and -9 and the histological features of tissues from 21 cases of human glioma were investigated. MMP-2 and -9 proteins were detected by immnohistochemical studies. Amplification of MMP-2 and -9 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) assay. MMP-2 and -9 mRNA was measured quantitatively by the real-time RT-PCR method. Immunohistochemically, 38% of the cases were positive for MMP-2. Amplification of MMP-2 mRNA by RT-PCR was detected in 62% of the cases. There was no significant relationship between the expression of MMP-2 protein or mRNA and the biological nature of the tumors, including aggressiveness and histologic classification. The quantity of MMP-2 mRNA was 0.035 +/- 0.113 (MMP-2/GAPDH %), which was significantly elevated in cases of neoplastic dissemination or recurrence (P < 0.05). Tumor cells were immunohistochemically positive for MMP-9 in 81% of the samples. A positive reaction was found not only in neoplastic cells but also in endothelial cells, suggesting that the expression of MMP-9 protein might be associated with tumoral angiogenesis. The expression of mRNA in MMP-9 was detected in 91% of the cases, suggesting a close relationship between expression of MMP-9 and malignancy. The quantity of MMP-9 was 0.097 +/- 0.113 (MMP-9/GAPDH %) in all samples, which was significantly elevated in cases of glioblastoma (P < 0.05). The average Ki-67 labeling index was 8.14 +/- 5.26 in samples from G2 glioma, 19.92 +/- 11.29 in samples from G3 glioma, and 23.52 +/- 10.14 in samples from glioblastoma. All of the cases with elevated indices had recurrence or dissemination. The results of our study suggest that quantity analyses of MMP-2 and -9 mRNA and Ki-67 labeling index should be useful for discerning tumoral behaviors such as invasion, dissemination, and recurrence.
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PMID:Expression and quantitative analysis of matrix metalloproteinase-2 and -9 in human gliomas. 1569 70

Hypoxia is a crucial factor in tumor aggressiveness and resistance to treatment, particularly in glioma. Our previous results have shown that inhibiting the small GTPase RhoB increased oxygenation of U87 human glioblastoma xenografts, in part, by regulating angiogenesis. We investigated here whether RhoB might also control a signaling pathway that would permit glioma cells to adapt to hypoxia. We first showed that silencing RhoB with siRNA induced degradation and inhibition of the transcriptional activity of the hypoxia-inducible factor by the proteasome in U87 hypoxic cells. This RhoB-dependent degradation of hypoxia-inducible factor-1alpha in hypoxic conditions was mediated by the Akt/glycogen synthase kinase-3beta pathway. While investigating how hypoxia could activate this signaling pathway, using the GST-Rhotekin RBD pulldown assay, we showed the early activation of RhoB by reactive oxygen species under hypoxic conditions and, subsequently, its participation in the ensuing cellular adaptation to hypoxia. Overall, therefore, our results have not only highlighted a new signaling pathway for hypoxia controlled by the small GTPase RhoB, but they also strongly implicate RhoB as a potentially important therapeutic target for decreasing tumor hypoxia.
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PMID:Activation of RhoB by hypoxia controls hypoxia-inducible factor-1alpha stabilization through glycogen synthase kinase-3 in U87 glioblastoma cells. 1639 64

In vitro and in vivo studies have demonstrated inhibition of glioblastoma growth by imatinib mesylate (Gleevec). Imatinib is an inhibitor of the tyrosine kinase activities of platelet-derived growth factor receptor (PDGF-r), which is involved in glioblastoma aggressiveness. In this study, we have investigated the link between 99mTc-(V)-DMSA, an imaging agent used in Single Photon Emission Computed Tomography, cellular accumulation and the biological effects of imatinib mediated by PDGF-r in a human glioblastoma cell line U87-MG. Cells treated with imatinib showed significant decreases in proliferation, invasion, migration and PDGF-rbeta expression. 99mTc-(V)-DMSA cellular uptake studies showed that the specific action of imatinib on PDGF-r signal pathway, in the human glioblastoma cell line U87-MG, could be followed by radioactive tracer. Furthermore, strong correlations between cellular 99mTc-(V)-DMSA uptake and the effect of imatinib therapy on U87-MG proliferation (r=0.896), invasion (r=0.621) and migration (r=0.822) were obtained, likewise for 99mTc-(V)-DMSA uptake and PDGF-r expression (r=0.958). Our results show that the biological effects of imatinib therapy on tumour cells properties are linked to PDGF-r phosphorylation and could be traced with 99mTc-(V)-DMSA, which also seems to be a potential tracer to evaluate the response to imatinib therapy in glioblastoma.
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PMID:Evaluation of imatinib mesylate effects on glioblastoma aggressiveness with SPECT radiotracer 99mTc-(v)-DMSA. 1656 90

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.
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PMID:TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells. 1662 57

Magnetic resonance imaging reveals heterogeneous regions within high-grade gliomas, such as a contrast-enhanced rim, a necrotic core, and non-contrast-enhanced abnormalities. It is unclear which of these regions best describes tumor aggressiveness. We hypothesized that the vascular leakage volume, reflecting disorganized angiogenesis typical of glioblastoma, would be a strong predictor of clinical outcome. The FLAIR tumor volume, post-gadolinium T1 tumor volume, tumor vascular leakage volume determined by dynamic contrast-enhanced imaging, and volume of the contrast-enhanced rim seen on post-gadolinium T1-weighted images were defined for 20 patients about to undergo treatment for newly diagnosed high-grade gliomas. The potential for imaging characteristics to improve prediction of survival and time to progression over clinical variables was tested by using Cox regression analysis. Single-variable Cox regression analysis of each of the four tumor subvolumes revealed that the vascular leakage volume was the only significant predictor of survival. When the joint effect of clinical variables and the vascular leakage volume were tested for prediction of survival, only the age and the vascular leakage volume were selected as significant predictors. However, when time to progression was tested as a dependent variable, both the vascular leakage volume and the vascular permeability were selected as copredictors, along with surgical status. Our findings suggest that for patients with high-grade glioma, time to progression after radiation therapy is influenced by both underlying biological aggressiveness (vascularity) and volume of aggressive tumor. In contrast, survival depends chiefly on the volume of aggressive tumor at the time of presentation.
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PMID:The extent and severity of vascular leakage as evidence of tumor aggressiveness in high-grade gliomas. 1695 Dec 9


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