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

Glioblastomas are the most aggressive primary brain tumors, characterized by their rapid proliferation and diffuse infiltration of the brain tissue. Survival patterns in patients with glioblastoma have been associated with a number of clinicopathologic factors including age and neurologic status, yet a significant quantitative link to in vivo growth kinetics of each glioma has remained elusive. Exploiting a recently developed tool for quantifying glioma net proliferation and invasion rates in individual patients using routinely available magnetic resonance images (MRI), we propose to link these patient-specific kinetic rates of biological aggressiveness to prognostic significance. Using our biologically based mathematical model for glioma growth and invasion, examination of serial pretreatment MRIs of 32 glioblastoma patients allowed quantification of these rates for each patient's tumor. Survival analyses revealed that even when controlling for standard clinical parameters (e.g., age and Karnofsky performance status), these model-defined parameters quantifying biological aggressiveness (net proliferation and invasion rates) were significantly associated with prognosis. One hypothesis generated was that the ratio of the actual survival time after whatever therapies were used to the duration of survival predicted (by the model) without any therapy would provide a therapeutic response index (TRI) of the overall effectiveness of the therapies. The TRI may provide important information, not otherwise available, about the effectiveness of the treatments in individual patients. To our knowledge, this is the first report indicating that dynamic insight from routinely obtained pretreatment imaging may be quantitatively useful in characterizing the survival of individual patients with glioblastoma. Such a hybrid tool bridging mathematical modeling and clinical imaging may allow for stratifying patients for clinical studies relative to their pretreatment biological aggressiveness.
 ...
PMID:Prognostic significance of growth kinetics in newly diagnosed glioblastomas revealed by combining serial imaging with a novel biomathematical model. 1993 35

Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways.
 ...
PMID:Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. 2008 Jun 66

The alpha5beta1 integrin represent a new therapeutic target for glioblastoma, which are malignant brain tumors difficult to cure with conventional therapies. Glioblastoma are known to be highly resistant to chemotherapy. We, therefore, investigated whether blocking alpha5beta1 integrin with specific nonpeptidic antagonists concomitantly with chemotherapy (ellipticine and temozolomide) may impact the response to chemotherapy of human glioblastoma. Here we show that inhibiting alpha5beta1 integrin with 2 selective ligands (SJ749 and K34c) decreases chemotherapy-induced premature senescence and facilitates cell apoptosis in a functional p53 background (U87MG cells). When p53 is mutated and inactive (U373 cells), chemotherapy induces p53-independent cell apoptosis instead of senescence that is not improved by integrin antagonists. Silencing p53 in U87MG cells with siRNA as well as evaluating HCT116 p53+/+ and p53-/- colon carcinoma cell behavior support the hypothesis of an as yet unknown effect of alpha5beta1 integrin antagonists on the control of chemotherapy-induced premature senescence and apoptosis. alpha5beta1 integrin antagonists modulate the p53 signaling induced by chemotherapy. Our results highlight a new role of the alpha5beta1 integrin in the control of glioblastoma aggressiveness and responsiveness to chemotherapy, which may have a crucial impact in the clinical management of patients suffering from brain tumors.
 ...
PMID:alpha5beta1 integrin antagonists reduce chemotherapy-induced premature senescence and facilitate apoptosis in human glioblastoma cells. 2009 78

Allergies and the use of anti-inflammatory medication appear to be associated with reduced glioblastoma risk. However, these observations may merely reflect systemic immunosuppression induced by the tumor. To better understand the effect of this tumor on allergies and inflammation, we used CD133 mRNA expression as an indicator of tumor aggressiveness and systematically examined its relation to mRNA expression levels of 919 allergy- and inflammation-related genes in 142 glioblastoma tissue samples. We found that 69% of these genes are negatively correlated with CD133 expression including allergy-related (eg, interleukin [IL]-4R-alpha; Pearson correlation coefficient [r] = - 0.40; 95% confidence interval [CI] = - 0.53, -0.25) and immunoregulatory genes (eg, TGF-beta1; r = - 0.35; 95% CI = - 0.49, -0.20). Exceptions to this negative trend include the proinflammatory cytokine IL-17-beta (r = 0.22; 95% CI = 0.06, 0.37) and 2 IL-17 receptors. Also positively related to CD133 expression are NCAM-1 (r = 0.45; 95% CI = 0.31, 0.57) and PDGFR-alpha (r = 0.45; 95% CI = 0.30, 0.57). Previous literature suggests that NCAM-1(+) T cells infiltrate glioblastoma and may cause suppression of antitumor immunity, whereas PDGFR-alpha is involved in neurogenesis and amplified in glioblastoma. Ours is the first study to document down-regulation of the majority of allergy- and inflammation-related genes with glioblastoma progression. However, IL-17 and NCAM-1 may play proinflammatory and immunosuppressive roles, respectively, during the late stage of glioblastoma progression. Our findings suggest that immune function continues to change as the tumor progresses.
 ...
PMID:Allergy and inflammatory transcriptome is predominantly negatively correlated with CD133 expression in glioblastoma. 2030 10

Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many reports indicate that YB-1 is highly expressed in tumor cells and is a marker for tumor aggressiveness and clinical prognosis. Here, we show clear evidence that YB-1 is expressed in the angiogenic endothelial cells of various tumors, such as glioblastoma, esophageal cancer, gastric cancer, colon cancer, and lung cancer, as well as in tumor cells. YB-1 was highly expressed in glomeruloid microvascular endothelial cells of brain tumors and microvessels in the desmoplastic region around multiple solid tumors. On the other hand, no or low YB-1 expression was observed in normal angiogenic endothelial cells from fetal kidney, newborn lung, and placenta. The endothelial cells in inflammatory regions of granulomas were also weakly labeled. Knockdown of YB-1 expression by small-interfering RNA induced G1 cell cycle arrest and inhibited the growth of human umbilical vein endothelial cells stimulated by growth factors. Taken together, YB-1 plays an important role in the growth of not only tumor cells but also tumor-associated endothelial cells, suggesting that YB-1 is a promising target for cancer therapy.
 ...
PMID:Y-box binding protein-1 is a novel molecular target for tumor vessels. 2039 58

Supratentorial ependymomas account for a minority of intracranial ependymomas, which still have uncertain prognostic markers. Among them, epidermal growth factor receptor (EGFR) overexpression correlates with a poor prognosis. In glioblastoma cells, EGFR function has been reported to be regulated by its migration from cell membrane infoldings called caveolae and by its colocalization with the caveolae-associated protein caveolin-1 (cav-1). Therefore, we decided to investigate cav-1 expression and coexpression with EGFR in a series of adult intracranial ependymomas. We analyzed 22 adult supratentorial ependymomas and compared tumor grades as determined by the WHO classification and patient survival rates with the expression of EGFR, cav-1, and p53 and the values of the proliferation marker Ki-67, all tested by immunohistochemistry; in addition, we investigated the mutational profile of cav-1. The results demonstrate that the tumor grade is directly correlated with EGFR, Ki-67, and cav-1 expression only, whereas (by univariate analysis) the expression of all the studied markers, as well as the tumor histological grade, significantly correlated with the patient's overall survival (OS). By multivariate analysis using the Cox proportional hazards model, among all variables considered, cav-1 was the only independent prognostic marker related to OS (relative risk = 13.92; P = .013). Among grade II ependymomas, only cav-1 correlated with poor OS (P = .011), distinguishing 2 distinct subgroups of tumors with different outcomes despite sharing identical grading. All the patients studied carried wild-type cav-1 sequences, demonstrating that cav-1 overexpression is not driven by activating mutations, as previously reported in other tumor types. Interestingly, after stratifying all cases into 4 distinct groups according to cav-1 and EGFR expression (cav-1+/EGFR+, cav-1-/EGFR-, cav-1+/EGFR-, and cav-1-/EGFR+), the coexpression of cav-1 and EGFR identified a subset of patients with definitively poor prognoses. Further studies are needed to support this evidence on a larger scale and to clarify how cav-1 and EGFR interaction can influence tumor aggressiveness.
 ...
PMID:Epidermal growth factor receptor and caveolin-1 coexpression identifies adult supratentorial ependymomas with rapid unfavorable outcomes. 2105 55

Experimental models relating to human glioblastoma multiformes (hGBMs) involve the intracranial or intracerebral injection of human GBM cells into nude mice or rats. The aim of the present study was to compare a number of biological characteristics of hGBMs as opposed to experimental GBMs obtained by grafting either human U87 or U373 glioblastoma cells into the brains of nude mice. Biological assessments involve four distinct sets of parameters, i.e. i) the determination of the nuclear DNA content, ii) the determination of proliferative activity, iii) the assessment of p53 nuclear phosphoprotein immunohistochemical reactivity, and iv) the assessment of GFAP, VIM, LEU-7, S-100 and CAT D protein immunohistochemical reactivity. While most of the human glioblastoma multiformes (hGBMs) under study were immunohistochemically reactive to GFAP, S-100, LEU-7 and VIM as indeed were the experimental U373 GBMs, the U87 ones were reactive to VIM only. Furthermore, the U87 GBMs appeared to be more aggressive than the U373 ones since the former were associated with a shorter tumor-bearing mouse survival time than the latter. Such aggressiveness was further associated with a proliferative activity and a cathepsin D immunoreactivity, both of which were markedly higher in the U87 GBMs than in the U373 GBMs. These two experimental GBM models also exhibited tumors which were predominantly diploid. The present study shows that it is possible to set up experimentally in vivo models which strongly mimic human glioblastoma multiformes. Such models consist of grafting human glioblastoma cell lines, namely U87 and U373, into the brains of nude mice. However, while it is true that experimental GBMs closely resemble the hGBMs with respect to some biological characteristics, they also differ in many other significant biological characteristics.
 ...
PMID:The characterization of nuclear-DNA content, the proliferative activity and the immunohistochemical expression of gfap, vim, leu-7, s-100, p53 and cathepsin-d in human glioblastoma multiformes (hgbms) versus human gbm cell-lines grafted into the brains of nude-mice. 2155 62

Glioblastoma multiforme, which represents 80% of malignant gliomas, is characterized by aggressiveness and high recurrence rates. Despite therapeutic advances, patients with glioblastoma multiforme show a poor survival, and identification of novel markers and molecular targets for therapy is needed. A role for BAG3, a member of the BAG family of HSC/HSP70 co-chaperones, in promoting tumor cell growth in vivo has recently been described. We analyzed BAG3 levels by IHC in specimens from patients affected by brain tumors and we found that BAG3, although negative in normal brain tissues, was highly expressed in astrocytic tumors and increasingly expressed in more aggressive types of cancer; it was particularly high in glioblastomas. Down-regulating BAG3 both in vitro and in vivo in a rat glioblastoma model resulted in increased sensitivity to apoptosis, suggesting that BAG3 is a potential target for novel therapies. Finally, we determined that the underlying molecular mechanism requires the formation of a complex of BAG3, HSP70, and BAX that prevents BAX translocation to mitochondria, thus protecting tumor cells from apoptosis. Our data identify BAG3 as a potential marker of glial brain tumor sensitivity to therapy and thus also an attractive candidate for new molecular therapies.
 ...
PMID:BAG3 protein is overexpressed in human glioblastoma and is a potential target for therapy. 2156 97

We examined nm23-H1 protein levels in human oligodendrogliomas by immunohistochemistry. This class of brain tumor does not form spontaneous metastases, but its progression from benign (oligodendroglioma) toward malignant phenotype (oligodendroglioma transitionale and glioblastoma oligodendrogliale) can be followed. Two types of tumors, ODG-II and ODG-T, were highly positive for nm23 protein. However, there was no clear correlation between the extent of protein expression and tumor aggressiveness. No nm23 protein was detected in nonproliferative normal brain tissues and was found in only a few ODG-I specimens. As cell proliferation becomes more pronounced (OGD-II, ODG-T), nm23 protein becomes detectable in almost all samples. However, of the glioblastoma oligodendrogliale samples examined, 76% were negative for nm23-H1 protein. suggesting a change in nm23-H1 gene expression with increasing neoplastic progression. Our findings are in contrast to a proposed role of nm23-H1 protein as a tumor metastasis suppressor and support that it cannot serve as a reliable prognostic tumor indicator in all cases. However, our findings may contribute to a better understanding of glial tumor development and improve the accuracy of tumor diagnosis.
 ...
PMID:Nm23-h1 protein in oligodendrogliomas. 2156 69

Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC(50) in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs.
 ...
PMID:Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca2+ release. 2622 72


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>