Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gliomatosis cerebri (GC) is a rare tumor characterized by widespread infiltration of the brain and spinal cord. Although GC usually demonstrates histomorphological features of a low-grade tumor, the formation of secondary highly malignant tumor regions may occur. In order to reveal molecular genetic changes associated with tumor progression in GC, we analyzed factors known to be associated with malignant progression in common astocytomas in an unusual GC case of an 18-year-old patient suffering from this disease for almost 7 years. We detected allelic losses in the Rb gene and in exon 4 of the TP53 gene in a tumor region corresponding to a glioblastoma multiforme. EGFR or MDM2 gene amplifications were absent, and no PTEN mutation or allelic loss on chromosome 10 could be detected. Moreover, compared to tumor-free brain tissue of this patient, tumor regions showed increased EGFR expression. These findings show that malignant progression in GC might be associated with the acquisition of molecular genetic changes also found in low-grade astrocytomas with progression to secondary glioblastoma. These data support the notion that GC can be regarded as a subtype of a common astrocytoma.
...
PMID:Evaluation of molecular genetic alterations associated with tumor progression in a case of gliomatosis cerebri. 1695 19

Glioblastomas are histologically and genetically heterogeneous. We have investigated to what extent histologic features reflect the genetic profile and whether they are predictive of clinical outcome. Key histologic characteristics, including major cell types (small cell, nonsmall cell), other components such as oligodendroglial components, gemistocytes, multinucleated giant cells, as well as necrosis and microvascular proliferation, of 420 cases of glioblastoma within a population-based study (1) were reassessed and correlated with patients' clinical outcome and key genetic alterations. EGFR amplification and p16 homozygous deletion were significantly more frequent in small cell glioblastomas than in nonsmall cell glioblastomas (EGFR, 46% vs 26%, p = 0.0002; p16 39% vs 25%, p = 0.0167). Multivariate analyses with adjustment for age and gender showed that small cell glioblastomas had frequent EGFR amplification and p16 deletion but infrequent PTEN mutations. An oligodendroglial component was detected in 20% of glioblastomas; these patients were significantly younger (54.4 +/- 13.6 vs 59.2 +/- 13.8 years; p = 0.0049) and survived longer (10.3 +/- 8.3 vs 8.2 +/- 8.4 months; p = 0.0647). However, multivariate analyses with adjustment for age and gender did not show the presence of an oligodendroglial component to be predictive of longer survival. After adjustment for age and gender, LOH 1p was associated with longer survival (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0), whereas LOH 10q was associated with shorter survival (hazard ratio, 1.4; 95% CI, 1.0-1.8) of patients with glioblastoma. Glioblastomas containing >or=5% multinucleated giant cells showed more frequent TP53 mutation and infrequent EGFR amplification than those containing <5% multinucleated giant cells (TP53, 45% vs 24%, p = 0.0001; EGFR, 24% vs 42%, p = 0.0005). Vascular proliferation was observed in all glioblastomas, whereas large ischemic and/or pseudopalisading necrosis was observed in 366 of 420 (87%) cases. Glioblastomas with necrosis were associated with older age (59.2 +/- 13.3 vs 51.6 +/- 15.3 years; p = 0.0001) and shorter survival (7.9 +/- 6.8 vs 12.9 +/- 14.2 months; p = 0.0017). Multivariate analyses with adjustment for age and gender confirmed this observation (hazard ratio, 1.5; 95% CI, 1.1-2.0). Multivariate analysis with adjustment for age and gender showed that necrosis was significantly associated with wild-type TP53 and absence of an oligodendroglial component. These results suggest that some histologic features in glioblastomas are associated with specific genetic alterations and with clinical outcome.
...
PMID:Correlation among pathology, genotype, and patient outcomes in glioblastoma. 1695 78

Glioblastoma, the most malignant form of brain cancer, is responsible for 23% of primary brain tumors and has extremely poor outcome. Confounding the clinical management of glioblastomas is the extreme local invasiveness of these cancer cells. The mechanisms that govern invasion are poorly understood. To gain insight into glioblastoma invasion, we conducted experiments on the patterns of growth and dispersion of U87 glioblastoma tumor spheroids in a three-dimensional collagen gel. We studied two different cell lines, one with a mutation to the EGFR (U87DeltaEGFR) that is associated with increased malignancy, and one with an endogenous (wild-type) receptor (U87WT). We developed a continuum mathematical model of the dispersion behaviors with the aim of identifying and characterizing discrete cellular mechanisms underlying invasive cell motility. The mathematical model quantitatively reproduces the experimental data, and indicates that the U87WT invasive cells have a stronger directional motility bias away from the spheroid center as well as a faster rate of cell shedding compared to the U87DeltaEGFR cells. The model suggests that differences in tumor cell dispersion may be due to differences in the chemical factors produced by cells, differences in how the two cell lines remodel the gel, or different cell-cell adhesion characteristics.
...
PMID:A mathematical model of glioblastoma tumor spheroid invasion in a three-dimensional in vitro experiment. 1704 Sep 92

Receptor tyrosine kinase aberrations are implicated in the genesis of gliomas. We investigated expression and amplification of KIT, PDGFRA, VEGFR2, and EGFR in 87 gliomas consisting of astrocytomas, anaplastic astrocytomas, oligodendrogliomas, or oligoastrocytomas in tumor samples collected at the time of the diagnosis and in samples of the same tumors at tumor recurrence. Gene amplifications were investigated using either chromogenic in situ hybridization or fluorescence in situ hybridization, and protein expression using immunohistochemistry. In samples collected at glioma diagnosis, KIT and PDGFRA amplifications were more frequent in anaplastic astrocytomas than in astrocytomas, oligodendrogliomas, and oligoastrocytomas [28% versus 5% (P = 0.012) and 33% versus 2% (P = 0.0008), respectively]. VEGFR2 amplifications occurred in 6% to 17% of the gliomas at diagnosis, and EGFR amplifications in 0% to 12%. Amplified KIT was more frequently present in recurrent gliomas than in newly diagnosed gliomas (P = 0.0066). KIT amplification was associated with KIT protein expression and with presence of PDGFRA and EGFR amplifications both at the time of the first glioma diagnosis and at tumor recurrence, and with VEGFR2 amplification at tumor recurrence. Three (4%) primary gliomas and 10 (14%) recurrent gliomas that were evaluable for coamplification of KIT, PDGFRA, and VEGFR2 showed amplification of at least two of these genes; the amplicon contained amplified KIT in all 13 cases. In conclusion, besides glioblastoma, amplified KIT, PDGFRA, and VEGFR may also occur in lower-grade gliomas and in their recurrent tumors. It is currently not known whether specific tyrosine kinase inhibitors are effective in the treatment of such gliomas.
...
PMID:Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. 1718 83

A novel method for synthesis of anti-EGFR immunoliposomes using folate-folate binding protein (FBP) affinity is described. An anti-EGFR antibody (cetuximab or C225) was covalently linked to FBP via a thioether bond. Liposomes incorporating a lipophilic folate derivative (folate-PEG-cholesterol) were prepared by polycarbonate membrane extrusion. Anti-EGFR immunoliposomes were then obtained by combining FBP-C225 and folate-liposomes and evaluated for uptake and cytotoxicity in EGFR-overexpressing U87 human glioblastoma cells. Anti-EGFR immunoliposomes constructed via folate-FBP affinity exhibited excellent stability under physiological pH, and quickly released the bound FBP-C225 upon low pH (pH 3.5) treatment. Flow cytometry and fluorescence microscopy showed similar receptor-specific binding and internalization for both folate-FBP affinity-coupled and covalently coupled C225-immunoliposomes, but not for the non-targeted IgG-immunoliposomes. C225-immunoliposomes loaded with anticancer drug doxorubicin were more cytotoxic than non-targeted immunoliposomes in EGFR-overexpressing U87 glioma cells. Folate-FBP affinity is a potential method for construction of immunoliposomes and may have applications in synthesis of targeted drug carriers in general.
...
PMID:Construction of anti-EGFR immunoliposomes via folate-folate binding protein affinity. 1721 81

We assessed alterations in the EGFR/PTEN/PI3K pathway in 107 primary (de novo) glioblastomas and 32 secondary glioblastomas that progressed from low-grade or anaplastic astrocytomas. SSCP followed by DNA sequencing in exons 9 and 20 of the PIK3CA gene revealed missense mutations in 5/107 (5%) primary and 1/32 (3%) secondary glioblastomas. Quantitative real-time PCR showed PIK3CA amplification (>3 copy numbers) in 14/107 (13%) primary and 3/32 (9%) secondary glioblastomas. Only one glioblastoma showed both PIK3CA mutation and amplification. Taken together with previously published data on EGFR amplification and PTEN mutations, at least one alteration in the EGFR, PTEN, or PIK3CA genes was detected in 63% of primary glioblastomas, which was significantly more frequent than in secondary glioblastomas (31%; P < 0.001). Furthermore, this signaling pathway was altered by either PTEN mutations or PIK3CA amplification in 10 of 12 (83%) malignant glioma cell lines analyzed. These results suggest that the EGFR/PTEN/PI3K pathway is frequently altered in glioblastomas and is a promising target for therapy, in particular for primary glioblastomas.
...
PMID:PIK3CA alterations in primary (de novo) and secondary glioblastomas. 1723 14

Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16(INK4a) deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C-->A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter ( approximately 70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.
...
PMID:Genetic pathways to primary and secondary glioblastoma. 1745 51

Mutations involving the TP53 gene are frequently identified in up to 50% of all human tumors, including glioblastomas. Analysis of expression patterns of TP53 in glioblastomas shows that it is mainly mutated in secondary glioblastomas and is less common in primary GBMs. However, the prognostic significance of TP53 loss of function in astrocytomas has always been controversial. In contrast, EGFR/erbB2 complexes have been implicated in the poor prognosis of several cancers, including glioblastomas. Our previous work showed that transforming phenotypes could be inhibited by interfering with active EGFR/erbB2 complex using mutant erbB2 proteins in wild-type p53 GBM cells. To assess the dependence of EGFR inhibited phenotype on p53, we used three mutant p53 glioblastoma cell lines in the present study and showed that mutant erbB2 can be exploited to inhibit EGFR-mediated oncogenic transformation irrespective of p53 status. Ectopic expression of a mutant erbB2 receptor (T691S) in mutant p53 GBM cells resulted in slower growth rate than empty vector controls. T691S-expressing clones exhibited a more flattened and nontransformed morphology. Consistently, T691S inhibited transformation in soft agar assays and tumor formation in nude mice independent of p53 status. Biochemical analysis showed reduced Akt and GSK-3 alpha/beta, but not p42/44MAPK phosphorylation, in T691S-expressing cells, when compared to parental controls, suggesting the P13-K pathway may be more relevant than MAPK for glial cell transformation. Cell cycle analysis showed reduced cyclin D1 and CDK6 and increased phospho-Cdc-2 (Tyr15) and p15INK4B in erbB2-inhibited cells, suggesting that nonfunctional EGFR/erbB2 complexes exert their inhibitory effects at various stages of the cell cycle to block the progression of cells through G2/M via Akt/GSK-3/Cdc2 pathway. Collectively, these observations provide a basis for receptor-based therapies that disable erbB receptors and inhibit proliferative signals in erbB-expressing human cancers including glioblastomas, regardless of their TP53 status.
...
PMID:EGFR inhibition in glioblastoma cells induces G2/M arrest and is independent of p53. 1745 42

Congenital central nervous system (CNS) tumors are uncommon, accounting for 1% of all childhood brain tumors. They present clinically either at birth or within the first 3 months. Glioblastoma (GBM) only rarely occurs congenitally and has not been fully characterized. We examined clinicopathologic features and genetic alterations of six congenital GBMs. Tumors were seen by neuroimaging as large, complex cerebral hemispheric masses. All showed classic GBM histopathology, including diffuse infiltration, dense cellularity, GFAP-positivity, high mitotic activity, endothelial proliferation and pseudopalisading necrosis. Neurosurgical procedures and adjuvant therapies varied. Survivals ranged from 4 days to 7.5 years; two of the three long-term survivors received chemotherapy, whereas the three short-term survivors did not. Paraffin-embedded tissue sections were used for FISH analysis of EGFR, chromosomes 9p21 (p16/CDKN2A) and 10q ( PTEN/DMBT1); sequencing of PTEN and TP53; and immunohistochemistry for EGFR and p53. We uncovered 10q deletions in two cases. No EGFR amplifications, 9p21 deletions, or mutations of TP53 or PTEN were noted; however, nuclear p53 immunoreactivity was strong in 5/6 cases. Tumors were either minimally immunoreactive (n = 3) or negative (n = 3) for EGFR. We conclude that congenital GBMs show highly variable survivals. They are genetically distinct from their adult counterparts and show a low frequency of known genetic alterations. Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis.
...
PMID:Congenital glioblastoma: a clinicopathologic and genetic analysis. 1746 90

The G protein-coupled formylpeptide receptor (FPR), which mediates leukocyte migration in response to bacterial and host-derived chemotactic peptides, promotes the chemotaxis, survival, and tumorigenesis of highly malignant human glioblastoma cells. Because glioblastoma cells may also express other receptors for growth signals, such as the epidermal growth factor (EGF) receptor (EGFR), we investigated the role of EGFR in the signaling cascade of FPR and how two receptors cross-talk to exacerbate tumor growth. We found that N-formyl-methionyl-leucyl-phenylalanine, an FPR agonist peptide, rapidly induced EGFR phosphorylation at tyrosine residue (Tyr) 992, but not residues 846, 1068, or 1173, in glioblastoma cells, whereas all these residues were phosphorylated after only EGF treatment. The FPR agonist-induced EGFR phosphorylation in tumor cells was dependent on the presence of FPR as well as Galphai proteins, and was controlled by Src tyrosine kinase. The transactivation of EGFR contributes to the biological function of FPR in glioblastoma cells because inhibition of EGFR phosphorylation significantly reduced FPR agonist-induced tumor cell chemotaxis and proliferation. Furthermore, depletion of both FPR and EGFR by short interference RNA abolished the tumorigenesis of the glioblastoma cells. Our study indicates that the glioblastoma-promoting activity of FPR is mediated in part by transactivation of EGFR and the cross-talk between two receptors exacerbates the malignant phenotype of tumor cells. Thus, targeting both receptors may yield antiglioblastoma agents superior to those targeting one of them.
...
PMID:Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant behavior of human glioblastoma cells. 1757 60


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

---