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)

Basic fibroblast growth factor (bFGF) is a broad spectrum mitogen for many cells of neuroectodermal origin, including glial cells. The human malignant glioblastoma cell line U87-MG expresses high steady state levels of the bFGF mRNA and contains abundant stores of biologically active bFGF protein. In the present study we have examined the contribution of endogenous bFGF to the autocrine growth of these cells. Using reverse transcription-polymerase chain reaction, U87-MG cells were shown to express the mRNAs for both bFGF and the bFGF receptor, confirming the existence of the basic requirements for an autocrine loop. Addition of 5 microM bFGF-specific antisense oligonucleotide to U87-MG cultures significantly inhibited the growth rate of these cells within 48 h and blocked proliferation beyond 2 days. The corresponding bFGF-specific sense oligonucleotide did not significantly inhibit cell proliferation over the course of these experiments. Similarly, antisense oligonucleotides significantly inhibited colony formation in soft agar, while the sense sequence was without effect. Western blotting with antihuman bFGF revealed that U87-MG cells synthesize three isoforms of bFGF, approximately 18, 23, and 25 kilodaltons (kDa) in size. The 23- and 25-kDa isoforms together comprise approximately 80% of the total cellular stores of bFGF. Antisense treatment for 4 days reduced the abundance of the 23- and 25-kDa isoforms by 64-74%, but had little effect on the 18-kDa isoform. The inhibitory effect of the antisense oligonucleotides on anchorage-dependent proliferation was reversed by the addition of recombinant 18-kDa human bFGF.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Phosphorothioate antisense oligonucleotides against basic fibroblast growth factor inhibit anchorage-dependent and anchorage-independent growth of a malignant glioblastoma cell line. 132 55

We report here that a neutralizing mouse monoclonal antibody against basic FGF inhibited both anchorage-dependent and anchorage-independent growth of U-87MG and T98G human glioblastoma cells and HeLa cells, all of which express both the basic FGF and the FGF receptor genes. In addition, the subcutaneous administration of this antibody significantly suppressed the tumor development of these tumor cells in nude mice. Therefore, basic FGF plays an important role in neoplastic growth of these cells. The neutralization of basic FGF will be effective in controlling the growth of tumors, such as glioblastoma and other cancer cells which bear basic FGF and FGF receptors.
 ...
PMID:Inhibition of cell growth and tumorigenesis of human glioblastoma cells by a neutralizing antibody against human basic fibroblast growth factor. 165 81

We have previously reported the tissue specific distribution of four different FGF-1 transcripts containing alternative 5' untranslated exons spliced to the first protein coding exon. The predominant transcript in brain is FGF-1.B and in kidney FGF-1.A. Others have shown, by in situ hybridization and immunohistochemical analysis, that expression of FGF-1 in the brain is exclusively in neural cells but not in glial cells. Here we have examined the distribution of FGF-1.B and FGF-1.A transcripts in glioblastoma and retinal tissues and in kidney carcinoma cell lines. Our results show that FGF-1.B is the predominant transcript in neural derived tissues including both the diabetic retina and normal retina tissues. Surprisingly, FGF-1.B transcript is highly expressed in glioblastoma tissues. In contrast, a normal brain glial cell line, CHII, expresses very low levels of FGF-1 mRNA. These results strongly implicate the role of FGF-1 in the etiology of glioblastoma. We also examined several kidney carcinoma derived cell lines for the expression of FGF-1 mRNA. Most of these kidney cell lines do not express any FGF-1 transcripts. An interpretation by deduction is that kidney adenocarcinomas are derived from cortex but medulla has been reported as the site of FGF-1 synthesis. Of the kidney derived cell lines which are positive for FGF-1 message, only one expressed FGF-1.A transcript. The data may suggest that the establishment of kidney cell lines results in a switch of promoter usage from the 1.A seen in kidney tissue. Similarly, culturing of glioma cell lines may result in a switch from FGF-1.B seen in glioma tissues to FGF-1.D seen in most glioma cell lines. Continued studies of the FGF-1 transcripts, their functional promoters and their tissues distribution will provide insight into the potential role of FGF-1 in cell growth, tissue differentiation and malignant transformation.
 ...
PMID:Different fibroblast growth factor 1 (FGF-1) transcripts in neural tissues, glioblastomas and kidney carcinoma cell lines. 754 53

Expression of alternatively spliced human FGF-1 (or aFGF) transcripts is regulated in a tissue-specific manner via multiple promoters. To identify the cis-regulatory elements in the brain-specific FGF-1.B promoter, we constructed a series of promoter deletions fused to the luciferase reporter gene and transfected into an FGF-1.B positive glioblastoma cell line, U1240MG, and a 1.B negative cell line, U1242MG. Results of transient transfections indicate three elements that are involved in the positive regulation of FGF-1.B expression. The core promoter is located in a 40-base pair region (between -92 and -49), and two regulatory regions (RR-1 and RR-2) are located within the 540-base pair region 5' to the major transcription start site (defined as +1). Electrophoretic mobility shift assays and footprinting analysis have identified sequence-specific binding sites in RR-1 and RR-2. Mutants of RR-2 abolished binding to nuclear proteins and showed diminished luciferase reporter activity. The effects seen are specific for the U1240MG cell line, supporting a role for RR-2 in the tissue-specific regulation of FGF-1.B. Southwestern analysis using an oligonucleotide probe derived from RR-2 (nucleotides -489 to -467) further identified a 37-kDa protein that is present in nuclear extracts from U1240MG and brain but not from U1242MG.
 ...
PMID:Functional characterization of the brain-specific FGF-1 promoter, FGF-1.B. 771 33

Mutations of the p53 gene are found in various human cancers. The frequency of its mutation is reported to increase during tumor progression in most tumors. In human gliomas, mutations of the p53 gene are found in about one-third of the malignant forms and in few of the benign ones, indicating their possible involvement in tumor progression. On the other hand, we have recently shown that basic fibroblast growth factor (basic FGF) plays a crucial role in tumor progression as an autocrine growth factor in tissues of human gliomas. Therefore, we hypothesized that p53 might regulate the promoter activity of the basic FGF gene, which has several GC boxes and no typical TATA box. In this study, cotransfection assays using human glioblastoma and hepatocellular carcinoma cells and establishment of stable cell lines expressing mutant-type p53 were performed. The basic FGF gene promoter was demonstrated to be regulated by p53 at the transcriptional level and its basal core promoter was found to be responsive to p53. Expression of endogenous basic FGF was also demonstrated to be activated by mutant type p53. Wild-type p53 repressed gene expression of the basic FGF and its mutant activated it in vitro, implying one of the possible pathways in tumor progression.
 ...
PMID:Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. 809 Jul 61

Four different transcripts encoding fibroblast growth factor 1 (FGF-1, also known as aFGF) have been previously identified in our laboratory. Among them, FGF-1.B is the major transcript expressed specifically in the neuronal cells in brain tissue. Using the transient transfection experiment in a glioblastoma cell line, U1240MG, that expresses 1.B, we previously identified two regulatory regions (RR1 and RR2) in the brain-specific promoter, FGF-1.B. In the present study, we showed that the minimal region required for the DNA-protein interaction in RR2 resides in an 18-base pair (-484 to -467) sequence, by using DNase I footprinting and methylation interference studies and electrophoretic mobility shift assays. This minimal cis-acting element was found to be sufficient in enhancing the reporter activity driven by the heterologous herpes simplex virus thymidine kinase promoter in the 1.B-positive U1240MG cell line. This enhancing effect, however, was not detected in a glioblastoma cell line, U1242MG, which is negative for 1.B expression. By electrophoretic mobility shift assays, we also identified a specific DNA-protein complex, namely complex I, which is specific for 1.B-positive cell lines and human brain tissue. By in situ UV cross-linking experiment, we further showed that complex I contains two major DNA-binding proteins of apparent molecular masses of 37 and 98 kDa. Our results suggest that the formation of complex I, resulting from the heterodimerization of a 37-kDa protein (1.B-specific) and a 98-kDa protein (ubiquitous) may likely be a prerequisite for the enhanced expression of 1.B transcript in neuronal cells.
 ...
PMID:Transcriptional activation of fibroblast growth factor 1.B promoter is mediated through an 18-base pair cis-acting element. 905 60

Fibroblast growth factor-9 (FGF-9) is a relatively new member of the FGF family isolated from the conditioned medium of a human glioblastoma cell line as a secreting-type factor that exhibits a growth-stimulating effect on cultured glial cells. In order to elucidate the roles of FGF-9 in the central nervous system, we investigated in detail the distribution of FGF-9 proteins in the normal human and rat brains by immunohistochemistry using two different antibodies specific to FGF-9. In both human and rat, a strong expression of FGF-9 immunoreactivity was localized mainly in neurons throughout the normal brain. Immunoreactive glial cells were rarely encountered. In the human brain, strong and uniform immunoreactivity was observed in neurons of cerebral cortex, hippocampus, substantia nigra, motor nuclei of the brainstem, and Purkinje cell layer. A detailed mapping in the rat brain showed a distribution of FGF-9 immunoreactivity in a widespread population of neurons, though the intensity varied between different locations and even among the same nucleus. The most prominent expression in rat was observed in neurons of the mitral cell layer of the olfactory bulb, red nucleus, mesencephalic trigeminal nucleus, motor trigeminal nucleus, facial nucleus, reticular nucleus and Purkinje cell layer. These findings suggest that FGF-9 plays an important role in the central nervous system and may have a potential function closely connected to neurons in the normal brain.
 ...
PMID:Neuronal localization of fibroblast growth factor-9 immunoreactivity in human and rat brain. 950 14

We recently developed a method for the isolation and purification of tumour-derived endothelium. In this study the phenotypic and functional properties of human tumour-derived microvascular endothelial cells (TdMEC) were examined. Endothelium obtained from human adrenal gland specimens (HAMEC) was used as a reference microvascular endothelial cell population. TdMEC formed a confluent monolayer with the typical morphological appearance of endothelium and were positive for endothelial markers such as Ulex-1 lectin, CD31 antigen, von Willebrand Factor and VE-cadherin. The addition of acidic Fibroblast Growth Factor (aFGF), basic FGF (bFGF) or Vascular Endothelial Growth Factor (VEGF) substantially improved proliferation of TdMEC; and kidney carcinoma derived endothelial cells were more responsive to FGFs, whereas glioblastoma derived endothelial cells greatly responded to VEGF TdMEC expressed high levels of the VEGF receptors, KDR/flk-1 and Flt-1, as shown by northern blot analysis. TdMEC expressed the adhesion molecules ICAM-1, VCAM-1 and E-selectin that could be further increased by exposing TdMEC culture to interleukin-1. All the TdMEC expressed interleukin-8 mRNA. These findings show that TdMEC in vitro maintain several of the features described for microvasculature. Thus, TdMEC represent a useful tool to study markers for tumor vasculature.
 ...
PMID:Phenotypic and functional characteristics of tumour-derived microvascular endothelial cells. 1091 10

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
 ...
PMID:AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. 1760 54

Fibroblast growth factor 1 (FGF1) has been suggested to have an important role in cell growth, proliferation, and neurogenesis. Human FGF1 gene 1B promoter (-540 to +31)-driven green fluorescence (F1BGFP) has been shown to monitor endogenous FGF1 expression. F1BGFP could also be used to isolate neural stem/progenitor cells from embryonic, neonatal, and adult mouse brains or to isolate glioblastoma stem cells (GBM-SCs) from human glioblastoma tissues. Here, we present evidence that transcription factor RFX1 could bind the 18-bp cis-elements (-484 to -467) of the F1B promoter, modulate F1BGFP expression and endogenous FGF1 expression, and further regulate the maintenance of GBM-SCs. These observations were substantiated by using yeast one-hybrid assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, gain- and loss-of-function assays, and neurosphere assays. Overexpression of RFX1 was shown to down-regulate FGF-1B mRNA expression and neurosphere formation in human glioblastoma cells, whereas RNA interference knockdown of RFX1 demonstrated the opposite effects. Our findings provide insight into FGF1 gene regulation and suggest that the roles of FGF1 and RFX1 in the maintenance of GBM-SCs. RFX1 may negatively regulate the self-renewal of GBM-SCs through modulating FGF-1B and FGF1 expression levels by binding the 18-bp cis-elements of the F1B promoter.
 ...
PMID:Regulation of FGF1 gene promoter through transcription factor RFX1. 2018 86


1 2 3 Next >>