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

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

We have shown previously that the multifunctional cytokine scatter factor/hepatocyte growth factor (SF/HGF) is elevated in human malignant gliomas. In this study we investigated how human SF/HGF expression affects the malignancy of the U373 human glioblastoma cell line in vivo and in vitro. Human SF/HGF gene transfer increased U373 glioblastoma tumorigenicity by > or = 20-fold and enhanced the growth rate of intracerebral U373 xenografts by 3- to 8-fold. SF/HGF expression had no effect on the proliferation of glioblastoma cell monolayers but increased their anchorage-independent colony formation in soft agar by 5- to 8-fold. These results are the first to show that SF/HGF expression by human glioblastoma cells enhances their growth dysregulation in vitro and malignancy in vivo.
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PMID:Scatter factor/hepatocyte growth factor expression enhances human glioblastoma tumorigenicity and growth. 920 32

Hepatocyte growth factor/scatter factor (HGF/SF) contributes to the malignant progression of human gliomas. We investigated the effect of HGF/SF on matrix metalloproteinase-2 (MMP-2), membrane type 1 matrix metalloproteinase (MT1-MMP) and tissue inhibitors of metalloproteinases (TIMPs), expressions of c-Met/HGF receptor-positive human glioblastoma cells. Treatment of U251 human glioblastoma cells with HGF/SF resulted in enhanced secretion of MMP-2 with an increased level of the active form. This was accompanied by enhanced expression (2.5-fold) of mRNA specific for MMP-2. The stimulatory effect of HGF/SF on MMP-2 expression did not occur in the presence of herbimycin A, a protein tyrosine kinase inhibitor. MT1 -MMP, a cell-surface activator of proMMP-2, was also up-regulated by HGF/SF in a dose-dependent manner. By contrast, the level of TIMP- 1 mRNAs was not altered significantly and that of TIMP-2 was reduced mildly by the HGF/SF treatment, suggesting that HGF/SF may eventually modulate a balance between MMP-2 and TIMPs in favor of the proteinase activity in the glioma cell microenvironment. HGF/SF also stimulated MMP-2 expression of other glioblastoma cell lines. Since glioblastomas frequently co-express HGF/SF and its receptor, our results suggest that HGF/SF might contribute to the invasiveness of glioblastoma cells through autocrine induction of MMP-2 expression and activation.
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PMID:Regulation of matrix metalloproteinase-2 (MMP-2) by hepatocyte growth factor/scatter factor (HGF/SF) in human glioma cells: HGF/SF enhances MMP-2 expression and activation accompanying up-regulation of membrane type-1 MMP. 1038 63

Strategies that antagonize growth factor signaling are attractive candidates for the biological therapy of brain tumors. HGF/NK2 is a secreted truncated splicing variant and potential antagonist of scatter factor/hepatocyte growth factor (SF/HGF), a multifunctional cytokine involved in the malignant progression of solid tumors including glioblastoma. U87 human malignant glioma cells that express an autocrine SF/HGF stimulatory loop were transfected with the human HGF/NK2 cDNA and clonal cell lines that secrete high levels of HGF/NK2 protein (U87-NK2) were isolated. The effects of HGF/NK2 gene transfer on the U87 malignant phenotype were examined. HGF/NK2 gene transfer had no effect on 2-dimensional anchorage-dependent cell growth. In contrast, U87-NK2 cell lines were approximately 20-fold less clonogenic in soft agar and approximately 4-fold less migratory than control-transfected cell lines. Intracranial tumor xenografts derived from U87-NK2 cells grew much slower than controls. U87-NK2 tumors were approximately 50-fold smaller than controls at 21 days post-implantation and HGF/NK2 gene transfer resulted in a trend toward diminished tumorigenicity. This report shows that the predominant effect of transgenic HGF/NK2 overexpression by glioma cells that are autocrine for SF/HGF stimulation is to inhibit their malignant phenotype.
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PMID:Glioma inhibition by HGF/NK2, an antagonist of scatter factor/hepatocyte growth factor. 1087

We have shown recently that the multifunctional growth factor, scatter factor/hepatocyte growth factor (SF/HGF), and its receptor c-met enhance the malignancy of human glioblastoma through an autocrine stimulatory loop (R. Abounader et al., J. Natl. Cancer Inst., 91: 1548-1556, 1999). This report examines the effects of SF/HGF:c-met signaling on human glioma cell responses to DNA-damaging agents. Pretreating U373 human glioblastoma cells with recombinant SF/HGF partially abrogated their cytotoxic responses to gamma irradiation, cisplatin, camptothecin, Adriamycin, and Taxol in vitro. This cytoprotective effect of SF/HGF occurred at least in part through an inhibition of apoptosis, as evidenced by diminished terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling index and reduced DNA laddering. Anti-c-met U1/ribozyme gene transfer inhibited the ability of SF/HGF to protect against single-strand DNA breakage, DNA fragmentation, and glioblastoma cell death caused by DNA-damaging agents, demonstrating a requirement for c-met receptor function. Phosphorylation of the cell survival-promoting kinase Akt (protein kinase B) resulted from SF/HGF treatment of U373 cells, and both Akt phosphorylation and cell survival induced by SF/HGF were inhibited by phosphatidylinositol 3-kinase inhibitors but not by inhibitors of mitogen-activated protein kinase kinase or protein kinase C. Cytoprotection by SF/HGF in vitro was also inhibited by transient expression of dominant-negative Akt. Transgenic SF/HGF expression by intracranial 9L gliosarcomas reduced tumor cell sensitivity to gamma irradiation, confirming the cytoprotective effect of SF/HGF in vivo. These findings demonstrate that c-met receptor activation by SF/HGF protects certain glioblastoma cells from DNA-damaging agents by activating phosphoinositol 3-kinase-dependent and Akt-dependent antiapoptotic pathways.
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PMID:Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways. 1094 42

Receptor tyrosine kinases (RTK) and the tumor suppressor PTEN co-regulate oncogenic cell signaling pathways. How these interactions influence gene transcription is inadequately understood. We used expression microarrays to investigate the effects of PTEN on gene expression changes caused by activating c-Met in human glioblastoma cells. c-Met activation by scatter factor/hepatocyte growth factor (SF/HGF) altered the expression of 27-fold more genes in PTEN-null U-373MG cells than in PTEN homozygous primary normal human astrocytes (523 vs 19 genes). Restoring wt-PTEN in U-373MG cells dramatically altered patterns of c-Met regulated gene expression. This effect was varied depending on the specific gene in question. PTEN reduced the number of c-Met regulated transcripts from 931 to 502, decreased the relative number of genes upregulated by c-Met from 46 to 25%, and increased the relative number of downregulated genes from 54 to 75%. PTEN and c-Met co-regulated many genes involved in cell growth regulation such as oncogenes, growth factors, transcription factors, and constituents of the ubiquitin pathway. c-Met activation in PTEN-null (but not PTEN reconstituted) cells led to upregulation of the EGFR agonist TGFalpha and subsequently to EGFR activation. Using PTEN mutants, we found that PTEN's transcriptional effects were either lipid-phosphatase dependent, protein-phosphatase dependent, or phosphatase-independent. These results show that PTEN has critical and mechanistically complex effects on RTK-regulated gene transcription. These findings expand our understanding of tumor promoter/suppressor inter-relationships and downstream transcriptional effects of PTEN loss and c-Met overexpression in malignant gliomas.
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PMID:Regulation of c-Met-dependent gene expression by PTEN. 1551 82

Hepatocyte growth factor/scatter factor-Met signaling has been implicated in tumor growth, invasion, and metastasis. Suppression of this signaling pathway by targeting the Met protein tyrosine kinase may be an ideal strategy for suppressing malignant tumor growth. Using RNA interference technology and adenovirus vectors carrying small-interfering RNA constructs (Ad Met small-interfering RNA) directed against mouse, canine, and human Met, we can knock down c-met mRNA. We show a dramatic dependence on Met in both ligand-dependent and ligand-independent mouse, canine, and human tumor cell lines. Mouse mammary tumor (DA3) cells and Met-transformed NIH3T3 (M114) cells, as well as both human and canine prostate cancer (PC-3 and TR6LM, human sarcoma (SK-LMS-1), glioblastoma (DBTRG), and gastric cancer (MKN45) cells, all display a dramatic reduction of Met expression after infection with Ad Met small-interfering RNA. In these cells, we observe suppression of tumor cell growth and viability in vitro as well as inhibition of hepatocyte growth factor/scatter factor-mediated scattering and invasion in vitro, whether Met activation was ligand dependent or not. Importantly, Ad Met small-interfering RNA led to apoptotic cell death in many of the tumor cell lines, especially DA3 and MKN45, but did not adversely affect MDCK canine kidney cells. Met small-interfering RNA also abrogated downstream Met signaling to molecules such as Akt and p44/42 mitogen-activated protein kinase. We further show that intratumoral infection with c-met small-interfering RNA adenovirus results in a substantial reduction in tumor growth. Thus, Met small-interfering RNA adenoviruses are reliable tools for studying Met function and raise the possibility of their application for cancer therapy.
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PMID:RNA interference reveals that ligand-independent met activity is required for tumor cell signaling and survival. 1552 Feb 3

Downstream signaling that results from the interaction of hepatocyte growth factor/scatter factor (HGF/SF) with the receptor tyrosine kinase Met plays critical roles in tumor development, progression, and metastasis. This ligand-receptor pair is an attractive target for new diagnostic and therapeutic agents, preclinical development of which requires suitable animal models. The growth of heterotopic and orthotopic Met-expressing human tumor xenografts in conventional strains of immunocompromised mice inadequately replicates the paracrine stimulation by human HGF/SF (hHGF/SF) that occurs in humans with cancer. We have therefore generated a mouse strain transgenic for hHGF/SF (designated hHGF-Tg) on a severe combined immunodeficiency (SCID) background. We report here that the presence of ectopically expressed hHGF/SF ligand significantly enhances growth of heterotopic subcutaneous xenografts derived from human Met-expressing cancer cells, including the lines SK-LMS-1 (human leiomyosarcoma), U118 (human glioblastoma), and DU145 (human prostate carcinoma), but not that of M14-Mel xenografts (human melanoma that expresses insignificant levels of Met). Our results indicate that ectopic hHGF/SF can specifically activate Met in human tumor xenografts. This new hHGF-Tg strain of mice should provide a powerful tool for evaluating drugs and diagnostic agents that target the various pathways influenced by Met activity.
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PMID:Enhanced growth of human met-expressing xenografts in a new strain of immunocompromised mice transgenic for human hepatocyte growth factor/scatter factor. 1553 25

Induction of the urokinase-type plasminogen activator (uPA) by hepatocyte growth factor/scatter factor (HGF/SF) plays an important role in tumor cell invasion and metastasis that is mediated through the Met receptor tyrosine kinase. Geldanamycins (GA) are antitumor drugs that bind and inhibit HSP90 chaperone activity at nanomolar concentrations (nM-GAi) by preventing proper folding and functioning of certain oncoproteins. Previously, we have shown that a subset of GA derivatives exhibit exquisite potency, inhibiting HGF/SF-induced uPA-plasmin activation at femtomolar concentrations (fM-GAi) in canine MDCK cells. Here, we report that (1) inhibition of HGF/SF-induced uPA activity by fM-GAi is not uncommon, in that several human tumor glioblastoma cell lines (DBTRG, U373 and SNB19), as well as SK-LMS-1 human leiomyosarcoma cells are also sensitive to fM-GAi; (2) fM-GAi drugs only display inhibitory activity against HGF/SF-induced uPA activity (rather than basal activity), and only when the observed magnitude of uPA activity induction by HGF/SF is at least 1.5 times basal uPA activity; and (3) not only do fM-GAi derivatives strongly inhibit uPA activity but they also block MDCK cell scattering and in vitro invasion of human glioblastoma cells at similarly low drug concentrations. These effects of fM-GAi drugs on the Met-activated signaling pathway occur at concentrations well below those required to measurably affect Met expression or cell proliferation. We also examined the effect of Radicicol (RA), a drug with higher affinity than GA for HSP90. RA displays uPA activity inhibition at nanomolar levels, but not at lower concentrations, indicating that HSP90 is not likely the fM-GAi molecular target. Thus, we show that certain GA drugs (fM-GAi) in an HGF/SF-dependent manner block uPA-plasmin activation in tumor cells at femtomolar levels. This inhibition can also be observed in scattering and in vitro invasion assays. Our findings also provide strong circumstantial evidence for a novel non-HSP90 molecular target that is involved in HGF/SF-mediated tumor cell invasion.
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PMID:Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion. 1578 29

Invasive and proliferative phenotypes are fundamental components of malignant disease, yet basic questions persist about whether tumor cells can express both phenotypes simultaneously and, if so, what are their properties. Suitable in vitro models that allow characterization of cells that are purely invasive are limited because proliferation is required for cell maintenance. Here, we describe glioblastoma cells that are highly invasive in response to hepatocyte growth factor/scatter factor (HGF/SF). From this cell population, we selected subclones that were highly proliferative or displayed both invasive and proliferative phenotypes. The biological activities of invasion, migration, urokinase-type plasminogen activation, and branching morphogenesis exclusively partitioned with the highly invasive cells, whereas the highly proliferative subcloned cells uniquely displayed anchorage independent growth in soft agar and were highly tumorigenic as xenografts in immune-compromised mice. In response to HGF/SF, the highly invasive cells signal through the MAPK pathway, whereas the selection of the highly proliferative cells coselected for signaling through Myc. Moreover, in subcloned cells displaying both invasive and proliferative phenotypes, both signaling pathways are activated by HGF/SF. These results show how the mitogen-activated protein kinase and Myc pathways can cooperate to confer both invasive and proliferative phenotypes on tumor cells and provide a system for studying how transitions between invasion and proliferation can contribute to malignant progression.
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PMID:Proliferation and invasion: plasticity in tumor cells. 1602 25

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that is involved in invasive growth of tumor cells via its receptor MET, a protein product of c-met proto-oncogene. HGF activator (HGFA) is a serine proteinase responsible for the activation of proform of HGF/SF (proHGF/SF). In our study, we examined the effects of engineered expression of HGFA on 2 human glioblastoma cell lines (YKG-1 and U251). Both cells expressed MET, while only YKG-1 expressed endogenous proHGF/SF. Enhanced MET phosphorylation and increased migratory activity were induced by the expression of HGFA in YKG-1 cells in vitro in the presence of thrombin, which is a known activator of proHGFA. In contrast, MET phosphorylation was consistently observed in U251 that lacked endogenous HGF/SF, suggesting ligand-independent activation of MET in this cell line. Consequently, the expression of HGFA in U251 did not enhance the MET phosphorylation and following cellular response even with the thrombin treatment. However, addition of exogenous proHGF/SF resulted in enhanced migratory activity of HGFA-expressing U251 cells in the presence of thrombin in vitro. The engineered HGFA expression resulted in significantly enhanced tumor growth with increased vascular density in vivo when YKG-1 cells were implanted in nude mouse brain. This effect was not observed in U251 lacking endogenous proHGF/SF. These results indicate the possible existence of multiple mechanisms of MET activation in glioblastomas and that the activation system of proHGF/SF is important in progression of glioblastomas that express endogenous proHGF/SF and require ligand-dependent MET activation.
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PMID:Role of hepatocyte growth factor activator (HGF activator) in invasive growth of human glioblastoma cells in vivo. 1610 3


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