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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When C6 glioma cells are stably transfected with a connexin43 cDNA and gap junctions are increased, the rate of cellular proliferation is decreased. To determine if this phenomenon is related to alterations in IGFBP and IGF synthesis, we have compared IGFBPs and IGFs in the conditioned media from primary rat astroglia, C6, and transfected C6 clones Cx43-13 (high expresser), and Cx43-12 and Cx43-14 (intermediate expressers). Primary astroglia produced IGFBP-2 (34 kDa) and IGFBP-3 (40-45 kDa). C6 cells synthesized high levels of IGFBP-3 and low levels of IGFBP-2, and a 24 kDa IGFBP (IGFBP-4). Cx43-13 cells did not synthesize IGFBP-3, but produced low levels of IGFBP-2 and high levels of IGFBP-4. Cx43-12 and Cx43-14 secreted IGFBP profiles similar to the parent C6 line, but with reduced levels of IGFBP-2. The lack of IGFBP-3 in Cx43-13 cells was not due to the presence of proteases. Northern analysis showed IGFBP-2 mRNA to be readily detectable only in the primary astroglia. IGFBP-3 mRNA was detected in the primary astroglia, C6, Cx43-12 and Cx43-14, but not in Cx43-13. In contrast, IGFBP-4 mRNA was readily detected only in the Cx43-13. IGF-II concentrations in the media were low to undetectable for both C6 and transfected cells. IGF-I concentrations were significantly lower in the media from transfected cells compared to the C6 cells. Stable mRNA levels for IGF-I were lower in transfected cells, with the lowest levels observed in the Cx43-13 cells. Although C6 cells did not respond mitogenically to exogenous IGF-I or IGF-II, Cx43-13 cells responded to IGF-I or IGF-II in a dose dependent manner. Conditioned media from Cx43-13 cells decreased the DNA synthesis of C6 cells, and this effect could be reversed by the addition of IGF-II. The decreased synthesis of the autocrine/paracrine growth factor IGF-I together with decreased levels of a positive modulator IGFBP-3, and the increased levels of a negative modulator IGFBP-4 in the extracellular milieu, may be responsible for the reduced proliferative capacity in cells expressing abundant connexin43.
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PMID:Alterations in the synthesis of insulin-like growth factor binding proteins and insulin-like growth factors in rat C6 glioma cells transfected with a gap junction connexin43 cDNA. 750 71

When C6 glioma cells are stably transfected with a connexin43 cDNA and the gene overexpressed, the rate of cellular proliferation is decreased. To determine if this phenomenon is related to alterations in IGFBP synthesis, we have compared the conditioned media of primary rat astroglia, C6, clones Cx43-13 (high expresser of the transfected connexin43 gene), and Cx43-12 and Cx43-14 (intermediate expressers). Primary astroglia produced IGFBP-2 (M(r) 34 K) and IGFBP-3 (40-45 K). C6 cells synthesized high levels of IGFBP-3 and low levels of IGFBP-2, and a 24 K IGFBP (IGFBP-4). Cx43-13 cells did not synthesize IGFBP-3, but produced low levels of IGFBP-2 and high levels of IGFBP-4. Cx43-12 and Cx43-14 secreted IGFBP profiles similar to the parent C6 line, but with reduced levels of IGFBP-2. Northern analysis showed the changes in IGFBPs in the conditioned media to be correlated with alterations in stable mRNA levels. IGFBP-4, a inhibitor of IGF biological action, was produced in greater quantities by the slowly proliferating Cx43-13 cells. Alterations in IGFBP-4 synthesis may be responsible, at least in part, for the reduced proliferative capacity in cells with abundant connexin43.
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PMID:Insulin-like growth factor binding protein-4 gene expression is induced by transfection of gap junction connexin43 gene in a C6 glioma cell line. 768 20

The relationship between growth properties and gap junctional communication properties of two glioma cell lines, 9L and C6, was compared. Using microinjection of a gap junction permeable fluorescent dye, it was demonstrated that 9L cells were extensively dye coupled through gap junctions, whereas C6 cells had low levels of dye coupling between the cells. More gap junctions were observed between 9L cells than between C6 cells both by electron microscopy and immunofluorescent labelling with specific antibodies. Immunoblotting and immunofluorescence labelling of cellular proteins from 9L and C6 cells also showed differences in the Cx43 connexin contents of these cells, reflecting the differences in their gap junctional communication. Northern blot analyses confirmed that the level of Cx43 mRNA was higher in 9L than in C6 cells. In spite of these differences in gap junctions, the two cell lines did not differ in their growth rates in cultures. These results suggest a lack of direct correlation between gap junctional communication and cell growth regulation in these two glioma cell lines.
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PMID:Gap junctions in 9L and C6 glioma cells: correlation with growth characteristics. 941 17

The 9L rat glioma cells communicate via gap junctions which are formed of connexin 43. The gap junctional communication was inhibited in these cells by transfecting them with an antisense Cx43 DNA construct, and its effect on their growth rate was investigated. This construct was induced by a Zn(2+)-inducible metallothionein promoter. Results showed that the induction of antisense RNA expression in rat 9L glioma cells produced the loss of gap junctions which was reflected in the loss of gap junctional communication. By inducing the antisense construct with zinc acetate, and using specific antibodies to connexin 43, the synthesis of this connexin was inhibited in the transfected cells and gap junctions were lost on the cell-cell appositions. There was no such effect on the untransfected cells. The loss of gap junctions at cell-cell appositions also correlated with the loss of Lucifer yellow fluorescent dye transfer between the cells. The effect of loss of gap junctions on the growth rate of the cells was assessed. In spite of the drastic decrease in the number of gap junctions between cells, their growth rate was only approximately 20% less than that of the transfected but non-induced cells. Therefore, gap junction communication is not negatively related to the rate of growth of these cells.
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PMID:Inhibition of connexin 43 synthesis by antisense RNA in rat glioma cells. 958 5

Evidence is accumulating that connexin (Cx) genes form a family of tumor-suppressor genes. Our long-standing study revealed that, in almost all tumors, some abnormality in gap junction is observed, including loss or reduction of expression, aberrant localization of gap junction. In this study, we have examined the dominant-negative effects of mutant (prepared by site-directed mutagenesis) Cx43 constructs in C6 glioma cells, and of mutant Cx26 constructs in HeLa cells, on tumorigenicity. The mutant Cx43 A253V (Ala 253 to Val) inhibited the tumor-suppressive function exerted by wild-type Cx43 in C6 cells. Similarly, the mutant Cx26 P87L (Pro 87 to Leu) manifested dominant-negative inhibition of connexin-mediated cell growth control in HeLa cells. These results suggest that mutations of connexin genes can affect the tumor-suppressive function of gap junction and that gap junctional intercellular communication can be regulated by not only non-genotoxic but also genotoxic activities of environmental carcinogens.
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PMID:Role of connexin (gap junction) genes in cell growth control: approach with site-directed mutagenesis and dominant-negative effects. 982 Jun 54

Gliomas are lethal because of local invasion into brain parenchyma. Glioma cells were isolated from different regions (white matter, gray matter and tumor core) of a glioma-bearing dog brain. Individual clonal cell lines were established from each area, and characterized for growth, migration and gap junctions. The regional clonal cell lines differed in rates and preferred substrate for migration. Cell lines generated from invaded white matter showed stimulated migration on collagen and variable migration on merosin, whereas migration of cell lines derived from invaded gray matter showed the reciprocal responses: stimulation on merosin and inhibition on collagen. Gap junctional communication showed significant degrees of variation between the different clones. A direct inverse relationship between the number of cells demonstrating gap junctional communication and migration rate of cells away from multicellular spheroids was evident. Glioma cells which have a reduced capacity to connect to each other have an accelerated migration rate onto autologous, glioma-derived matrix. These results suggest that invasive glioma cells suppress autologous cell-to-cell cohesion, partly evident as reduced formation of gap junctions. In addition, glioma cells were stimulated to migrate in a dose-dependant manner in response to epidermal growth factor (EGF) coincident with the reduction of Cx43 levels and increased serine phosphorylation. We speculate that in order for glioma cells to invade locally into brain parenchyma they must first detach from neighboring cells ("let go...let's go" paradigm of invasion).
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PMID:Gap junction intercellular communication in gliomas is inversely related to cell motility. 1057 21

Gap junction expression has been reported to control the growth of a variety of transformed cells. We undertook parallel analysis of connexins Cx32 and Cx43 in glioma cells, which revealed potential mechanisms underlying this phenomenon and led to several novel findings. Cx43, but not Cx32, suppressed C6 glioma cell growth. Paradoxically, Cx32 transfection resulted in severalfold more dye transfer than Cx43. However, Cx43 transfectants shared endogenous metabolites more efficiently than Cx32 transfectants. Interestingly, a significant portion of Cx43 permeants were incorporated into macromolecules more readily than those that transferred via Cx32. Cx43 induced contact inhibition of cell growth but in contrast to other reports, did not affect log phase growth rates. Cell death, senescence, or suppression of growth factor signaling was not involved because no significant alterations were seen in cell viability, telomerase, or mitogen-activated protein kinase activity. However, suppression of cell growth by Cx43 entailed the secretion of growth-regulatory factors. Most notably, a major component of conditioned medium that was affected by Cx43 was found to be MFG-E8 (milk fat globule epidermal growth factor 8), which is involved in cell anchorage and integrin signaling. These results indicate that Cx43 regulates cell growth by the modulation of extracellular growth factors including MFG-E8. Furthermore, the ability of a Cx to regulate cell growth may rely on its ability to mediate the intercellular transfer of endogenous metabolites but not artificial dyes.
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PMID:Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells. 1108 22

Calcium is one of the most universal signal-transduction elements in a large variety of cells ranging from bacteria to specialized neurons. Ca2+ acts as a second messenger controlling such processes as secretion, cell differentiation or signal transmission. In order to be able to execute their specific functions and to react in a coordinated way to stimuli, multicellular organs need a precise orchestration of cellular functions. For this purpose cells have developed different forms of intercellular communication (IC). In this study we investigated a number of mechanisms of intracellular propagation and IC using experiments with fluorescent Ca(2+)-indicators, confocal microscopy and digital imaging techniques. In ROS 17/2.8 osteoblasts, retinal pigment epithelial cells (RPE) and CPAE endothelial cells, a small mechanical deformation of the plasma membrane results in a transient increase of free cytoplasmic Ca2+ concentration ([Ca2+]i). This Ca(2+)-rise starts at the site of stimulation and propagates concentrically to neighboring cell layers. The intracellular Ca(2+)-wave in RPE and ROS cells is caused by Ca(2+)-influx followed by Ca(2+)-release from the intracellular stores and by intercellular propagation of the Ca(2+)-wave. The [Ca2+]i-transient upon mechanical stimulation of LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes was limited and/or variable. In CPAE cells only the intracellular release is important for evoking the Ca(2+)-transient, and is followed by IC. IC can occur via gap junctions (GJ) consisting of membrane-spanning proteins, connexins (Cx). It was demonstrated that IC and GJ in RPE and ROS cells can be reversibly blocked by gap-junction inhibitors such as heptanol or halothane. We demonstrated important differences in modulation of gap junctional communication between these cell types. While in RPE cells stimulation of PKC activity was able to inhibit IC, this was not the case in ROS cells. We screened LE-RPE cDNA via PCR using specific primers for different connexins and found no effect of high glucose solutions, which cause decreased intercellular communication, on the Cx-isoforms expressed. Cx43 is the only Cx-isoform present at the protein level for which Western blot analysis revealed the presence of different forms corresponding to different phosphorylated states. Increased phosphorylation of Cx43 was only seen after direct PKC activation by PMA, but not by indirect PKC activation by high glucose levels. The decreased communication by high glucose concentrations was however associated by a decreased expression of cellular Cx43 to about 3/4 of the level in control conditions. High glucose concentrations therefore decrease Cx43 at the protein level via a PKC effect that appears to be independent of the direct activation of PKC by phorbolesters. Mechanical stimulation did not evoke intercellular Ca(2+)-waves in LLC-PK1 epithelial cells, C6 glioma cells and MLO-Y4 osteocytes. In CPAE-endothelial cells, the contribution of gap junctions to IC following mechanical stimulation is negligible, and modulation of gap junctions via phosphorylation or high glucose solutions is absent. Perfusion experiments and pharmacological studies demonstrated that IC following mechanical stimulation of these cells occurs via release of an extracellular mediator. Our experiments provide strong evidence in favor of purinergic agonists as mediators, such as ATP but mainly ADP. In conclusion we can say that cells contain a wide spectrum of mechanisms for intra- and intercellular communication, and that widely different mechanisms can evoke the same phenomenon of intra- and intercellular Ca(2+)-waves.
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PMID:[Intra- and intercellular Ca(2+)-signal transduction]. 1119 79

Tumour cells often exhibit erratic cell growth, as well as decreased gap junctional intercellular communication (GJIC). C6 glioma cells are characterized by low levels of gap junction mRNA and protein, and decreased amounts of GJIC when compared with astrocytes. Previous work has shown that C6 glioma cells transfected with connexin43 (C6-Cx43) exhibit decreased proliferation in vivo and in vitro, as well as genes that are differentially expressed between these cells. In this study, RNA levels of two CCN (connective tissue growth factor [CTGF], Cyr61/Cef-10, nephroblastoma overexpressed [NOV]) gene family members are shown to be upregulated in C6-Cx43 cells: Cyr61 and Nov. Cyr61 has previously been shown to increase adhesion, migration and growth in many cell types, whereas NOV has growth suppressive capacities. Cyr61 RNA expression is shown here to respond to serum in quiescent cells in an immediate early gene fashion, independent of Cx43 expression. In contrast, Nov RNA levels remain constant, reflective of transfected Cx43 expression. Furthermore, confocal microscopy indicates that NOV colocalizes with Cx43 plaques at the cell membrane. These findings provide insight into the possible role of Nov and Cyr61 in tumour cells.
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PMID:Determination of a potential role of the CCN family of growth regulators in connexin43 transfected C6 glioma cells. 1206 32

Neoplastic transformation is frequently associated with a loss of gap junctional intercellular communication and reduced expression of connexins. The introduction of connexin genes into tumor cells reverses the proliferative characteristics of such cells. However, there is very little comparative information on the effects of different connexins on cancer cell growth. We hypothesized that Cx26, Cx32, or Cx43 would display differential growth suppression of C6 glioma cells and uniquely modulate the bystander effect following transduction of C6 cells with HSVtk followed by suicide gene therapy. The bystander phenomenon is the death of a greater number of tumor cells than are expressing the HSVtk gene, presumably due to the passage of toxic molecules through gap junction channels. To test this hypothesis, we used retroviral vectors to infect C6 glioma cells producing connexin-expressing and HSVtk-expressing cell lines. All three connexin-expressing cell lines grew significantly slower than GFP-infected or native C6 cells. Cx32 and Cx26 were significantly more effective at mediating the bystander effect in cocultures of C6-connexin cells with C6-HSVtk cells. These studies indicate that connexins have unique properties that contribute to their tumor suppressive function.
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PMID:Connexin over-expression differentially suppresses glioma growth and contributes to the bystander effect following HSV-thymidine kinase gene therapy. 1661 82


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