Gene/Protein Disease Symptom Drug Enzyme Compound
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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

The mitogenic action of insulin-like growth factors (IGFs) on target cells is determined by interaction with signaling IGF-I receptors and modulated by interactions with IGF-binding proteins (IGFBPs). IGFBP-3, an abundant IGFBP that binds IGF-I and IGF-II with high affinity, can form soluble inhibitory complexes with the IGFs that prevent them from binding to IGF-I receptors. Alternatively, IGFBP-3 can bind to the cell surface and possibly potentiate IGF action or act independently of the IGFs. Previous studies showed that heparin inhibited IGFBP-3 binding to the cell surface and increased its accumulation in the medium, suggesting that it might act as a competitive inhibitor of IGFBP-3 binding to structurally similar heparan sulfate proteoglycans on the cell surface. We evaluated this hypothesis by binding 125I-labeled recombinant glycosylated human IGFBP-3 to human fetal skin fibroblasts (GM-10) and to C6 rat glioma cells at 12 C. Heparin inhibited [125I]IGFBP-3 binding more effectively than chondroitin sulfate and dextran sulfate. Complete digestion of cell surface heparan sulfate and chondroitin sulfate glycosaminoglycans using heparitinase and chondroitinase ABC, however, did not significantly decrease IGFBP-3 binding. Quantitative removal was demonstrated by analysis of parallel cultures of cells whose glycosaminoglycans had been biosynthetically labeled using Na2 35SO4. These results suggested that IGFBP-3 did not bind to heparan sulfate glycosaminoglycans on the cell surface, and that the inhibition of IGFBP-3 binding by heparin most likely resulted from its direct interaction with the heparin-binding domains of IGFBP-3. When [125I]IGFBP-3 was incubated with GM-10 fibroblasts or C6 glioma cells at 37 C for 4 h, only 10% of the bound ligand remained associated with the cell surface; approximately 90% of the cell-associated radio-activity was internalized and could be recovered in lysates of acid-washed cells. Incubation with IGF-I or heparin decreased the total cell-associated radioactivity, but did not affect internalization. These results suggest that direct interaction of heparin or IGF-I with IGFBP-3 inhibits its ability to bind to the surface of GM-10 fibroblasts and C6 glioma cells.
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PMID:Heparin inhibition of insulin-like growth factor-binding protein-3 binding to human fibroblasts and rat glioma cells: role of heparan sulfate proteoglycans. 882 97

Glioma tumour growth is associated with the expression of insulin-like growth factors I and II (IGFs) and of both type I and type II IGF receptors. It has also been shown that IGFs can stimulate proliferation of cultured glioma cells. We previously reported that histamine too can stimulate the growth of glioma cells in vitro. In this report, we study whether the histamine-induced growth of G47 glioma cells is mediated by the IGFs. We found that histamine stimulates the expression of both IGF-I and IGF-II mRNAs, as determined by a semiquantitative in situ hybridization analysis. Furthermore, incubation of G47 cells with histamine also induced cellular immunostaining for IGF-II. It could be shown that IGF-I-stimulated proliferation is inhibited by IGFBP-3, which decreases the availability of IGFs for binding to the IGF receptors, and by beta-galactosidase, which may decrease IGF binding to the type II IGF receptor, but is not inhibited by the anti-type I IGF receptor monoclonal antibody alphaIR3. However, neither IGFBP-3 nor beta-galactosidase nor alphaIR3 inhibited the histamine-induced proliferation. These results show that the growth-stimulatory effect of histamine is accompanied by the induction of IGFs. This histamine-induced growth stimulation is not mediated by activation of cell surface IGF receptors, although intracrine activation of type II IGF receptors may be involved.
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PMID:Histamine-stimulated expression of insulin-like growth factors in human glioma cells. 909 54

We previously demonstrated the presence of insulin-like growth factors (IGFs) and IGF-receptors in human glioma cell lines derived from primary glioblastomas. The biological action of IGFs is modulated by specific IGF-binding proteins (IGFBP)-1 to -7. By means of polymerase chain reaction (PCR), we detected mRNA transcripts for IGFBP-1 in 42%, IGFBP-2 in 65%, IGFBP-3 in 97%, IGFBP-4 in 3%, IGFBP-5 in 74%, IGFBP-6 in 94% and IGFBP-7 in 87% of the glioma cell lines. The specificity of the PCR reaction was verified by direct sequencing of the PCR product. In addition, the content of the most prevalent IGFBP-3 was measured in conditioned medium from glioma cells by specific radioimmunoassay with levels ranging from < 1 to 620 ng/ml. Moreover, the presence of membrane-bound IGFBPs (44, 50 and 60 kDa) as well as IGF-II receptors was demonstrated by using 125I-labelled IGF-II as a ligand. In conclusion, IGFBPs may modulate the IGF-mediated effects in these cell lines.
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PMID:Expression and synthesis of insulin-like growth factor-binding proteins in human glioma cell lines. 945 96

In the present study, we examined the specific binding of IGF-I and IGF-II to their receptors in C6 glioma cells taken during different growth phases in culture: phase A, early stage of the exponential growth (48 h after seeding); phase B, late stage of the exponential phase (96 h after seeding); phase C, confluent phase (at 144 h after seeding); and phase D, stopped at 48 h post-confluence. Scatchard analysis revealed higher Ka values for the IGF-IR during the exponential phases (A and B). The affinity of IGF-I for its receptor during the post-confluent phase (D) decreased to about half that at phase A (p < 0.01). Although lower at the later phase (D), the number of binding sites of the IGF-IR in the different tested growth stages in culture (A, B, and C) was not statistically different (p > 0.05). Conversely, the number of binding sites of the IGF-II/mannose-6-phosphate receptor appeared to increase during time in culture. The Ka values of the IGF-II/mannose-6-phosphate receptor decreased significantly during the culture time, phase D showing the largest decrease (50%) as compared with phase A (p < 0.005). These binding data suggest that IGF-I and IGF-II receptors are differentially expressed in rat C6 glioma cells in culture and are a function of the growth phase.
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PMID:Expression of IGF-I and IGF-II receptors in rat C6 glioma cells as a function of the growth phase. 994 56

Antagonists of growth hormone-releasing hormone(GH-RH)inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF)-I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1 -36 at the dose of 20 microg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GH-RH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1 -36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1 -36 at 1 microM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U-87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-1-36 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.
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PMID:Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice. 1093 10

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are known to be mitogens for many types of neoplasms. To investigate their role in tumors of glial origin, in vitro and in vivo experiments were performed with a panel of immortalized glioma cell lines (D54, SNB-19, U87, U251 and U373). Initial analysis for mRNA expression demonstrated the following: GH receptor (5/5 cell lines positive), IGF-I (0/5), IGF-II (0/5), IGF-I receptor (5/5), IGF-II receptor (2/5). Thus, each cell line expressed the necessary receptors to respond to GH and the IGFs but there was no autocrine IGF production by the tumors themselves. IGF-I stimulated mitogenesis as measured by [(3)H]thymidine uptake experiments in U251 and U373 cells. However, when these two IGF-responsive cell lines were xenografted into mice, tumor development and growth rates were not significantly different in GH-deficient animals (despite having IGF-I serum concentrations only 31% of normal). Because our studies were performed in immunocompromised animals, GH or IGF effects on immune surveillance, known to be important from some syngeneic glioma models, would not be likely to contribute to our findings. Nevertheless, these studies are important because they demonstrate that the growth of glioma cell lines in an in vivo environment can remain robust in a GH/IGF-I-deficient setting, even if in vitro experiments indicate that IGF-I is mitogenic.
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PMID:Growth hormone and insulin-like growth factor-I: effects on the growth of glioma cell lines. 1147 74

Tamoxifen, a non-steroidal anti-estrogen widely used against breast cancer, is also useful for treatment of other malignancies, due to its sensitizing effect on other chemotherapeutic agents and radiation. We have investigated the advantages of combining tamoxifen with one of the commonly used cancer chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines. While tamoxifen (10 microM) increased etoposide cytotoxicity 8.3-fold in the human glioma cell line (HTB-14), it increased etoposide cytotoxicity 47.5- and 40-fold in two primary cell lines established from pediatric medulloblastoma patients (MCH-BT-31 and MCH-BT-39), respectively. Similarly, in the pediatric ependymoma cell lines (MCH-BT-30 and MCH-BT-52), tamoxifen enhanced etoposide cytotoxicity 6- and 2.68-fold, respectively. CalcuSyn analysis of cytotoxicity data showed that tamoxifen and etoposide combinations were synergistic with combination index values ranging from 0.243 to 0.369 at IC50 level among different pediatric brain tumor cell lines. Tamoxifen is also cytotoxic at higher concentrations (> 20 microM) in brain tumor cells. To understand the mechanism underlying the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of P-glycoprotein (P-gp), insulin-like growth factor-I receptor (IGF-IR), IGF-I, IGF-II and estrogen receptor as well as protein kinase C (PKC) activity. While P-gp, IGF-IR and IGF-I were not affected, enhanced inhibition of PKC, and IGF-II were observed in brain tumor cells treated with tamoxifen and etoposide combination as compared to cells treated with either drug alone. Tamoxifen at 10 microM when combined with etoposide at 0-100 microM concentrations reduced PKC activity 77% compared to only 58% without tamoxifen. IGF-II expression decreased to 48.6% of the untreated control in the combination treatment as compared to 31.2% for etoposide alone and 26.2% for tamoxifen alone treatments. These results suggest that inhibitory effect of tamoxifen on brain tumor cells manifest through different mechanisms involving inhibition of targets such as PKC and IGF-II.
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PMID:Tamoxifen modulation of etoposide cytotoxicity involves inhibition of protein kinase C activity and insulin-like growth factor II expression in brain tumor cells. 1507 44

Inappropriate activation of the IGF (insulin-like growth factor) system has been implicated in the growth and progression of a number of tumor types. Recent evidence indicates a possible role for the IGF system in modulating/mediating tumor cell response to hypoxia, a common occurrence in solid tumors, and particularly in malignant gliomas, causing tumor cells either to die, or to mount a pleiotropic adaptive response that is mainly orchestrated through activation of the hypoxia-inducible transcription factor HIF1. Experimental evidence suggests possible links between IGF- and HIF1-dependent signaling pathways, as well as a role for activated STAT3 in mediating their activities. Interestingly, igf2 is among the target genes transactivated by HIF1, thereby providing the missing link in a hypothetical autocrine self-amplifying circuit. The present study investigates the presence of the IGF-HIF1-VEGF axis in the human glioma cell line U-87 MG, and characterizes its molecular effectors. Our results show that exogenous IGF-I causes IGF1R and STAT3 activation, and increases HIF1alpha protein levels and HIF1 trascriptional activity, inducing VEGF release; a similar response, mediated by IGF-II release, is observed following HIF1alpha stabilization. The existence of an autocrine loop is confirmed by its down-regulation following inactivation of IGF1R (using the IGF1R-specific tyrosine kinase inhibitor NVP-AEW541), STAT3 (transfecting the cells with an expression vector encoding a dominant negative form of STAT3), or HIF1 (using the small molecule inhibitor YC-1). The ability of NVP-AEW541 to block this circuit could be beneficial in suppressing the growth and angiogenic potential of hypoxic glial tumors.
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PMID:The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells. 2048 64

Insulin-like growth factor (IGF)-I and -II are involved in the regulation of brain development and are thought to play a pivotal role in the proliferation of gliomas. Expression of IGF-I, IGF-II, the type I and type II IGF receptor were studied in a panel of thirty glioma cell lines by Northern blotting and PCR analysis. IGF-II mRNA expression with transcripts of 4.8 and 6.0 kb was shown only in one glioma cell line (NCE-G96) and no transcripts for IGF-I, IGF-I-R and IGF-II-R could be detected by Northern analysis in total RNA. However, PCR analysis revealed signals in 19/28 cell lines for IGF-I, 27/30 for ICE-II, 19/28 for IGF-I-R and 22/28 glioma cell lines for IGF-II-R. Additional IGF-I, IGF-II, IGF-I-R and IGF-II-R PCR products were detected which might represent alternative splicing products or variants. In addition, the secretion of IGF-I and IGF-II peptides was measured by radioimmunoassay. IGF receptor status and binding characteristics were established by Scatchard analysis. Proliferation assays showed different effects of IGFs and IGF analogues on the proliferation of these cell lines. Des-(1-3)IGF-I showed an unexpected inhibitory activity on glioma cell proliferation. This may have either been due to a direct effect of the ligand for the induction of a more differentiated state refractory to its action.
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PMID:Expression and synthesis of insulin-like growth factor (IGF)-I, -II and their receptors in human glioma cell lines. 2154 5


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