Interleukin-6 overexpression as a marker of malignancy in human gliomas

Rolhion, Christine; Penault‐Llorca, Frédérique; Kémény, Jean-Louis; Lemaire, Jean‐Jacques; Jullien, Christiane; Labit-Bouvier, Corinne; Finat‐Duclos, Françoise; Verrelle, Pierre

doi:10.3171/jns.2001.94.1.0097

Cited by 94 publications

(48 citation statements)

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“…38,39 In human gliomas, however, both factors are expressed at increased levels that correlate with the grade of malignancy. 4,10,38 We investigated the underlying mechanism of the functional relationship between IL-6 and VEGF in glioma angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…9 Moreover, a strong and significant association between glioma aggressiveness and IL-6 gene expression was found. 10 Finally, by abrogation of IL-6 gene expression in glial fibrillary acidic protein (GFAP)-viral src kinase (v-src) transgenic mice that phenocopy the neuropathology of human astrocytomas, 11 we have recently shown that IL-6 is crucial for glioma development. 12 IL-6 is a member of the neuropoietic cytokine family, which also includes, among others, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF).…”

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confidence: 99%

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Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

Loeffler

Fayard

Weis

et al. 2005

Intl Journal of Cancer

191

134

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Interleukin-6 (IL-6) expression is strongly correlated with the degree of human glioma malignancy and necessary for tumor formation in a mouse model of spontaneous astrocytomas. Yet, exactly how IL-6 contributes to malignant progression of these brain tumors is still unclear. We have scrutinized the mechanism of transcriptional activation of vascular endothelial growth factor (VEGF) expression by IL-6 in the mouse brain and in glioblastoma cells. We demonstrate here that IL-6 drives transcriptional upregulation of VEGF in astrocytes in vivo using glial fibrillary acidic protein (GFAP)-IL-6/VEGF-green fluorescent protein (GFP) double transgenic mice. We further show that IL-6-induced VEGF transcription and VEGF secretion by human glioblastoma cells is dependent on signal transducer and activator of transcription 3 (STAT3). By progressive 5 0 -deletion analysis we defined the minimal VEGF promoter region for IL-6-responsiveness to nucleotides 288/250. Surprisingly, this promoter region is rich in GC-boxes and does not contain STAT3 binding elements. Electrophoretic mobility shift and supershift assays revealed binding of Sp1 and Sp3 to the 288/250 element upon IL-6 stimulation. Interestingly, preincubation with STAT3 antibody prevented the binding of Sp1 and Sp3 to the 288/250 element, indicating that STAT3 is involved in IL-6-driven Sp1/Sp3 protein-DNA complex formation. Physical interaction of STAT3 and Sp1 was demonstrated by coimmunoprecipitation. The functional relevance of the STAT3/ Sp1 association was corroborated by transient transfection experiments, which showed that overexpression of constitutively active STAT3 increased the minimal VEGF promoter activity. Taken together, our study suggests that IL-6 promotes tumor angiogenesis in gliomas and describes a novel transcriptional activation mechanism for STAT3 in the context of a STAT3 binding element (SBE)-free promoter. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

Loeffler

Fayard

Weis

et al. 2005

Intl Journal of Cancer

191

134

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“…These in turn persistently activate multiple intracellular signaling pathways contributing to the pathogenesis of cancer (Rasheed et al, 1999;Hanahan and Weinberg, 2000;Holland, 2000;Maher et al, 2001;Wechsler-Reya and Scott, 2001;Zhu and Parada, 2002). A number of studies have demonstrated that malignant glioma cells express the IL-6 gene both in vivo and in vitro (Van Meir et al, 1990;Goswami et al, 1998;Rolhion et al, 2001;Tchirkov et al, 2001;Rahaman et al, 2002). These studies have also suggested that the upregulation of IL-6 gene expression that often results from an amplification of the IL-6 gene could be correlated with the aggressiveness of human gliomas .…”

Section: Discussionmentioning

confidence: 99%

“…Many cancer cells acquire growth advantage by producing cytokines and growth factors that act in an autocrine manner (Catlett-Falcone et al, 1999;Grandis et al, 2000;Hanahan and Weinberg, 2000). Both GBM cell lines and primary tumors secrete IL-6 (Van Meir et al, 1990;Goswami et al, 1998;Rolhion et al, 2001;Tchirkov et al, 2001;Rahaman et al, 2002). Previously, we have shown that the GBM cell line U251 persistently activates Stat3 by an autocrine action of IL-6 (Rahaman et al, 2002).…”

Section: Egfr Is a Major Activator Of Stat3 In U87 And D54 Cellsmentioning

confidence: 99%

“…Here, we show that persistent activation of Stat3 in U87 and D54 cells is mediated by activated EGFR not IL-6 receptor complex, although these cells produce IL-6 (Van Meir et al, 1990;Goswami et al, 1998;Rolhion et al, 2001;Tchirkov et al, 2001;Rahaman et al, 2002). Amplification and subsequent overexpression of the EGFR gene are present in B50% of GBM in adults (Wong et al, 1987(Wong et al, , 1992Ekstrand et al, 1991;Maher et al, 2001;Wechsler-Reya and Scott, 2001).…”

Section: Introductionmentioning

confidence: 99%

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PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells

et al. 2005

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Glioblastoma multiforme (GBM) cells frequently harbor amplification and/or gain-of-function mutation of the EGFR gene leading to the activation of multiple signaling pathways. Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis, which were associated with reduction in the steady-state level of Mcl-1. Surprisingly, inhibition of PI3 kinase (PI3K) activity, which in turn inhibited AKT activation, significantly increased the DNA-binding activity of Stat3 in U87 and D54 cells. This was not due to an increase in the level of tyrosine-phosphorylated Stat3. Conversely, ectopic expression of constitutively activated AKT significantly decreased the DNA-binding activity of Stat3 in 293T cells. Interestingly, blockade of protein phosphatase 2A activity in GBM or 293T cells by calyculin A, which activated AKT, stabilized the phosphorylation of multiple Ser/Thr residues that were located in the transactivation domain (TAD) of Stat3 and this in turn completely ablated the DNA-binding activity of Stat3. Collectively, these results suggest that both Stat3 and AKT provide survival signals in U87 and D54 cells, and Ser/Thr phosphorylation of Stat3-TAD by the PI3K-AKT pathway negatively controls the DNA-binding function of Stat3.

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Combined targeting of interleukin‐6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness

Saidi

Hagedorn

Allain

et al. 2009

Intl Journal of Cancer

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Interleukin‐6 (IL6) and vascular endothelial growth factor (VEGFA) are abundantly produced by glioma cells and contribute to malignancy by promoting angiogenesis, cell proliferation and resistance to apoptosis. We compared the effect of inhibiting IL6 and VEGF on U87‐derived experimental glioma grown on the chick chorio‐allantoic membrane (CAM) or in the brain of xenografted mice. Tumor growth was monitored by biomicroscopy and immunohistology. In vitro, IL6 knockdown had no effect on proliferation but substantially enhanced invasion. In the CAM experimental glioma, IL6 or VEGF knockdown reduced growth and vascularization of the tumors with a comparable efficiency, but increased invasion of residual tumor cells. In contrast, combined IL6/VEGF knockdown not only showed enhanced reduction of tumor growth and angiogenesis but also significantly prevented invasion of residual tumor cells. In mice, combining IL6 knockdown and Avastin™ treatment completely abrogated tumor development and infiltration. Molecular response of tumor cells to single or combined treatment was studied by transcriptomic profiling. Many cell cycle promoting genes and chromatin components were silenced in the double knockdown. In addition, specific migratory signatures detected in tumors under single IL6 or VEGF knockdown were partially erased in combined IL6/VEGF knockdown tumors. Our results show that treatment with a combination of IL6 and VEGF inhibitors brings synergistic antitumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL6 inhibitors alone. © 2009 UICC

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Interleukin-6 overexpression as a marker of malignancy in human gliomas

Abstract: It can be inferred from these findings that IL-6 gene expression is related to glioma aggressiveness and that IL-6 may play a central role in GBM behavior. Interleukin-6, therefore, could be considered as a new potential target in the treatment of GBMs.

Cited by 94 publications

References 19 publications

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells

Combined targeting of interleukin‐6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness

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