IL-6 is required for glioma development in a mouse model

Weissenberger, Jakob; Loeffler, Sébastien; Каппелер, Андреас; Köpf, Manfred; Lukes, Anton; Afanasieva, Tatiana A.; Aguzzi, Adriano; Weis, Joachim

doi:10.1038/sj.onc.1207455

Cited by 178 publications

(140 citation statements)

References 41 publications

(50 reference statements)

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“…Recent studies have shown that STAT3 is constitutively activated in the vast majority of malignant glioma tissues and cell lines (Rahaman et al, 2002;Schaefer et al, 2002;Weissenberger et al, 2004). However, there is controversy regarding which cell types in tumor tissues express activated STAT3: tumor cells or tumor endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…One of the main molecular signatures of malignant glioma is dysregulation of the EGFR pathway manifesting as amplification and mutation of EGFR and mutation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) (Kapoor and O'Rourke, 2003;Kondo et al, 2004). Another line of evidence has shown that interleukin 6 (IL-6) expression or STAT3 activation is often detected in malignant glioma tissues, whereas neither feature is detected in normal brain tissue (Van Meir et al, 1990;Lichtor and Libermann, 1994;Rahaman et al, 2002;Schaefer et al, 2002;Weissenberger et al, 2004). Taken together, these findings suggest that STAT3 is activated through EGFR dysregulation and the aberrant expression of IL-6 in malignant glioma cells and that the inhibition of STAT3 may be a new tumor-selective strategy for malignant glioma.…”

Section: Introductionmentioning

confidence: 99%

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A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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“…Elevated levels of these two interleukins are correlated with the degree of malignancy in gliomas (Huettner et al, 1995;Sasaki et al, 2001) as well as increased proliferation and migration of glioma cell lines (Huettner et al, 1997;Wang et al, 2009). In particular, interleukin-6 ablation prevents tumor formation in a v-src-induced model of gliomagenesis (Weissenberger et al, 2004).…”

Section: Stromal Determinants Of Glioma Formation and Growthmentioning

confidence: 99%

The ecology of brain tumors: lessons learned from neurofibromatosis-1

Pong

Gutmann

2010

Oncogene

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Traditionally, cancer studies have primarily focused on mutations that activate growth or survival pathways in susceptible pre-neoplastic/neoplastic cells. However, recent research has revealed a critical role for nonneoplastic cells within the tumor microenvironment in the process of cancer formation and progression. In addition, the existence of regional and developmental variations in susceptible cell types and supportive microenvironments support a model of tumorigenesis in which the dynamic symbiotic relationship between neoplastic and non-neoplastic cell types dictate where and when cancers form and grow. In this review, we highlight advances in neurofibromatosis type 1 (NF1) genetically engineered mouse brain tumor (glioma) modeling to reveal how cellular and molecular heterogeneity in both the pre-neoplastic/ neoplastic and non-neoplastic cellular compartments contribute to gliomagenesis and glioma growth.

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“…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). IL-6 not only promotes the survival of certain neuronal cell populations 13 but also the reactive transformation of astrocytes.…”

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

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192

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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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IL-6 is required for glioma development in a mouse model

Cited by 178 publications

References 41 publications

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

The ecology of brain tumors: lessons learned from neurofibromatosis-1

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

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