Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas

Chaudhry, Iskander H.; O’Donovan, Dominic G; Brenchley, Paul; Reid, H; Roberts, I S D

doi:10.1046/j.1365-2559.2001.01230.x

Cited by 171 publications

(140 citation statements)

References 45 publications

(47 reference statements)

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“…This is consistent with previous work demonstrating that EGFR activation transcriptionally upregulates VEGF expression in GBM cells (Maity et al, 2000). VEGF plays a major role in promoting angiogenesis and tumor growth of GBMs in vivo (Berkman et al, 1993;Cheng et al, 1996;Yuan et al, 1996;Chan et al, 1998;Brat and van Meir, 2001;Chaudhry et al, 2001), and may therefore be critical for EGFR-mediated pathogenesis. This also suggests an important molecular basis on which to select GBM patients for anti-angiogenic therapy.…”

Section: Discussionsupporting

confidence: 91%

Identification of molecular subtypes of glioblastoma by gene expression profiling

et al. 2003

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Epidermal growth factor receptor (EGFR) overexpression occurs in nearly 50% of cases of glioblastoma (GBM), but its clinical and biological implications are not well understood. We have used Affymetrix high-density oligonucleotide arrays to demonstrate that EGFR-overexpressing GBMs (EGFR+) have a distinct global gene transcriptional profile. We show that the expression of 90 genes can distinguish EGFR+ from EGFR nonexpressing (EGFRÀ) GBMs, including a number of genes known to act as growth/survival factors for GBMs. We have also uncovered two additional novel molecular subtypes of GBMs, one of which is characterized by coordinate upregulation of contiguous genes on chromosome 12q13-15 and expression of both astrocytic and oligodendroglial genes. These results define distinct molecular subtypes of GBMs that may be important in disease stratification, and in the discovery and assessment of GBM treatment strategies.

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Section: Discussionsupporting

confidence: 91%

Identification of molecular subtypes of glioblastoma by gene expression profiling

et al. 2003

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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%

“…The ability of a VEGF antisense construct to reduce angiogenicity and tumorigenicity of human U87MG GBM cells suggested that VEGF plays a key role in glioma development. 3 In human brain cancers, a close correlation was found between VEGF expression, tumor vascularization and grade of malignancy, 4 with 95% of GBMs staining positive for VEGF. 5 The signals were localized in both perinecrotic and vital tumor areas suggesting that both hypoxia and other stimuli may control the expression of VEGF in gliomas.…”

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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

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Weis

et al. 2005

Intl Journal of Cancer

191

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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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“…GBM are highly vascularized tumors and VEGF is a leading regulator of GBM angiogenesis [49][50][51][52][53][54].…”

Section: Overview Of the Marketmentioning

confidence: 99%

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

et al. 2011

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Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks 3 and 5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study cancer subtypes including glioblastoma (GBM), the most common and deadliest central nervous system (CNS) tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide (TMZ) and radiation demonstrate consistent anti-tumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized phase III study (CENTRIC) for newly diagnosed GBM. In addition, randomized, controlled phase II studies with cilengitide are ongoing for non-small cell lung cancer and squamous cell carcinoma of the head and neck.Cilengitide is the first integrin-inhibitor in clinical phase III development for oncology.

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Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas

Cited by 171 publications

References 45 publications

Identification of molecular subtypes of glioblastoma by gene expression profiling

Identification of molecular subtypes of glioblastoma by gene expression profiling

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

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

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