EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway.

Abstract

Sustaining a high growth rate requires tumors to exploit resources in their microenvironment. One example of this is the extensive angiogenesis that is a typical feature of high-grade gliomas. Here, we show that expression of the constitutively active mutant epidermal growth factor receptor, ΔEGFR (EGFRvIII, EGFR*, de2-7EGFR) is associated with significantly higher expression levels of the pro-angiogenic factor interleukin (IL)-8 in human glioma specimens and glioma stem cells. Furthermore, the ectopic expression of ΔEGFR in different glioma cell lines caused up to 60-fold increases in the secretion of IL-8. Xenografts of these cells exhibit increased neovascularization, which is not elicited by cells overexpressing wild-type (wt)EGFR or ΔEGFR with an additional kinase domain mutation. Analysis of the regulation of IL-8 by site-directed mutagenesis of its promoter showed that ΔEGFR regulates its expression through the transcription factors nuclear factor (NF)-κB, activator protein 1 (AP-1) and CCAAT/enhancer binding protein (C/EBP). Glioma cells overexpressing ΔEGFR showed constitutive activation and DNA binding of NF-κB, overexpression of c-Jun and activation of its upstream kinase c-Jun N-terminal kinase (JNK) and overexpression of C/EBPβ. Selective pharmacological or genetic targeting of the NF-κB or AP-1 pathways efficiently blocked promoter activity and secretion of IL-8. Moreover, RNA interference-mediated knock-down of either IL-8 or the NF-κB subunit p65, in ΔEGFR-expressing cells attenuated their ability to form tumors and to induce angiogenesis when injected subcutaneously into nude mice. On the contrary, the overexpression of IL-8 in glioma cells lacking ΔEGFR potently enhanced their tumorigenicity and produced highly vascularized tumors, suggesting the importance of this cytokine and its transcription regulators in promoting glioma angiogenesis and tumor growth.

• Authors: R Bonavia, M M Inda, S Vandenberg, S-Y Cheng, M Nagane, P Hadwiger, P Tan, D W Y Sah, W K Cavenee, F B Furnari
• Journal: Oncogene (Oncogene) Vol. 31 Issue 36 Pg. 4054-66 (Sep 06 2012) ISSN: 1476-5594 [Electronic] England
• PMID: 22139077 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• CCAAT-Enhancer-Binding Proteins
• Interleukin-8
• NF-kappa B
• Nitriles
• Protein Kinase Inhibitors
• Sulfones
• Transcription Factor AP-1
• epidermal growth factor receptor VIII
• Phosphatidylinositol 3-Kinases
• ErbB Receptors
• JNK Mitogen-Activated Protein Kinases
• ras Proteins

Topics

• Animals
• CCAAT-Enhancer-Binding Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• ErbB Receptors
• Female
• Gene Expression Regulation, Neoplastic
• Glioblastoma (blood supply, pathology)
• Human Umbilical Vein Endothelial Cells (physiology)
• Humans
• Interleukin-8 (genetics, metabolism)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System
• Mice
• Mice, Nude
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplasm Transplantation
• Neoplastic Stem Cells (metabolism)
• Neovascularization, Pathologic (metabolism)
• Nitriles (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Processing, Post-Translational
• Response Elements
• Sulfones (pharmacology)
• Transcription Factor AP-1 (metabolism)
• Transcriptional Activation
• Tumor Burden
• ras Proteins (metabolism)