EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis
| Autor: | Narve Brekka, Olav Karsten Vintermyr, Per Øystein Sakariassen, Philipp Euskirchen, Anke Soentgerath, Hrvoje Miletic, Eskil Eskilsson, Simone P. Niclou, Morten Lund-Johansen, Gro V. Røsland, Ingrid Moen, Krishna M. Talasila, Olivier Keunen, Lars Prestegarden, Janice M. Nigro, Rolf Bjerkvig, Per Øyvind Enger, Daniel Stieber, Kai Ove Skaftnesmo, Sverre Mørk, Peter C. Huszthy, Jian Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Transcriptional Activation
Pathology medicine.medical_specialty Angiogenesis Clinical Neurology Cell Culture Techniques Cetuximab Antineoplastic Agents Antibodies Monoclonal Humanized Pathology and Forensic Medicine Neovascularization Cellular and Molecular Neuroscience Invasion Cell Line Tumor medicine Humans EGFR Gene Amplification EGFR amplification Neoplasm Invasiveness Epidermal growth factor receptor Original Paper biology Neovascularization Pathologic Brain Neoplasms Mesenchymal stem cell Gene Amplification Cancer Genes erbB-1 medicine.disease Xenograft Model Antitumor Assays ErbB Receptors Cell culture Cancer research biology.protein Neurology (clinical) medicine.symptom Glioblastoma medicine.drug |
| Zdroj: | Acta Neuropathologica |
| ISSN: | 1432-0533 0001-6322 |
| Popis: | Angiogenesis is regarded as a hallmark of cancer progression and it has been postulated that solid tumor growth depends on angiogenesis. At present, however, it is clear that tumor cell invasion can occur without angiogenesis, a phenomenon that is particularly evident by the infiltrative growth of malignant brain tumors, such as glioblastomas (GBMs). In these tumors, amplification or overexpression of wild-type (wt) or truncated and constitutively activated epidermal growth factor receptor (EGFR) are regarded as important events in GBM development, where the complex downstream signaling events have been implicated in tumor cell invasion, angiogenesis and proliferation. Here, we show that amplification and in particular activation of wild-type EGFR represents an underlying mechanism for non-angiogenic, invasive tumor growth. Using a clinically relevant human GBM xenograft model, we show that tumor cells with EGFR gene amplification and activation diffusely infiltrate normal brain tissue independent of angiogenesis and that transient inhibition of EGFR activity by cetuximab inhibits the invasive tumor growth. Moreover, stable, long-term expression of a dominant-negative EGFR leads to a mesenchymal to epithelial-like transition and induction of angiogenic tumor growth. Analysis of human GBM biopsies confirmed that EGFR activation correlated with invasive/non-angiogenic tumor growth. In conclusion, our results indicate that activation of wild-type EGFR promotes invasion and glioblastoma development independent of angiogenesis, whereas loss of its activity results in angiogenic tumor growth. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1101-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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