EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors
Abstract Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti‐VEGF (vascu...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708420 |
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| author | Nevenka Dudvarski Stanković Frank Bicker Stefanie Keller David TW Jones Patrick N Harter Arne Kienzle Clarissa Gillmann Philipp Arnold Anna Golebiewska Olivier Keunen Alf Giese Andreas von Deimling Tobias Bäuerle Simone P Niclou Michel Mittelbronn Weilan Ye Stefan M Pfister Mirko HH Schmidt |
| author_facet | Nevenka Dudvarski Stanković Frank Bicker Stefanie Keller David TW Jones Patrick N Harter Arne Kienzle Clarissa Gillmann Philipp Arnold Anna Golebiewska Olivier Keunen Alf Giese Andreas von Deimling Tobias Bäuerle Simone P Niclou Michel Mittelbronn Weilan Ye Stefan M Pfister Mirko HH Schmidt |
| author_sort | Nevenka Dudvarski Stanković |
| collection | DOAJ |
| description | Abstract Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti‐VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression‐free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives. In an attempt to improve the efficacy of anti‐VEGF treatment, we explored the role of the egfl7 gene in malignant glioma. We found that the encoded extracellular matrix protein epidermal growth factor‐like protein 7 (EGFL7) was secreted by glioma blood vessels but not glioma cells themselves, while no major role could be assigned to the parasitic miRNAs miR‐126/126*. EGFL7 expression promoted glioma growth in experimental glioma models in vivo and stimulated tumor vascularization. Mechanistically, this was mediated by an upregulation of integrin α5β1 on the cellular surface of endothelial cells, which enhanced fibronectin‐induced angiogenic sprouting. Glioma blood vessels that formed in vivo were more mature as determined by pericyte and smooth muscle cell coverage. Furthermore, these vessels were less leaky as measured by magnetic resonance imaging of extravasating contrast agent. EGFL7‐inhibition using a specific blocking antibody reduced the vascularization of experimental gliomas and increased the life span of treated animals, in particular in combination with anti‐VEGF and the chemotherapeutic agent temozolomide. Data allow for the conclusion that this combinatorial regimen may serve as a novel treatment option for GBM. |
| format | Article |
| id | doaj-art-da5be89c68214918bc8541961d52a2fb |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-da5be89c68214918bc8541961d52a2fb2025-08-20T03:46:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-08-0110911910.15252/emmm.201708420EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumorsNevenka Dudvarski Stanković0Frank Bicker1Stefanie Keller2David TW Jones3Patrick N Harter4Arne Kienzle5Clarissa Gillmann6Philipp Arnold7Anna Golebiewska8Olivier Keunen9Alf Giese10Andreas von Deimling11Tobias Bäuerle12Simone P Niclou13Michel Mittelbronn14Weilan Ye15Stefan M Pfister16Mirko HH Schmidt17Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg UniversityMolecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg UniversityMolecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg UniversityGerman Cancer Research Center (DKFZ)German Cancer Consortium (DKTK)Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg UniversityInstitute of Radiology, University Medical Center ErlangenAnatomical Institute, Kiel UniversityNORLUX Neuro‐Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.)NORLUX Neuro‐Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.)Department of Neurosurgery, University Medical Center of the Johannes Gutenberg UniversityGerman Cancer Research Center (DKFZ)Institute of Radiology, University Medical Center ErlangenNORLUX Neuro‐Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.)NORLUX Neuro‐Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (L.I.H.)Vascular Biology Program, Molecular Oncology Division, GenentechGerman Cancer Research Center (DKFZ)Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg UniversityAbstract Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti‐VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression‐free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives. In an attempt to improve the efficacy of anti‐VEGF treatment, we explored the role of the egfl7 gene in malignant glioma. We found that the encoded extracellular matrix protein epidermal growth factor‐like protein 7 (EGFL7) was secreted by glioma blood vessels but not glioma cells themselves, while no major role could be assigned to the parasitic miRNAs miR‐126/126*. EGFL7 expression promoted glioma growth in experimental glioma models in vivo and stimulated tumor vascularization. Mechanistically, this was mediated by an upregulation of integrin α5β1 on the cellular surface of endothelial cells, which enhanced fibronectin‐induced angiogenic sprouting. Glioma blood vessels that formed in vivo were more mature as determined by pericyte and smooth muscle cell coverage. Furthermore, these vessels were less leaky as measured by magnetic resonance imaging of extravasating contrast agent. EGFL7‐inhibition using a specific blocking antibody reduced the vascularization of experimental gliomas and increased the life span of treated animals, in particular in combination with anti‐VEGF and the chemotherapeutic agent temozolomide. Data allow for the conclusion that this combinatorial regimen may serve as a novel treatment option for GBM.https://doi.org/10.15252/emmm.201708420angiogenesisEGFL7endothelial cellglioblastomaintegrin |
| spellingShingle | Nevenka Dudvarski Stanković Frank Bicker Stefanie Keller David TW Jones Patrick N Harter Arne Kienzle Clarissa Gillmann Philipp Arnold Anna Golebiewska Olivier Keunen Alf Giese Andreas von Deimling Tobias Bäuerle Simone P Niclou Michel Mittelbronn Weilan Ye Stefan M Pfister Mirko HH Schmidt EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors EMBO Molecular Medicine angiogenesis EGFL7 endothelial cell glioblastoma integrin |
| title | EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors |
| title_full | EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors |
| title_fullStr | EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors |
| title_full_unstemmed | EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors |
| title_short | EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors |
| title_sort | egfl7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors |
| topic | angiogenesis EGFL7 endothelial cell glioblastoma integrin |
| url | https://doi.org/10.15252/emmm.201708420 |
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