DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo
Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Jg. 71; H. 18; S. 6073 |
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15.09.2011
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| Abstract | Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic. |
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| AbstractList | Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic.Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic. Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic. |
| Author | Wu, Herren Li, Ji-Liang Chowdhury, Partha S Shi, Wen Montgomery, Craig P Harris, Adrian L Leek, Russell Russell, Angela J Bowden, Emma T Oon, Chern Ein Turley, Helen Sheldon, Helen Poulsom, Richard Sainson, Richard C A Bridges, Esther Snell, Cameron |
| Author_xml | – sequence: 1 givenname: Ji-Liang surname: Li fullname: Li, Ji-Liang email: ji-liang.li@imm.ox.ac.uk organization: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. ji-liang.li@imm.ox.ac.uk – sequence: 2 givenname: Richard C A surname: Sainson fullname: Sainson, Richard C A – sequence: 3 givenname: Chern Ein surname: Oon fullname: Oon, Chern Ein – sequence: 4 givenname: Helen surname: Turley fullname: Turley, Helen – sequence: 5 givenname: Russell surname: Leek fullname: Leek, Russell – sequence: 6 givenname: Helen surname: Sheldon fullname: Sheldon, Helen – sequence: 7 givenname: Esther surname: Bridges fullname: Bridges, Esther – sequence: 8 givenname: Wen surname: Shi fullname: Shi, Wen – sequence: 9 givenname: Cameron surname: Snell fullname: Snell, Cameron – sequence: 10 givenname: Emma T surname: Bowden fullname: Bowden, Emma T – sequence: 11 givenname: Herren surname: Wu fullname: Wu, Herren – sequence: 12 givenname: Partha S surname: Chowdhury fullname: Chowdhury, Partha S – sequence: 13 givenname: Angela J surname: Russell fullname: Russell, Angela J – sequence: 14 givenname: Craig P surname: Montgomery fullname: Montgomery, Craig P – sequence: 15 givenname: Richard surname: Poulsom fullname: Poulsom, Richard – sequence: 16 givenname: Adrian L surname: Harris fullname: Harris, Adrian L |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21803743$$D View this record in MEDLINE/PubMed |
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| Snippet | Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate... |
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| SubjectTerms | Angiogenesis Inhibitors - pharmacology Animals Antibodies, Monoclonal, Humanized - pharmacology Bevacizumab Cell Hypoxia - physiology Cell Line, Tumor Dibenzazepines - pharmacology Drug Resistance, Neoplasm Female Fibrosarcoma - blood supply Fibrosarcoma - drug therapy Fibrosarcoma - metabolism Glioblastoma - blood supply Glioblastoma - drug therapy Glioblastoma - metabolism Humans Intracellular Signaling Peptides and Proteins - metabolism Membrane Proteins - metabolism Mice Mice, Inbred BALB C Mice, SCID Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology Receptors, Notch - metabolism Signal Transduction Transplantation, Heterologous Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - biosynthesis |
| Title | DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo |
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