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 ?-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. Cancer Res; 71(18); 6073–83. ©2011 AACR.
DOI
10.1158/0008-5472.can-11-1704
Publication Date
2011-09-15
Publication Title
Cancer Research
Volume
71
Issue
18
Publisher
American Association for Cancer Research (AACR)
ISSN
1538-7445
Embargo Period
2024-11-19
First Page
6073
Last Page
6083
Recommended Citation
Li, J., Sainson, R., Oon, C., Turley, H., & et al. (2011) 'DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo', Cancer Research, 71(18), pp. 6073-6083. American Association for Cancer Research (AACR): Available at: https://doi.org/10.1158/0008-5472.can-11-1704
