The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo
Open accessAbstract
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. Cancer Res; 71(18); 6073–83. ©2011 AACR.
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Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032691 · Cited by 10,968
Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer
Sandler, A., Gray, R., Perry, M. C., Brahmer, J., Schiller, J. H., Dowlati, A., Lilenbaum, R., & Johnson, D. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa061884 · Cited by 5,761
Modes of resistance to anti-angiogenic therapy
Bergers, G., & Hanahan, D. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2442 · Cited by 2,953 · cited 4×
“Our findings may explain why so many patients in clinical trials do not respond to bevacizumab (13).”
BackgroundInfluentialInhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis
Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., et al. (2006) · Nature · doi:10.1038/nature05313 · Cited by 986
Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells
Shojaei, F., Wu, X., Malik, A. K., Zhong, C., Baldwin, M. E., Schanz, S., Fuh, G., Gerber, H.-P., & Ferrara, N. (2007) · Nature Biotechnology · doi:10.1038/nbt1323 · Cited by 849
Gale, N. W., Dominguez, M. G., Noguera, I., Pan, L., Hughes, V., Valenzuela, D. M., Murphy, A. J., Adams, N. C., Lin, H. C., Holash, J., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407290101 · Cited by 600
Cited by
Zhu, A. X., Abbas, A. R., de Galarreta, M. R., Guan, Y., Lu, S., Koeppen, H., Zhang, W., Hsu, C.-H., He, A. R., Ryoo, B.-Y., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01868-2 · Cited by 652
Bensaad, K., Favaro, E., Lewis, C. A., Peck, B., Lord, S., Collins, J. M., Pinnick, K. E., Wigfield, S., Buffa, F. M., Li, J.-L., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.056 · Cited by 665
Self-citationRecent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer
Welti, J., Loges, S., Dimmeler, S., & Carmeliet, P. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70212 · Cited by 591
A history of exploring cancer in context
Maman, S., & Witz, I. P. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0006-7 · Cited by 502
Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy
Patel, S. A., Nilsson, M. B., Le, X., Cascone, T., Jain, R. K., & Heymach, J. V. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-1366 · Cited by 481
Metadata
- Authors
- Li, J.-L., Sainson, R. C. A., Oon, C. E., Turley, H., Leek, R., Sheldon, H., Bridges, E., Shi, W., Snell, C., Bowden, E. T., Wu, H., Chowdhury, P. S., Russell, A. J., Montgomery, C. P., Poulsom, R., & Harris, A. L.
- Venue
- Cancer Research
- Published
- 2011-09-13
- Volume
- 71
- Issue
- 18
- Pages
- 6073-6083
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2124396025
- Cited by
- 224
- References
- 7
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Li, J.-L., Sainson, R. C. A., Oon, C. E., Turley, H., Leek, R., Sheldon, H., Bridges, E., Shi, W., Snell, C., Bowden, E. T., Wu, H., Chowdhury, P. S., Russell, A. J., Montgomery, C. P., Poulsom, R., & Harris, A. L. (2011). DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo. Cancer Research. https://doi.org/10.1158/0008-5472.can-11-1704
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