Understanding the signals that control blood vessel growth has allowed new therapies for treating solid tumors based on inhibition of angiogenesis. However, some tumors are resistant to the inhibitory effects of the antiangiogenesis agents that target vascular endothelial cell growth factor (VEGF) signaling. Noguera-Troise et al. and Ridgway et al. report that selective inhibition of Notch signaling in endothelial cells, with agents that disrupt the interaction between Notch and Delta-like ligand 4 (Dll4), reduces tumor size in mouse models even for tumors resistant to agents targeting VEGF signaling. Surprisingly, inhibition of endothelial Notch signaling resulted in enhanced vascular density in the tumors because of increased vessel sprouting. However, perfusion studies indicated that these vessels were nonfunctional and that the tumors showed increased regions of hypoxia. Systemic application of the Notch-Dll4 inhibitors did not cause side effects associated with nonselective Notch inhibition, such as loss of the crypt stem cells in the intestine. Thus, endothelial Notch signaling appears to serve as a negative regulator of vessel growth, and disruption of this pathway in tumors causes the production of nonfunctional vessels and regression of the tumor.
I. Noguera-Troise, C. Daly, N. J. Papadopoulos, S. Coetzee, P. Boland, N. W. Gale, H. C. Lin, G. D. Yancopoulos, G. Thurston, Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032-1037 (2006). [PubMed]
J. Ridgway, G. Zhang, Y. Wu, S. Stawicki, W.-C. Liang, Y. Chanthery, J. Kowalski, R. J. Watts, C. Callahan, I. Kasman, M. Singh, M. Chien, C. Tan, J.-A. S. Hongo, F. de Sauvage, G. Plowman, M. Yan, Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083-1087 (2006). [PubMed]