Yan Minhong, Plowman Greg D
Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, CA 94080, USA.
Clin Cancer Res. 2007 Dec 15;13(24):7243-6. doi: 10.1158/1078-0432.CCR-07-1393.
Intense research efforts have been focused toward the identification of regulators of angiogenesis and the development of antiangiogenesis-based cancer therapies. The approval of anti-vascular endothelial growth factor (VEGF) monoclonal antibody (bevacizumab) for use in colorectal and lung cancer provides clinical validation for targeting angiogenesis for the treatment of cancer. Delta-like 4 (Dll4)-mediated Notch signaling represents another key pathway essential for vascular development. Recent studies yield substantial insights into the role of Dll4 in angiogenesis. Dll4 is downstream of VEGF signaling and its activation triggers a negative feedback that restrains the effects of VEGF. Attenuation of Dll4/Notch signaling results in chaotic vascular network with excessive branching and sprouting. In preclinical studies, blocking of Dll4/Notch signaling is associated with a paradoxical increase in tumor vessel density, yet causes marked growth inhibition due to functionally defective vasculature. Dll4 blockade holds promise as an additional strategy for angiogenesis-based cancer therapy, especially when resistance to and/or escape from existing therapies evolve.
大量的研究工作都集中在确定血管生成的调节因子以及开发基于抗血管生成的癌症治疗方法上。抗血管内皮生长因子（VEGF）单克隆抗体（贝伐单抗）被批准用于治疗结直肠癌和肺癌，这为靶向血管生成治疗癌症提供了临床验证。Delta样蛋白4（Dll4）介导的Notch信号通路是血管发育的另一条关键途径。最近的研究对Dll4在血管生成中的作用有了深入了解。Dll4位于VEGF信号通路的下游，其激活会触发负反馈，从而抑制VEGF的作用。Dll4/Notch信号通路的减弱会导致血管网络紊乱，出现过度分支和出芽。在临床前研究中，阻断Dll4/Notch信号通路与肿瘤血管密度的反常增加有关，但由于血管功能缺陷，会导致明显的生长抑制。Dll4阻断有望成为基于血管生成的癌症治疗的另一种策略，尤其是当对现有治疗产生耐药性和/或出现逃避现象时。
