PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors.
PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors.
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DOI：
10.1126/sciadv.1400244
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发表时间：
2015-04
期刊：
影响因子：
13.6
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
Iwamoto H;Zhang Y;Seki T;Yang Y;Nakamura M;Wang J;Yang X;Torimura T;Cao Y
Notch抑制剂在表达PlGF β蛋白的肿瘤中引起癌症生长。抑制Dll 4（δ样配体4）-Notch信号传导介导的肿瘤血管生成是癌症治疗中有吸引力的方法。然而，D114-Notch信号传导的抑制在各种肿瘤中产生了不同的效果，并且没有生物标志物可用于预测抗D114-Notch相关的抗肿瘤活性。我们发现人和小鼠肿瘤细胞衍生的胎盘生长因子（PlGF）是Dll 4-Notch诱导的血管重塑和肿瘤生长的关键决定因素。在天然的表达PlGF的人肿瘤中，Dll 4-Notch信号传导的抑制通过增加非渗漏肿瘤血管中的血液灌注而显著加速肿瘤生长。相反，在PlGF阴性肿瘤中，Dll 4抑制通过形成非生产性和渗漏的血管抑制肿瘤生长。令人惊讶的是，血管内皮生长因子受体1（VEGFR 1）的基因失活完全消除了PDGF调节的血管重塑和肿瘤生长，表明VEGFR 1介导的信号在调节D114-Notch功能中的关键作用。这些发现提供了关于PlGF-VEGFR 1信号传导在血管生成和肿瘤生长中D114-Notch途径的调节中的机制见解，并且具有PlGF作为生物标志物用于预测D114和Notch抑制剂的抗肿瘤益处的治疗意义。
Notch inhibitors cause cancer growth in tumors expressing PIGFβ protein. Inhibition of Dll4 (delta-like ligand 4)–Notch signaling–mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti–Dll4-Notch–associated antitumor activity. We show that human and mouse tumor cell–derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch–induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors.