Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.
Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.
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通过靶向血管内皮细胞的人 Delta-like 1 的 DSL 结构域抑制肿瘤血管生成和肿瘤生长。
作者：
Qin, Hong-Yan;Wang, Chun-Mei;Zhang, Ping;Han, Hua
实体瘤的生长依赖于新生血管的形成。已经开发了几种靶向肿瘤血管生成的疗法。然而，在某些肿瘤中的不良反应和新出现的耐药性需要进一步研究新的药物靶点。Notch信号通路在血管发育和肿瘤血管生成中起着关键作用。阻断或强制激活该途径都可以抑制血管生成。由于阻断Notch通路导致血管性肿瘤的形成，因此激活Notch通路以阻止肿瘤血管生成可能是一种替代选择。然而，尚未开发出具有高效Notch活化能力的体内可递送试剂。在这里，我们产生了一种多肽，hD 1 R，它由人Notch配体Delta-like 1的Delta-Serrate-Lag-2片段和靶向内皮细胞（EC）的精氨酸-甘氨酸-天冬氨酸（RGD）基序组成。我们发现hD 1 R可以通过其RGD基序与EC特异性结合，并有效地触发EC中的Notch信号。我们证明了在体外和体内，hD 1 R抑制血管生成发芽和EC增殖。在荷瘤小鼠中，注射hD 1 R有效地抑制了肿瘤生长，最有可能是通过增加肿瘤缺氧和组织坏死。经hD 1 R处理的小鼠肿瘤中血管的数量和宽度显著减少。此外，用hD 1 R治疗的小鼠肿瘤中的血管招募了更多的NG 2（+）血管周围细胞，并且灌注更好。hD 1 R与顺铂、替尼泊苷联合应用具有协同抗肿瘤作用。本研究为肿瘤的抗血管生成治疗提供了新的策略。
The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.
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影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
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20.3
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4
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作者：
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通讯作者：
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