VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors.
VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors.
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DOI：
10.1038/onc.2015.507
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发表时间：
2016-08-18
期刊：
影响因子：
8
通讯作者：
Eckert RL
中科院分区：
文献类型：
--
作者：
Grun D;Adhikary G;Eckert RL
我们在鳞状细胞癌中发现了有限的表皮癌干细胞（ECS细胞）亚群，与非干细胞相比，它们形成快速生长、侵袭性和高度血管化的肿瘤。这些ECS细胞生长为非附着的球体，并表现出增强的迁移和侵袭。我们发现，ECS细胞产生的血管内皮生长因子(VEGF)-A是维持这种表型所必需的，因为敲低VEGF-A基因表达或用VEGF-A灭活抗体治疗可减少这些反应。此外，贝伐单抗治疗可减少肿瘤的血管性和生长。令人惊讶的是，由于这些细胞缺乏VEGFR1和VEGFR2， VEGF- a通过与VEGF受体相互作用的经典机制并不能介导这些事件。相反，VEGF-A通过神经肽-1 （NRP-1）共受体起作用。下调NRP-1可抑制ECS细胞球状体的形成、侵袭和迁移，减轻肿瘤的形成。这些研究表明VEGF-A通过与NRP-1的相互作用触发细胞内事件，导致ECS细胞存活并形成侵袭性、侵袭性和高度血管化的肿瘤。
We identify a limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, that form rapidly growing, invasive and highly vascularized tumors, as compared with non-stem cancer cells. These ECS cells grow as non-attached spheroids, and display enhanced migration and invasion. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses. In addition, treatment with bevacizumab reduces tumor vascularity and growth. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the neuropilin-1 (NRP-1) co-receptor. Knockdown of NRP-1 inhibits ECS cell spheroid formation, invasion and migration, and attenuates tumor formation. These studies suggest that VEGF-A acts via interaction with NRP-1 to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors.