间质细胞
血管生成
生物
内皮干细胞
癌症研究
细胞生物学
转录组
Notch信号通路
细胞
血管内皮生长因子
肿瘤微环境
血管内皮生长因子A
信号转导
体外
血管内皮生长因子受体
遗传学
基因
基因表达
肿瘤细胞
作者
Qi Zhao,Alexandra Eichten,Asma Parveen,Christina Adler,Ying Huang,Wei Wang,Yueming Ding,Alexander P. Adler,Thomas D. Nevins,Min Ni,Yi Wei,Gavin Thurston
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2018-04-30
卷期号:78 (9): 2370-2382
被引量:153
标识
DOI:10.1158/0008-5472.can-17-2728
摘要
Abstract Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here, we characterized by single-cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition, and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell-cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts responded to antiangiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to antiangiogenic therapies. Significance: These findings provide a framework for defining subpopulations of endothelial cells and tumor-associated fibroblasts and their rapid changes in gene expression following antiangiogenic treatment. Cancer Res; 78(9); 2370–82. ©2018 AACR.
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