A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis

Yasuhiro Funahashi, Sonia L. Hernandez, Indranil Das, Audrey Ahn, Jianzhong Huang, Marina Vorontchikhina, Anshula Sharma, Emi Kanamaru, Valeriya Borisenko, Dinuka M. DeSilva, Akihiko Suzuki, Xing Wang, Carrie J. Shawber, Jessica J. Kandel, Darrell J. Yamashiro, Jan Kitajewski

研究成果: Article査読

132 被引用数 (Scopus)

抄録

Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor-induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy.

本文言語English
ページ(範囲)4727-4735
ページ数9
ジャーナルCancer Research
68
12
DOI
出版ステータスPublished - 2008 6 15
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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