Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy

被引:69
作者
D'Amico, Gabriela [1 ]
Korhonen, Emilia A. [1 ]
Anisimov, Andrey [1 ]
Zarkada, Georgia [1 ,2 ]
Holopainen, Tanja [1 ]
Haegerling, Rene [3 ]
Kiefer, Friedemann [3 ]
Eklund, Lauri [4 ,5 ]
Sormunen, Raija [6 ]
Elamaa, Harri [4 ,5 ]
Brekken, Rolf A. [7 ]
Adams, Ralf H. [8 ,9 ]
Koh, Gou Young [10 ]
Saharinen, Pipsa [1 ,2 ]
Alitalo, Kari [1 ,2 ]
机构
[1] Univ Helsinki, Translat Canc Biol Program, FI-00014 Helsinki, Finland
[2] Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, FI-00014 Helsinki, Finland
[3] Max Planck Inst Mol Biomed, Mammalian Cell Signaling Lab, Dept Vasc Cell Biol, D-48149 Munster, Germany
[4] Univ Oulu, Oulu Univ Hosp, Oulu Ctr Cell Matrix Res, Dept Med Biochem & Mol Biol, Oulu, Finland
[5] Univ Oulu, Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland
[6] Univ Oulu, Oulu Univ Hosp, Dept Pathol, Oulu, Finland
[7] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
[8] Univ Munster, Dept Tissue Morphogenesis, D-48149 Munster, Germany
[9] Max Planck Inst Mol Biomed, D-48149 Munster, Germany
[10] Korea Adv Inst Sci & Technol, Grad Sch Biomed Sci & Engn, Taejon 305701, South Korea
基金
芬兰科学院; 欧洲研究理事会;
关键词
RECEPTOR TYROSINE KINASE; ENDOTHELIAL CELL-CELL; ENHANCED EXPRESSION; ANTI-VEGF; ANGIOGENESIS; MOUSE; TIP; IDENTIFICATION; METASTASIS; ACTIVATION;
D O I
10.1172/JCI68897
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in tumor vessels, without affecting normal vasculature. Treatment with VEGF or VEGFR-2 blocking antibodies similarly reduced tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted retinal hypervasularization. Moreover, substantial additive inhibition of the retinal vascular front migration was observed when Angpt2 blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic therapy.
引用
收藏
页码:824 / 834
页数:11
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