Tie1 on for angiogenesis
Current therapies aimed at limiting tumor angiogenesis are based on our understanding of factors that regulate blood vessel sprouting during growth and development. For example, inhibition of the pro-angiogenic VEGF pathway can successfully inhibit growth of some tumors; however, many forms of cancer are not responsive to anti-VEGF therapies. Gabriela D’Amico and colleagues determined that endothelium-specific deletion of Tie1, which encodes an orphan receptor that interacts with the angiopoietin receptor Tie2, inhibited tumor angiogenesis and growth without disrupting normal vasculature. Furthermore, lack of Tie1 delayed developmental angiogenesis in the eye via enhanced Notch signaling. This study indicates that targeting Tie1 has therapeutic potential to limit tumor angiogenesis and growth. The accompanying image shows the localization of Tie1 (green) within tumor vasculature (red) and nuclei stained with DAPI (blue).
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Abstract
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.
Authors
Gabriela D’Amico, Emilia A. Korhonen, Andrey Anisimov, Georgia Zarkada, Tanja Holopainen, René Hägerling, Friedemann Kiefer, Lauri Eklund, Raija Sormunen, Harri Elamaa, Rolf A. Brekken, Ralf H. Adams, Gou Young Koh, Pipsa Saharinen, Kari Alitalo
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ISSN: 0021-9738 (print), 1558-8238 (online)