title: Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy.
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.forename: Gabriela
authors.initials: G
authors.lastname: D'Amico
authors.forename: Emilia A
authors.initials: EA
authors.lastname: Korhonen
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Georgia
authors.initials: G
authors.lastname: Zarkada
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.forename: René
authors.initials: R
authors.lastname: Hägerling
authors.forename: Friedemann
authors.initials: F
authors.lastname: Kiefer
authors.forename: Lauri
authors.initials: L
authors.lastname: Eklund
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Harri
authors.initials: H
authors.lastname: Elamaa
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Pipsa
authors.initials: P
authors.lastname: Saharinen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D017353:Gene Deletion; D006720:Homozygote; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010641:Phenotype; D042810:Receptor, TIE-1 / Q000235:genetics* / Q000502:physiology; D042787:Receptor, TIE-2 / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism; D012171:Retinal Vessels / Q000473:pathology*; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D008024:Ligands; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2