We show that a membrane-associated protease, aminopeptidase A (APA), is upregulated and enzymatically active in blood vessels of human tumors. To gain mechanistic insight, we evaluated angiogenesis in APA null mice. We found that, although these mice develop normally, they fail to mount the expected angiogenic response to hypoxia or growth factors. We then isolated peptide inhibitors of APA from a peptide library and show that they specifically bind to and inhibit APA, suppress migration and proliferation of endothelial cells, inhibit angiogenesis, and home to tumor blood vessels. Finally, we successfully treated tumor-bearing mice with APA binding peptides or anti-APA blocking monoclonal antibodies. These data show that APA is a regulator of blood vessel formation, and can serve as a functional vascular target.

Aminopeptidase A is a functional target in angiogenic blood vessels

MARCHIO', Serena;VALDEMBRI, Donatella;BUSSOLINO, Federico;
2004-01-01

Abstract

We show that a membrane-associated protease, aminopeptidase A (APA), is upregulated and enzymatically active in blood vessels of human tumors. To gain mechanistic insight, we evaluated angiogenesis in APA null mice. We found that, although these mice develop normally, they fail to mount the expected angiogenic response to hypoxia or growth factors. We then isolated peptide inhibitors of APA from a peptide library and show that they specifically bind to and inhibit APA, suppress migration and proliferation of endothelial cells, inhibit angiogenesis, and home to tumor blood vessels. Finally, we successfully treated tumor-bearing mice with APA binding peptides or anti-APA blocking monoclonal antibodies. These data show that APA is a regulator of blood vessel formation, and can serve as a functional vascular target.
2004
5
151
162
angiogenesis; phage display
MARCHIÒ S; LAHDENRANTA J; SCHLINGEMANN RO; VALDEMBRI D; WESSELING P; ARAP MA; HAJITOU A; OZAWA MG; TREPEL M; GIORDANO RJ; NANUS DM; DIJKMAN HB; OOSTERWIJK E; SIDMAN RL; COOPER MD; BUSSOLINO F; PASQUALINI R; ARAP W
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/36608
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