● ● ● VASCULAR BIOLOGY Comment on Lee et al, page 1987 The antitumorigenic trifecta

protein angiostatin in 1994.1 In this issue ofBlood, Lee and colleagues propose 2 newmechanisms of action for angiostatin that may represent promising targets for new cancer therapeutics.2 Angiostatin, a proteolytic fragment of plas-minogen, blocks angiogenesis and inhib-its tumor growth.1,3 Previous studies of an-giostatin emphasized its inhibition of angiogenesis via endothelial cell–specific pro-apoptotic, antimigratory, and antiproliferative effects. F1F0 ATP synthase was identified as a cell-surface receptor for angiostatin.4,5 An-giostatin blocks the enzymatic activity of this receptor, namely transmembrane pro-ton transport coupled to ATP synthesis/ hydrolysis. Inhibition of ATP synthase induces intracellular acidification and de