Angiostatin's molecular mechanism: aspects of specificity and regulation elucidated.
Tumor growth requires the development of new vessels that sprout from pre-existing normal vessels in a process known as "angiogenesis" [Folkman (1971) N Engl J Med 285:1182-1186]. These new vessels arise from local capillaries, arteries, and veins in response to the release of soluble growth factors from the tumor mass, enabling these tumors to grow beyond the diffusion-limited size of approximately 2 mm diameter. Angiostatin, a naturally occurring inhibitor of angiogenesis, was discovered based on its ability to block tumor growth in vivo by inhibiting the formation of new tumor blood vessels [O'Reilly et al. (1994a) Cold Spring Harb Symp Quant Biol 59:471-482]. Angiostatin is a proteolytically derived internal fragment of plasminogen and may contain various members of the five plasminogen "kringle" domains, depending on the exact sites of proteolysis. Different forms of angiostatin have measurably different activities, suggesting that much remains to be elucidated about angiostatin biology. A number of groups have sought to identify the native cell surface binding site(s) for angiostatin, resulting in at least five different binding sites proposed for angiostatin on the surface of endothelial cells (EC). This review will consider the data supporting all of the various reported angiostatin binding sites and will focus particular attention on the angiostatin binding protein identified by our group: F(1)F(O) ATP synthase. There have been several developments in the quest to elucidate the mechanism of action of angiostatin and the regulation of its receptor. The purpose of this review is to describe the highlights of research on the mechanism of action of angiostatin, its' interaction with ATP synthase on the EC surface, modulators of its activity, and issues that should be explored in future research related to angiostatin and other anti-angiogenic agents.
Wahl
Miriam L
ML
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kenan
Daniel J
DJ
Gonzalez-Gronow
Mario
M
Pizzo
Salvatore V
SV
D025181:ATP Synthetase Complexes / Q000378:metabolism; D043168:Angiostatins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017306:Annexin A2 / Q000378:metabolism; D000941:Antigens / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
D025181:ATP Synthetase Complexes; D043168:Angiostatins; D017306:Annexin A2; D000941:Antigens; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4