Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Abstract

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.

Biology of Angiogenesis and Invasion in Glioma

“…10 Angiostatin is derived from degradation of plasminogen by proteases such as cathepsin D and MMPs, resulting in a molecule comprised of kringle domains 1 through 4. 81,82 Studies in mice indicate that angiostatin inhibits glioma angiogenesis and growth 83,84 through binding of ␣ v ␤ 3 on proliferating endothelial cells, result in apoptosis. 81,85 NG2 chondroitin sulfate proteoglycan made by tumor-associated pericytes acts in a pro-angiogenic manner by sequestering angiostatin and decreasing its bioactivity.…”

Proteomic Characterization of Angiogenic Endothelial Cells Stimulated with Cancer Cell-Conditioned Medium

“…17) Since our results showed that ANXA2 expression was downregulated by HT1080-CM but upregulated by VEGF, HT1080-CM treatment may cause a response similar to prostate cancer. ANXA2 is also a cell surface receptor for angiostatin, which is a potent endoge- 19,20) It is possible that the downregulation of ANXA2 expression by HT1080-CM promotes CM-induced angiogenesis through the suppression of the effect of angiostatin.…”

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

“…However, some of these enzymes can also, in defined circumstances, inhibit angiogenesis. Angiostatin, a potent inhibitor of angiogenesis, is a proteolytic fragment of plasminogen [10,11] and matrix metalloproteinases can generate anti-angiogenic fragments by proteolytic processing of some ECM proteins (see above, and [12]). As another example, two metalloproteinases of the ADAMTS family, ADAMTS-1 and -8, were also reported to strongly inhibit angiogenesis [13,14].…”