A novel fragment derived from the beta chain of human fibrinogen, beta 43-63, is a potent inhibitor of activated endothelial cells in vitro and in vivo

作者：Krajewska E; Lewis C E; Chen Y Y; Welford A; Tazzyman S; Staton C A^*

来源：British Journal of Cancer, 2010, 102(3): 594-601.

DOI：10.1038/sj.bjc.6605495

• fibrinogen
• beta 43-63
• endothelial
• anti-angiogenic
• haemostasis

BACKGROUND: Angiogenesis and haemostasis are closely linked within tumours with many haemostatic proteins regulating tumour angiogenesis. Indeed we previously identified a fragment of human fibrinogen, fibrinogen E-fragment (FgnE) with potent anti-angiogenic properties in vitro and cytotoxic effects on tumour vessels in vivo. We therefore investigated which region of FgnE was mediating vessel cytotoxicity.
METHODS: Human dermal microvascular endothelial cells (ECs) were used to test the efficacy of peptides derived from FgnE on proliferation, migration, differentiation, apoptosis and adhesion before testing the efficacy of an active peptide on tumour vasculature in vivo.
RESULTS: We identified a 20-amino-acid peptide derived from the beta chain of FgnE, beta 43-63, which had no effect on EC proliferation or migration but markedly inhibited the ability of activated ECs to form tubules or to adhere to various constituents of the extracellular matrix - collagen IV, fibronectin and vitronectin. Furthermore, our data show that beta 43-63 interacts with ECs, in part, by binding to alpha(v)beta(3), so soluble alpha(v)beta(3) abrogated beta 43-63 inhibition of tubule formation by activated ECs. Finally, when injected into mice bearing tumour xenografts, beta 43-63 inhibited tumour vascularisation and induced formation of significant tumour necrosis.
CONCLUSIONS: Taken together, these data suggest that beta 43-63 is a novel anti-tumour peptide whose anti-angiogenic effects are mediated by alpha(v)beta(3). British Journal of Cancer (2010) 102, 594-601. doi:10.1038/sj.bjc.6605495 www.bjcancer.

• 出版日期2010-2-2