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

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Krajewska, E. ; Lewis, C.E. ; Chen, Y.Y. ; Welford, A. ; Tazzyman, S. ; Staton, C.A. (2010)
  • Publisher: Cancer Research UK

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.\ud \ud 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.\ud \ud Results: We identified a 20-amino-acid peptide derived from the β chain of FgnE, β43–63, 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 β43–63 interacts with ECs, in part, by binding to αvβ3, so soluble αvβ3 abrogated β43–63 inhibition of tubule formation by activated ECs. Finally, when injected into mice bearing tumour xenografts, β43–63 inhibited tumour vascularisation and induced formation of significant tumour necrosis.\ud \ud Conclusions: Taken together, these data suggest that β43–63 is a novel anti-tumour peptide whose anti-angiogenic effects are mediated by αvβ3.
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