Alphastatin, a 24–amino acid fragment of human fibrinogen, is a potent new inhibitor of activated endothelial cells in vitro and in vivo

Staton, Carolyn A.; Brown, Nicola J.; Rodgers, Gary; Corke, Kevin P.; Tazzyman, Simon; Underwood, James; Lewis, Claire E.

doi:10.1182/blood-2003-07-2192

Cited by 53 publications

(49 citation statements)

References 25 publications

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“…Although there was no statistically significant difference in vessel number in the tumours of all three groups at the time point examined, vessels in tumours expressing PAPP-Aresistant IGFBP4 were of poorer quality than in the other groups with patchy staining and occluded lumen. A similar effect was previously observed in tumours treated with the angiogenesis inhibitor, alphastatin, where vessels also had a discontinuous endothelial cell wall and occluded lumen (Staton et al, 2004). Tumour sections were then stained with CD31 and TUNEL to identify apoptotic endothelial cells.…”

Section: Discussionmentioning

confidence: 83%

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

et al. 2009

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BACKGROUND: Insulin-like growth factor 1 (IGF1) promotes breast cancer and disease progression. Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1. METHODS: Expression of IGF pathway components and PAPP-A was assessed by western blot or RT -PCR. IGFBP4 (dBP4) resistant to PAPP-A cleavage, but retaining IGF-binding capacity, was used to block IGF activity in vivo. 4T1.2 mouse mammary adenocarcinoma cells transfected with empty vector, vector expressing wild-type IGFBP4 or vector expressing dBP4 were implanted in the mammary fat pad of BALB/c mice and tumour growth was assessed. Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry. RESULTS: 4T1.2 cells expressed the IGF1R receptor and IGFBP4. PAPP-A was expressed within mammary tumours but not by 4T1.2 cells. Proliferation and vascular endothelial growth factor (VEGF) production by 4T1.2 cells was increased by IGF1(E3R) (recombinant IGF1 resistant to binding by IGFBPs) but not by wild-type IGF1. IGF1-stimulated microvascular endothelial cell proliferation was blocked by recombinant IGFBP4. 4T1.2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild-type IGFBP4. Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis. CONCLUSION: Protease-resistant IGFBP4 blocks IGF activity, tumour growth and angiogenesis .

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Section: Discussionmentioning

confidence: 83%

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

et al. 2009

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“…hotspots per section and the sum of the Chalkley scores for each section was termed the cumulative Chalkley score (CSS) [16]. Ki67 staining was assessed as the percentage of tumour cells showing positive staining for Ki67 antigen by counting a minimum of 1000 cells per tumour section in a total of four areas of viable tumour per section [17].…”

Section: Histological Analysismentioning

confidence: 99%

Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo

Bluff

Amarzguioui

Slattery

et al. 2010

Breast Cancer Res Treat

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Purpose: In breast cancer there is a correlation between tissue factor (TF) expression, angiogenesis and disease progression. TF stimulates tumour angiogenesis, in part, through up-regulation of vascular endothelial growth factor (VEGF). Therefore, this study aim ed to establish whether TF stimulates angiogenesis and tumour progression directly and independent of VEGF up-regulation.Methods: Initially the effects of TF and VEGF were assessed on endothelial cell migration (Boyden chamber) and differentiation (tubule formation on Matrigel). Susbequently MDA-MB-436 breast cancer cells, which produce high levels of both TF and VEGF (western blot analysis), were established in vivo, following which tumours were treated three times per week for three weeks with intra-tumoural injections of either anti-VEGF siRNA, anti-TF shRNA, the two treatments combined or relevant controls. 136.3+/-9.2 mm 3 vs control 400.4+/-32.7 mm 3 : p<0.005). Microvessel density, a measure of angiogenesis, was also significantly inhibited in all groups (MVD in control=29+/-2.9; TFshRNA=18+/-1.1; VEGFsiRNA=16.7+/-1.5; both=12+/-2.1; p<0.004), whereas the proliferative index of the tumours was only reduced in the TFshRNA treated groups (control=0.51+/-0.011; TFshRNA=0.41+/-0.014; VEGFsiRNA=0.49+/-0.013; both=0.41+/-0.004; p<0.008).Conclusions: These data suggest that TF has a direct effect on primary breast cancer growth and angiogenesis, and that specific inhibition of the TF signalling pathway has potential for the treatment of primary breast cancer.

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“…This peptide exhibited antiangiogenic effects by inhibiting growth factor-mediated migration, proliferation and tubule formation of human dermal microvascular ECs. In a syngeneic tumor model, alphastatin disrupted endothelium layers, caused widespread thrombosis and attenuated tumor growth (72).…”

Section: Fibrin Fragmentsmentioning

confidence: 99%

Novel Aspects of Fibrin(ogen) Fragments during Inflammation

Jennewein

Tran

Paulus

et al. 2011

Mol Med

208

139

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Coagulation is fundamental for the confinement of infection and/or the inflammatory response to a limited area. Under pathological inflammatory conditions such as arthritis, multiple sclerosis or sepsis, an uncontrolled activation of the coagulation system contributes to inflammation, microvascular failure and organ dysfunction. Coagulation is initiated by the activation of thrombin, which, in turn, triggers fibrin formation by the release of fibrinopeptides. Fibrin is cleaved by plasmin, resulting in clot lysis and an accompanied generation of fibrin fragments such as D and E fragments. Various coagulation factors, including fibrinogen and/or fibrin [fibrin(ogen)] and also fibrin degradation products, modulate the inflammatory response by affecting leukocyte migration and cytokine production. Fibrin fragments are mostly proinflammatory, however, Bβ15-42 in particular possesses potential antiinflammatory effects. Bβ15-42 inhibits Rho-kinase activation by dissociating Fyn from Rho and, hence prevents stress-induced loss of endothelial barrier function and also leukocyte migration. This article summarizes the state-of-the-art in inflammatory modulation by fibrin(ogen) and fibrin fragments. However, further research is required to gain better understanding of the entire role fibrin fragments play during inflammation and, possibly, disease development.

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Alphastatin, a 24–amino acid fragment of human fibrinogen, is a potent new inhibitor of activated endothelial cells in vitro and in vivo

Cited by 53 publications

References 25 publications

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo

Novel Aspects of Fibrin(ogen) Fragments during Inflammation

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