title: Peptides inhibiting heparanase procoagulant activity significantly reduce tumour growth and vascularisation in a mouse model.
abstract: Heparanase is implicated in angiogenesis and tumour progression. We previously demonstrated that heparanase might also affect the haemostatic system in a non-enzymatic manner. It forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF). Peptides that we generated from TF pathway inhibitor (TFPI)-2, which inhibit heparanase procoagulant activity, were recently demonstrated to attenuate inflammation in a sepsis mouse model. The present study was designated to explore peptides effects on tumour growth and vascularisation. Cell lines of mouse melanoma (B16), mouse breast cancer (EMT-6), and human breast cancer (MDA-231) were injected subcutaneously to mice. Inhibitory peptides 5, 6 and 7 were injected subcutaneously in the area opposite to the tumour side. In the three tumour cell lines, peptides 5, 6 and 7 inhibited tumour growth and vascularisation in a dose-dependent manner, reaching a 2/3 reduction compared to control tumours (p<0.001). Additionally, a survival advantage (p<0.05) and reduced plasma thrombin-antithrombin complex (p<0.05) were observed in the treatment groups. Peptides delayed tumour relapse by six days and inhibited relapsed tumour size (p<0.001). In vitro, peptides did not inhibit tumour cell proliferation, migration or heparanase degradation of heparan sulfate chains, but significantly decreased tube formation. In conclusion, peptides inhibiting heparanase procoagulant activity significantly reduced tumour growth, vascularisation, and relapse. The procoagulant domain in heparanase protein may play a role in tumour growth, suggesting a new mechanism of coagulation system involvement in cancer.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Crispel
authors.forename: Elena
authors.initials: E
authors.lastname: Axelman
authors.forename: Mifleh
authors.initials: M
authors.lastname: Tatour
authors.forename: Inna
authors.initials: I
authors.lastname: Kogan
authors.forename: Neta
authors.initials: N
authors.lastname: Nevo
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brenner
authors.affiliation: Yona Nadir, MD, PhD, Thrombosis and Hemostasis Unit, Rambam Health Care Campus, Haifa, Israel, Tel.: +972 4 8453520, Fax: +972 4 8543886, E-mail: ynadir@netvision.net.il.
authors.forename: Yona
authors.initials: Y
authors.lastname: Nadir
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005966:Glucuronidase / Q000494:pharmacology*; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000494:pharmacology; D013925:Thromboplastin; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D010455:Peptides; D013925:Thromboplastin; D000099175:Heparanase
keywords: Heparanase; inhibitory peptides; tissue factor; tumour