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Carcinogenesis Advance Access originally published online on July 20, 2006
Carcinogenesis 2007 28(2):280-288; doi:10.1093/carcin/bgl123
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

In vivo inhibition of angiogenesis by a soluble form of melanotransferrin

Jonathan Michaud-Levesque, Michel Demeule and Richard Béliveau*

Laboratoire de Médecine Moléculaire, Service d‘Hémato-Oncologie Hôpital Ste-Justine- UQAM, C.P. 8888, Succursale Centre-ville, Université du Québec à Montréal, Montréal, Québec, Canada H3C 3P8

*To whom correspondence should be addressed. Email: oncomol{at}nobel.si.uqam.ca

Melanotransferrin (MTf), the membrane-bound human melanoma antigen p97, binds to plasminogen and stimulates its activation, thus regulating a crucial step involved in angiogenesis. In our study, a truncated soluble form of MTf (sMTf) inhibits, in a dose-dependent manner, the in vitro tubulogenesis of human umbilical vessel endothelial cells (HUVEC) induced by media conditioned with MTf-expressing cells. Following these results, we used the in vivo MatrigelTM plug angiogenesis assay to investigate whether truncated sMTf could inhibit neovascularization in mice. We found that basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and MTf-expressing cells strongly stimulate in vivo MatrigelTM neovascularization. However, subcutaneous (s.c.) administration of truncated sMTf inhibits both bFGF- and VEGF- as well as human melanoma SK-Mel-28-induced angiogenesis. This inhibition was dependent on the truncated sMTf concentration and reached maximal inhibition at 40 mg/kg/week. Furthermore, we found that a single s.c. injection of truncated sMTf into nude mice at 5 mg/kg produced a maximal blood concentration of ~40 nM, which is comparable with the level required to inhibit in vitro HUVEC tubulogenesis. Overall, our results strongly suggest that s.c. administration of truncated sMTf may provide a novel therapeutic strategy for the treatment of angiogenesis-related disorders.

Abbreviations: bFGF, basic fibroblast growth factor; CHO, Chinese hamster ovary; EC, endothelial cells; Hb, hemoglobin; HUVEC, human umbilical vessel EC; mAb, monoclonal antibody; MTf, melanotransferrin; R/H, Ringer/HEPES; sMTf, soluble form of MTf; PA, plasminogen activator; s.c, subcutaneous; VEGF, vascular endothelial growth factor

Received May 5, 2006; accepted June 30, 2006.


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