In vivo inhibition of angiogenesis by a soluble form of melanotransferrin.
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 Matrigel 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 Matrigel 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 approximately 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.
Michaud-Levesque
Jonathan
J
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.
Demeule
Michel
M
Béliveau
Richard
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000951:Antigens, Neoplasm; D002478:Cells, Cultured; D005341:Fibrinolysin / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009389:Neovascularization, Pathologic; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000951:Antigens, Neoplasm; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D005341:Fibrinolysin