title: The human melanoma associated protein melanotransferrin promotes endothelial cell migration and angiogenesis in vivo.
abstract: Melanotransferrin is a member of the transferrin family, which is comprised of serum transferrin, lactoferrin and ovotransferrin, and is highly expressed on melanoma cells compared to normal melanocytes. Since melanoma is an highly vascularized tumour that expresses melanotransferrin at high levels, we tested purified recombinant melanotransferrin for its capability to induce angiogenesis in the chick chorioallantoic membrane. Macroscopic and microscopic evaluation of the vascular density demonstrated that melanotransferrin exerts an angiogenic response quantitatively similar to that elicited by fibroblast growth factor-2. Overexpression of vascular endothelial growth factor-receptor-2 was observed in newly formed vessels, suggesting that the angiogenic activity of melanotransferrin may depend on activation of endogenous vascular endothelial growth factor. In addition, when antibodies against vascular endothelial growth factor were included in the assay, the angiogenic response was inhibited by 50%. In a Boyden chamber assay purified recombinant melanotransferrin induced chemotactic migration of vascular cells, which was decreased in the the presence of anti-vascular endothelial growth factor antibodies suggesting an involvement of vascular endothelial growth factor present in endothelial cells also in this assay. However, melanotransferrin was found not to directly bind to integrin alphavbeta3 or the vascular endothelial growth factor-receptor-2 as assessed in a BlAcore assay. A possible correlation between vascularization occurring during melanoma progression and the expression of melanotransferrin and vascular endothelial growth factor was established by immunolocalization of the two factors in sections of melanoma at different clinical steps of melanoma progression. These latter data strongly imply that melanotransferrin may participate in the vascularization of solid tumours and that inhibition of melanotransferrin could form the basis for intervention in tumours which use this pathway.
authors.affiliation: Istituto Nazionale per la Ricerca sul Cancro, Centro Biotecnologie Avanzate, Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sala
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: Jefferies
authors.forename: Brandie
authors.initials: B
authors.lastname: Walker
authors.forename: Joseph
authors.initials: J
authors.lastname: Yang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tiong
authors.forename: S K Alex
authors.initials: SK
authors.lastname: Law
authors.forename: Mariella F
authors.initials: MF
authors.lastname: Carlevaro
authors.forename: Eddy
authors.initials: E
authors.lastname: Di Marco
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.forename: Ranieri
authors.initials: R
authors.lastname: Cancedda
authors.forename: Fiorella Descalzi
authors.initials: FD
authors.lastname: Cancedda
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
mesh_terms: D000328:Adult; D000818:Animals; D000951:Antigens, Neoplasm; D015152:Blotting, Northern; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002642:Chick Embryo; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D058950:Melanoma-Specific Antigens; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology*; D009389:Neovascularization, Pathologic; D016133:Polymerase Chain Reaction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D016222:Fibroblast Growth Factor 2; D040301:Vascular Endothelial Growth Factor Receptor-2