title: Bovine lactoferrin inhibits tumor-induced angiogenesis.
abstract: Recent studies have demonstrated that bovine lactoferrin (bLF) suppresses tumor growth and metastasis in the mouse and rat and moreover may inhibit angiogenesis. To determine whether angiogenesis inhibition might contribute to antitumor activity, we examined the influence of bLF on tumor-induced angiogenesis and endothelial cell functions as well as angiogenesis-related cytokine production. Bovine LF exhibited dose-dependent inhibition of angiogenesis on 4-6-day-old chick embryo chorioallantoic membranes (CAMs) that lack a mature immune response. This inhibition was reversed when bLF was simultaneously treated with basic fibroblast growth factor (bFGF). It also inhibited in vitro formation of tube-like structures of mouse endothelial KOP2.16 cells. Moreover, it potently suppressed bFGF- or VEGF-induced proliferation of mouse endothelial KOP2.16 cells, but not of mouse fibroblast A31 cells and Lewis lung carcinoma (3LL) cells. In mice, both orally and intraperitoneally administered bLF significantly and dose-dependently suppressed 3LL cell-induced angiogenesis in a dorsal air sac assay. As orally administered bLF was reported to exhibit antitumor activity through production of interferon (IFN)-gamma and interleukin (IL)-18 in intestinal mucosa (Kuhara T et al., Nutr Cancer 2000;38:192-9), production of these cytokines in mouse serum and peritoneal macrophages by bLF was examined. IFN-gamma was not detected in serum by bLF administration. However, bLF markedly elevated IL-18 concentration in serum by oral administration, but not by intraperitoneal administration. It also induced IL-18 in peritoneal macrophages in vitro. These results suggest that bLF participates as a regulator of angiogenesis, possibly explained by blocking endothelial function and inducing IL-18 production. Antitumor activity of bLF may thus be partly mediated by angiogenesis inhibition.
authors.affiliation: Medical R&D Center, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Shimamura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ashino
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Oikawa
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Hazato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iigo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002417:Cattle; D002642:Chick Embryo; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D007263:Infusions, Parenteral; D020382:Interleukin-18 / Q000494:pharmacology; D007781:Lactoferrin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D007781:Lactoferrin