Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1997 Feb;88(2):184–190. doi: 10.1111/j.1349-7006.1997.tb00364.x

Bovine Lactoferrin and Lactoferricin, a Peptide Derived from Bovine Lactoferrin, Inhibit Tumor Metastasis in Mice

Yung–Choon Yoo 1,✉, Shikiko Watanabe 2, Ryosuke Watanabe 1, Katsusuke Hata 1, Kei–ichi Shimazaki 2, Ichiro Azuma 1
PMCID: PMC5921353  PMID: 9119747

Abstract

We investigated the effect of a bovine milk protein, lactoferrin (LF–B), and a pepsin–generated peptide of LF–B, lactoferricin (Lfcin–B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16–BL6 melanoma and L5178Y–ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo–lactoferrin (apo–LF–B, 1 mg/mouse) and Lfcin–B (0.5 mg/monse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y–ML25 cells. However, human apo–lactoferrin (apo–LF–H) and bovine holo–lactoferrin (holo–LF–B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y–ML25 cells. Similarly, the s.c. administration of apo–LF–B as well as Lfcin–B, but not apo–LF–H and holo–LF–B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16–BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor–induced angiogenesis, both apo–LF–B and Lfcin–B inhibited the number of tumor–induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long–term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo–LF–B significantly suppressed the growth of B16–BL6 cells throughout the examination period, whereas Lfcin–B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16–BL6 melanoma cells, multiple administration of both apo–LF–B and Lfcin–B into tumor–bearing mice significantly inhibited lung metastasis produced by B16–BL6 cells, though only apo–LF–B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo–LF–B and Lfcin–B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of LF–B on tumor metastasis may he related to iron (Fe3+)–saturation.

Keywords: Bovine lactoferrin, Bovine lactoferricin, Host defense, Tumor metastasis, Antitumor activity

Full Text

The Full Text of this article is available as a PDF (425.4 KB).

REFERENCES

  • 1. ) Montreuil , J. , Tonnelat , J. and Mullet , S.Préparation et propriétés de la lactosidérophili ne (lactotransferrine) du lait de femme . Biochim. Biophys. Acta , 45 , 413 – 421 ( 1960. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Reiter , B.In “ Development in Dairy Chemistry–3, Lactose and Minor Constituents ,” ed. Fox P.F. , pp. 281 – 336 ( 1985. ). Elsevier Applied Scientific Publishers; , London . [Google Scholar]
  • 3. ) Masson , P. L. , Heremans , J. F. and Schonne , E.Lactofer–rtn, an iron–binding protein in neutrophilic leukocytes . J Exp. Med. , 130 , 643 – 658 ( 1969. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Hagiwara , T. , Shinoda , I. , Fukuwatari , Y. and Shimamura , S.Effect of lactoferrin and its peptides on proliferation of rat intestinal epithelial cell line, IEC–18, in the presence of epidermal growth factor . Biosci Biotech, Biochem. , 59 , 1875 – 1881 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Hauer , J. , Voetsh , W. and Anderer , F. A.Identification of a mannose–acetate–speciflc 87–kDa receptor responsible for human NK and LAK activity . Immunol. Lett. , 42 , 7 – 12 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Zagulski , T. , Lipinski , P. , Zagulska , A. , Broniek , S. and Jarzabek , Z.Lactoferrin can protect mice against a lethal dose of Escherichia coli in experimental infection in vivo . Br. J. Exp. Pathol , 70 , 697 – 704 ( 1989. ). [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Aisen , P. and Listowsky , I.Iron transport and storage proteins . Annu. Rev. Biochem. , 49 , 357 – 393 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Arnold , R. R. , Brewer , M. and Cauthier , J. J.Bactericidal activity of human lactoferrin: sensitivity of a variety of microorganisms . Infect. Immun. , 28 , 893 – 898 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) He , J. and Furmanski , P.Sequence specificity and tran–scriptional activation in the binding of lactoferrin to DNA . Nature , 373 , 721 – 724 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Shau , H. , Kim , A. and Golub , H.Modulation of natural killer and lymphokine–activated killer cell cytotoxicity by lactoferrin. J . Leukocyte Biol , 51 , 343 – 349 ( 1992. ). [PubMed] [Google Scholar]
  • 11. ) Horwitz , D. A. , Bakke , A. C. , Abo , W. and Nishiya , K.Monocyte and NK cell cytotoxic activity in human adherent cell preparations: discriminating effects of interferon and lactoferrin . J. Immunol. , 312 , 2370 – 2374 ( 1984. ). [PubMed] [Google Scholar]
  • 12. ) Gahr , M. , Speer , C. P. , Damerau , B. and Sawatzki , Q.Influence of lactoferrin on the function of human poly–morphonuclear leukocytes and monocytes . J. Leukocyte Biol , 49 , 427 – 433 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Sawazski , G. and Rich , I.N.Lactoferrin stimulates colony stimulating factor production in vitro and in vivo . Blood Cells , 15 , 371 – 385 ( 1989. ). [PubMed] [Google Scholar]
  • 14. ) DeSousa , M. , Breedvelt , F. , Dynesius–Trentham , R. , Trentham , D. and Lum , J.Iron, iron–binding proteins and immune system cells . Ann. NY Acad. Sci. , 526 , 310 – 322 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Nishiya , K. and Horwitz , D. A.Contrasting effects of lactoferrin on human lymphocyte and monocyte natural killer activity and antibody–dependent cell–mediated cytotoxicity. J . Immunol. , 129 , 2519 – 2523 ( 1982. ). [PubMed] [Google Scholar]
  • 16. ) Tomita , M. , Bellamy , W. , Takase , M. , Yamauchi , K. , Wakabayashi , H. and Kawase , K.Potent antibacterial peptides generated by pepsin digestion of bovine lactoferrin . J. Dairy Sci. , 74 , 4137 – 4142 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Bellamy , W. , Takase , M. , Yamauchi , K. , Wakabayashi , H. , Kawase , K. and Tomita , M.Identification of the bactericidal domain of lactoferrin . Biochim. Biophys. Acta , 1121 , 130 – 136 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Bellamy , W. , Takase , M. , Wakabayashi , H. , Kawase , K. and Tomita , M.Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N–terminal region of bovine lactoferrin . J.Appl. Bacterial. , 73 , 472 – 479 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Bezault , J. , Bhimani , R. , Wiprovnick , J. and Furmanski , P.Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice . CancerRes. , 54 , 2310 – 2312 ( 1994. ). [PubMed] [Google Scholar]
  • 20. ) Pierce , A. , Colavizza , D. , Benaissa , M. , Maes , P. , Tartar , A. , Montreuil , J. and Spik , G.Molecular cloning and sequenceanalysisof bovine lactotransferrin . Eur. J. Biochem. , 196 , 177 – 184 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Yoo , Y. C , Saiki , I. , Sato , K. and Azuma , I.MDP–Lys (LI8), a lipophilic derivative of muramyl dipeptide, inhibits the metastasis of haematogenous and non–haemato–genous tumours in mice . Vaccine , 12 , 175 – 180 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Law , B. A. and Reiter , B.The isolation and bacteriostatic properties of lactoferrin from bovine milk whey . J.Dairy Res. , 44 , 595 – 599 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Shimazaki , K. , Kawano , N. and Yoo , Y. C.Comparison of bovine, sheep and goat milk lactoferrins in their elec–trophoretic behavior, conformation, immunological properties and lectin reactivity . Comp. Biochem. Physiol. , 98 , 417 – 422 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Yoo , Y. C. , Saiki , I. , Sato , K. and Azuma , I.B30–MDP, a synthetic derivative for tumour vaccination to enhance antitumour immunity and antimetastatic effect in mice . Vaccine , 10 , 792 – 797 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Saiki , I. , Sato , K. , Yoo , Y. C. , Murata , J. , Yoneda , J. , Kiso , M. , Hasegawa , M. and Azuma , I.Inhibition of tumor–induced angiogenesis by the administration of recombinant interferon‐γ followed by a synthetic lipid–A subunit analogue (GLA–60) . Int. J. Cancer , 51 , 641 – 645 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Weinberg , E. DIron depletion: a defense against intra–cellular infection and neoplasia . Life Sci. , 50 , 1289 – 1297 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Tomita , M. , Takase , M. , Bellamy , W. and Shimamura , S.A review: the active peptide of lactoferrin . Acta Paediatr. J. , 36 , 585 – 591 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Anderson , B. F. , Baker , H. M. , Norris , G. E. , Rice , D. W. and Baker , E. N.Structure of human lactoferrin: crystal–lographic structure analysis and refinement at 2.8 A resolution . J. Mol. Biol , 209 , 711 – 734 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Christenson , B. , Fink , J. , Merrifield , R. B. and Mauzerall , D.Channel–forming properties of cecropins and related model compounds incorporated into planar lipid membrane . Proc. Natl. Acad. Sci. USA , 85 , 5072 – 5076 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES