Download PDF
Semin Thromb Hemost 2004; 30(1): 137-144
DOI: 10.1055/s-2004-822978
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Control of Angiogenesis and Tumor Invasion by Platelet Factor-4 and Platelet Factor-4-Derived Molecules

Andreas Bikfalvi1 , Guillermo Gimenez-Gallego2
  • 1Professor, INSERM E 0113, Molecular Mechanisms of Angiogenesis Laboratory, University Bordeaux I, Talence, France
  • 2Centro Investigaciones Biologicas, Madrid, Spain
Further Information

Publication History

Publication Date:
22 March 2004 (online)

    Permissions and Reprints

Platelet factor-4 (PF-4) is an ELR-negative chemokine that exhibits antiangiogenesis properties. PF-4 inhibits endothelial cell proliferation and migration, angiogenesis in vitro and in vivo, and tumor growth. However, tumor cells are not directly inhibited by PF-4. To date, a cell surface receptor that would explain the biological effects mediated by PF-4 has not been identified. PF-4 is able to interact directly with angiogenesis growth factors such as fibroblast growth factors (FGFs) and vascular endothelial growth factors and inhibits their interaction with cell surface receptors. Furthermore, dimerization of fibroblast growth factors is abrogated by PF-4. Whether PF-4 plays a role as an endogenous angiogenesis regulator is at present not clear. Several PF-4 fragments and modified molecules have been made that exhibit antiangiogenesis properties. Among these is a C-terminal fragment that has a defined structure, retains all the antiangiogenesis properties of the parent molecule, inhibits growth factor receptor binding, associates with FGFs, and destabilizes their three-dimensional structure. The relevance of these observations for the treatment of malignant disease is discussed.

KEYWORDS

Platelet factor-4 - angiogenesis - cancer

REFERENCES

  • 1 Liotta L A, Kohn E C. The microenvironment of the tumour-host interface.  Nature. 2001;  411 375-379
    CrossrefPubMedGoogle Scholar
  • 2 Bikfalvi A, Bicknell R. Recent advances in angiogenesis, anti-angiogenesis and vascular targeting.  Trends Pharmacol Sci. 2002;  23 576-582
    CrossrefPubMedGoogle Scholar
  • 3 Javerzat S, Auguste P, Bikfalvi A. The role of fibroblast growth factors in vascular development.  Trends Mol Med. 2002;  8 483-489
    CrossrefPubMedGoogle Scholar
  • 4 Hagedorn M, Bikfalvi A. Target molecule for anti-angiogenesis therapy: from basic research to clinical trials.  Crit Rev Oncol Hematol. 2000;  34 89-110
    PubMedGoogle Scholar
  • 5 Maione T E, Gray G S, Petro J et al.. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides.  Science. 1990;  247 77-79
    CrossrefPubMedGoogle Scholar
  • 6 Sharpe R J, Byers H R, Scott C F, Bauer S I, Maione T E. Growth inhibition of murine melanoma and human colon carcinoma by recombinant human platelet factor-4.  J Natl Cancer Inst. 1990;  82 848-853
    CrossrefPubMedGoogle Scholar
  • 7 Maione T E, Gray G S, Hunt A J, Sharpe R J. Inhibition of tumor growth in mice by an analog of platelet factor-4 that lacks affinity for heparin and retains potent angiostatic activity.  Cancer Res. 1991;  51 2077-2083
    PubMedGoogle Scholar
  • 8 Kolber D L, Knisely T L, Maione T E. Inhibition of development of murine melanoma lung metastases by systemic administration of recombinant platelet factor-4.  J Natl Cancer Inst. 1995;  87 304-309
    CrossrefPubMedGoogle Scholar
  • 9 Tanaka T, Manome Y, Wen P, Kufe D, Fine H A. Viral vector-mediated transduction of a modified platelet factor-4 cDNA inhibits angiogenesis and tumor growth.  Nat Med. 1997;  3 437-442
    CrossrefPubMedGoogle Scholar
  • 10 Deuel T F, Keim P F, Farmer M, Heinrickson R L. Amino acid sequence of human platelet factor 4.  Proc Natl Acad Sci USA. 1977;  74 2256-2258
    CrossrefPubMedGoogle Scholar
  • 11 Belperio J A, Keane M P, Arenberg D A et al.. CXC chemokines in angiogenesis.  J Leukoc Biol. 2000;  68 1-8
    PubMedGoogle Scholar
  • 12 Miller M D, Krangel M S. Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines.  Crit Rev Immunol. 1992;  12 17-46
    PubMedGoogle Scholar
  • 13 Daly T, La Rosa G, Dolich S, Maione T, Cooper S, Broxmeyer H. High activity suppression of myeloid progenitor proliferation by chimeric mutants of interleukin-8 and platelet factor-4.  J Biol Chem. 1995;  270 23282-23292
    CrossrefPubMedGoogle Scholar
  • 14 Zhang X, Chen L, Bancroft D L, Lai C K, Maione T M. Crystal structure of recombinant human platelet factor 4.  Biochemistry. 1994;  33 8361-8366
    CrossrefPubMedGoogle Scholar
  • 15 Stuckey J A, St Charles R, Edwards B. A model of the platelet factor-4 complex with heparin.  Proteins. 1992;  14 277-287
    CrossrefPubMedGoogle Scholar
  • 16 Gupta S K, Singh J P. Inhibition of endothelial cell proliferation by platelet factor-4 involves a unique action on S phase progression.  J Cell Biol. 1994;  127 1121-1127
    CrossrefPubMedGoogle Scholar
  • 17 Perollet C, Han Z C, Savona C, Caen J P, Bikfalvi A. Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization.  Blood. 1998;  91 3289-3299
    PubMedGoogle Scholar
  • 18 Feraud O, Cao Y, Vittet D. Embryonic stem cell-derived embryoid bodies development in collagen gels recapitulates sprouting angiogenesis.  Lab Invest. 2001;  81 1669-1681
    PubMedGoogle Scholar
  • 19 Hansell P, Maione T E, Borgstrom P. Selective binding of platelet factor-4 to regions of active angiogenesis in vivo.  Am J Physiol. 1995;  269(3 pt 2) H829-836
    PubMedGoogle Scholar
  • 20 Borgstrom P, Discipio R, Maione T E. Recombinant platelet factor 4, an angiogenic marker for human breast carcinoma.  Anticancer Res. 1998;  18 4035-4041
    PubMedGoogle Scholar
  • 21 Myler H A, West J L. Heparanase and platelet factor-4 induce smooth muscle cell proliferation and migration via bFGF release from the ECM.  J Biochem (Tokyo). 2002;  131 913-922
    PubMedGoogle Scholar
  • 22 Gentilini G, Kirschbaum N E, Augustine J A, Aster R H, Visentin G P. Inhibition of human umbilical vein endothelial cell proliferation by the CXC chemokine, platelet factor 4 (PF4), is associated with impaired downregulation of p21(Cip1/WAF1).  Blood. 1999;  93 25-33
    PubMedGoogle Scholar
  • 23 Sulpice E, Bryckaert M, Lacour J, Contreres J O, Tobelem G. Platelet factor 4 inhibits FGF2-induced endothelial cell proliferation via the extracellular signal-regulated kinase pathway but not by the phosphatidylinositol 3-kinase pathway.  Blood. 2002;  100 3087-3094
    CrossrefPubMedGoogle Scholar
  • 24 Gengrinovitch S, Greenberg S M, Cohen T et al.. Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms.  J Biol Chem. 1995;  270 15059-15065
    CrossrefPubMedGoogle Scholar
  • 25 Watson J B, Getzler S B, Mosher D F. Platelet factor-4 modulates the mitogenic activity of basic fibroblast growth factor.  J Clin Invest. 1994;  94 261-268
    PubMedGoogle Scholar
  • 26 Nash G F, Walsh D C, Kakkar A K. The role of the coagulation system in tumour angiogenesis.  Lancet Oncol. 2001;  2 608-613
    CrossrefPubMedGoogle Scholar
  • 27 Mohle R, Green D, Moore M A, Nachman R L, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets.  Proc Natl Acad Sci USA. 1997;  94 663-668
    CrossrefPubMedGoogle Scholar
  • 28 Gupta S K, Hassel T, Singh J P. A potent inhibitor of endothelial cell proliferation is generated by proteolytic cleavage of the chemokine platelet factor 4.  Proc Natl Acad Sci USA. 1995;  92 7799-7803
    PubMedGoogle Scholar
  • 29 Jouan V, Canron X, Alemany M et al.. Modulation of in vitro angiogenesis by platelet factor-4 derived peptides and mechanism of action.  Blood. 1999;  94 984-993
    PubMedGoogle Scholar
  • 30 Lozano R M, Redondo-Horcajo M, Jimenez M A et al.. Solution structure and interaction with basic and acidic fibroblast growth factor of a 3-kDa human platelet factor-4 fragment with antiangiogenic activity.  J Biol Chem. 2001;  276 35723-35734
    CrossrefPubMedGoogle Scholar
  • 31 Hagedorn M, Zilberberg L, Lozano R M et al.. A short peptide domain of platelet factor 4 blocks angiogenic key events induced by FGF-2.  FASEB J. 2001;  15 550-552
    PubMedGoogle Scholar
  • 32 Griffioen A W, van der Schaft D W, Barendsz-Janson A F et al.. Anginex, a designed peptide that inhibits angiogenesis.  Biochem J. 2001;  354 233-242
    CrossrefPubMedGoogle Scholar
  • 33 Mayo K H, van der Schaft D W, Griffioen A W. Designed beta-sheet peptides that inhibit proliferation and induce apoptosis in endothelial cells.  Angiogenesis. 2001;  4 45-51
    CrossrefPubMedGoogle Scholar
  • 34 Butcher D J, Kowalska M A, Li S et al.. A natural motif approach to protein design: a synthetic leucine zipper peptide mimics the biological function of the platelet factor 4 protein.  FEBS Lett. 1997;  409 183-187
    CrossrefPubMedGoogle Scholar
  • 35 Kozin S V, Boucher Y, Hicklin D J, Bohlen P, Jain R K, Suit H D. Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts.  Cancer Res. 2001;  61 39-44
    PubMedGoogle Scholar
  • 36 Bergers G, Javaherian K, Lo K M, Folkman J, Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice.  Science. 1999;  284 808-812
    CrossrefPubMedGoogle Scholar
  • 37 Klement G, Huang P, Mayer B et al.. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts.  Clin Cancer Res. 2002;  8 221-232
    PubMedGoogle Scholar
  • 38 Bello L, Carrabba G, Giussani C et al.. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo.  Cancer Res. 2001;  61 7501-7506
    PubMedGoogle Scholar
  • 39 Reiher F K, Volpert O V, Jimenez B et al.. Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics.  Int J Cancer. 2002;  98 682-689
    CrossrefPubMedGoogle Scholar
  • 40 Hampl M, Tanaka T, Albert P S, Lee J, Ferrari N, Fine H A. Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites.  Hum Gene Ther. 2001;  12 1713-1729
    CrossrefPubMedGoogle Scholar
  • 41 Ciafre S A, Barillari G, Bongiorno-Borbone L, Wannenes F, Izquierdo M, Farace M G. A tricistronic retroviral vector expressing natural antiangiogenic factors inhibits angiogenesis in vitro, but is not able to block tumor progression in vivo.  Gene Ther. 2002;  9 297-302
    CrossrefPubMedGoogle Scholar
  • 42 Giussani C, Carrabba G, Pluderi M et al.. Local intracerebral delivery of endogenous inhibitors by osmotic minipumps effectively suppresses glioma growth in vivo.  Cancer Res. 2003;  63 2499-2505
    PubMedGoogle Scholar
  • 43 Hagedorn M, Zilberberg L, Wilting J et al.. Domain swapping in a C-terminal fragment of platelet factor-4 generates potent angiogenesis inhibitors.  Cancer Res. 2002;  62 6884-6890
    PubMedGoogle Scholar
  • 44 Lasagni L, Francalanci M, Annunziato F et al.. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.  J Exp Med. 2003;  197 1537-1549
    CrossrefPubMedGoogle Scholar

Andreas BikfalviM.D. Ph.D. 

Molecular Angiogenesis Laboratory, (INSERM E0113), Université Bordeaux I

Avenue des Facultés

33 405 Talence, France

Email: a.bikfalvi@angio.u-bordeaux.fr