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)

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.

REFERENCES

  • 1 Liotta L A, Kohn E C. The microenvironment of the tumour-host interface.  Nature. 2001;  411 375-379
  • 2 Bikfalvi A, Bicknell R. Recent advances in angiogenesis, anti-angiogenesis and vascular targeting.  Trends Pharmacol Sci. 2002;  23 576-582
  • 3 Javerzat S, Auguste P, Bikfalvi A. The role of fibroblast growth factors in vascular development.  Trends Mol Med. 2002;  8 483-489
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 11 Belperio J A, Keane M P, Arenberg D A et al.. CXC chemokines in angiogenesis.  J Leukoc Biol. 2000;  68 1-8
  • 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
  • 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
  • 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
  • 15 Stuckey J A, St Charles R, Edwards B. A model of the platelet factor-4 complex with heparin.  Proteins. 1992;  14 277-287
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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

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