Abstract
It is established that experimental metastasis requires platelet activity. CD154 expressed on and released from activated platelets induces an inflammatory response in endothelial cells and monocytes, including tissue factor production. CD154 has also been shown to activate platelets in vitro and promote thrombus stability in vivo. These CD154 effects may be mediated, at least in part, by CD40 signaling on platelets and vascular endothelial cells. We have previously demonstrated prolonged bleeding and PFA-100 closure times in mice deficient for Cd154 or its receptor Cd40. In the present study, we hypothesized that Cd40 and Cd154 promote lung tumor formation in experimental metastasis in mice. We created mice doubly deficient in Cd40 and Cd154 (Dbl KO) and found them to be both fertile and viable. Injected tumor cells seeded poorly in mice deficient in Cd40 or Cd154, as well as Dbl KO, compared to wild-type mice. We sought to determine whether blood-borne Cd40 versus endothelial Cd40 contribute differentially to reduced experimental lung metastasis, as observed in Cd40 deficient mice. By bone marrow transplantation, we created mice deficient for Cd40 either in the blood compartment but not in the endothelium, or vice versa. We found that mice deficient in blood compartment Cd40 had fewer lung nodules compared to wild-type mice and mice deficient in endothelial Cd40. Our findings suggest an important contribution of the Cd40-Cd154 pathway to experimental lung metastasis. Furthermore, the data points to a selective role for peripheral blood cell Cd40 in this process.
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References
Axcrona K, Gray D, Leanderson T (1996) Regulation of B cell growth and differentiation via CD21 and CD40. Eur J Immunol 26:2203–2207
Stout RD, Suttles J (1996) The many roles of CD40 in cell-mediated inflammatory responses. Immunol Today 17:487–492
Henn V, Slupsky JR et al (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594
Inwald DP, McDowall A et al (2003) CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ Res 92:1041–1048
Armitage RJ, Fanslow WC et al (1992) Molecular and biological characterization of a murine ligand for CD40. Nature 357:80–82
Gauchat JF, Aubry JP et al (1993) Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production. FEBS Lett 315:259–266
Gordon J, Millsum MJ et al (1987) Synergistic interaction between interleukin 4 and anti-Bp50 (CDw40) revealed in a novel B cell restimulation assay. Eur J Immunol 17:1535–1538
Yellin MJ, Winikoff S et al (1995) Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation. J Leukoc Biol 58:209–216
Henn V, Steinbach S et al (2001) The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood 98:1047–1054
Andre P, Nannizzi-Alaimo L et al (2002) Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 106:896–899
Langer F, Ingersoll SB et al (2005) The role of CD40 in CD40L- and antibody-mediated platelet activation. Thromb Haemost 93:1137–1146
Prasad KS, Andre P et al (2003) Soluble CD40 ligand induces beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA 100:12367–12371
Andre P, Prasad KS et al (2002) CD40L stabilizes arterial thrombi by a beta3 integrin—dependent mechanism. Nat Med 8:247–252
Amirkhosravi A, Amaya M et al (2002) Platelet-CD40 ligand interaction with melanoma cell and monocyte CD40 enhances cellular procoagulant activity. Blood Coagul Fibrinolysis 13:505–512
Langer F, Amirkhosravi A et al (2006) Experimental metastasis and primary tumor growth in mice with hemophilia A. J Thromb Haemost 4:1056–1062
Bennett SR, Carbone FR et al (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393:478–480
Ridge JP, Di RF et al (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474–478
Schoenberger SP, Toes RE et al (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480–483
French RR, Chan HT et al (1999) CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 5:548–553
Gurunathan S, Irvine KR et al (1998) CD40 ligand/trimer DNA enhances both humoral and cellular immune responses and induces protective immunity to infectious and tumor challenge. J Immunol 161:4563–4571
Sotomayor EM, Borrello I et al (1999) Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med 5:780–787
Turner JG, Rakhmilevich AL et al (2001) Anti-CD40 antibody induces antitumor and antimetastatic effects: the role of NK cells. J Immunol 166:89–94
Amirkhosravi A, Meyer T et al (2002) Tissue factor pathway inhibitor reduces experimental lung metastasis of B16 melanoma. Thromb Haemost 87:930–936
Karpatkin S, Pearlstein E et al (1988) Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. J Clin Invest 81:1012–1019
Amirkhosravi A, Mousa SA et al (2003) Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454. Thromb Haemost 90:549–554
Amirkhosravi A, Meyer T et al (2007) The role of tissue factor pathway inhibitor in tumor growth and metastasis. Semin Thromb Hemost 33:643–652
Donnelly KM, Bromberg ME et al (1998) Ancylostoma caninum anticoagulant peptide blocks metastasis in vivo and inhibits factor Xa binding to melanoma cells in vitro. Thromb Haemost 79:1041–1047
Esumi N, Fan D et al (1991) Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor. Cancer Res 51:4549–4556
Fischer EG, Riewald M et al (1999) Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. J Clin Invest 104:1213–1221
Mueller BM, Reisfeld RA et al (1992) Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc Natl Acad Sci USA 89:11832–11836
Mueller BM, Ruf W (1998) Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis. J Clin Invest 101:1372–1378
Amirkhosravi M, Francis JL (1993) Procoagulant activity of the MC28 fibrosarcoma cell line in vitro and in vivo. Br J Haematol 85:736–744
Francis JL, Amirkhosravi A (2002) Effect of antihemostatic agents on experimental tumor dissemination. Semin Thromb Hemost 28:29–38
Fidler IJ (1970) Metastasis: guantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst 45:773–782
Hara Y, Steiner M (1980) Characterization of the platelet-aggregating activity of tumor cells. Cancer Res 40:1217–1222
Kepner N, Lipton A (1981) A mitogenic factor for transformed fibroblasts from human platelets. Cancer Res 41:430–432
Li JJ, Huang YQ (2001) Thrombin induces the release of angiopoietin-1 from platelets. Thromb Haemost 85:204–206
Mohle R, Green D (1997) Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 94:663–668
Leveille C, Bouillon M (2007) CD40 ligand binds to alpha5beta1 integrin and triggers cell signaling. J Biol Chem 282:5143–5151
Brodeur SR, Angelini F (2003) C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Immunity 18:837–848
Acknowledgments
This study was funded by the Florida Hospital Gala Endowed Program for Oncologic Research. We thank Robert Banks at the University of Central Florida Animal Facility for his excellent technical help. We thank the Radiation Oncology Department at Florida Hospital for their assistance with this study.
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Ingersoll, S.B., Langer, F., Walker, J.M. et al. Deficiencies in the CD40 and CD154 receptor-ligand system reduce experimental lung metastasis. Clin Exp Metastasis 26, 829–837 (2009). https://doi.org/10.1007/s10585-009-9282-7
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DOI: https://doi.org/10.1007/s10585-009-9282-7