Platelet–CD40 ligand interaction with melanoma cell and monocyte CD40 enhances cellular procoagulant activity

Platelet–tumor cell interactions are believed to be important in tumor metastasis. Tumor cell tissue factor (TF) expression enhances metastasis and angiogenesis, and is primarily responsible for tumor-induced thrombin generation and the formation of tumor cell–platelet aggregates. Activated platelets express and release CD40 ligand (CD40L), which induces endothelial TF expression by ligation to CD40. We investigated the effect of platelet-derived CD40L on the TF activity of human CD40-positive melanoma cells and monocytes by incubating supernatants from activated or resting platelets with tumor cells or monocytes, and by bringing resting or activated platelets into close apposition with tumor cell monolayers. CD40L was present on the surface of activated (but not resting) platelets and was also released following platelet activation. Both recombinant soluble CD40L (rsCD40L) and activated platelet supernatants increased procoagulant activity (PCA) and TF antigen in tumor cells and monocytes. The increase in TF activity induced by both rsCD40L and activated platelet supernatants was inhibited by anti-CD40L antibody. Furthermore, contact of activated platelets with tumor cells increased cellular PCA, and this effect was also inhibited by anti-CD40L. In malignancy, the increase in cellular TF activity via CD40 (tumor cell)–CD40L (platelet) interaction may possibly enhance intravascular coagulation and hematogenous metastasis.

[1]  R. Kroczek,et al.  The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. , 2001, Blood.

[2]  K. Schrör,et al.  Molecular Identity of Platelet CD40 Ligand (CD40L) , 2001, Thrombosis and Haemostasis.

[3]  G. Lip,et al.  Increased soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor , 2001, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[4]  H. Verheul,et al.  Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. , 2000, Blood.

[5]  I. Stamenkovic.  Matrix metalloproteinases in tumor invasion and metastasis. , 2000, Seminars in cancer biology.

[6]  C. Kooten.  Immune regulation by CD40-CD40-l interactions - 2; Y2K update. , 2000 .

[7]  M. Sabel,et al.  CD40 expression on human lung cancer correlates with metastatic spread , 2000, Cancer Immunology, Immunotherapy.

[8]  K. Forfang,et al.  Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. , 1999, Circulation.

[9]  M. Goldman,et al.  CD40 Engagement on Endothelial Cells Promotes Tissue Factor-dependent Procoagulant Activity , 1998, Thrombosis and Haemostasis.

[10]  Reinhold Förster,et al.  CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells , 1998, Nature.

[11]  P. Libby,et al.  Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? , 1997, Circulation research.

[12]  P. Libby,et al.  Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P. Nawroth,et al.  Molecular mechanisms linking thrombosis and angiogenesis in cancer. , 1997, Trends in cardiovascular medicine.

[14]  R. Flavell,et al.  The Cd40 ligand , 1997, Immunologic research.

[15]  P. Hersey,et al.  Expression of the co‐stimulatory molecule CD40 on melanoma cells , 1996 .

[16]  G. Warnes,et al.  Determination of tumor cell procoagulant activity by Sonoclot analysis in whole blood. , 1996, Thrombosis research.

[17]  J. Suttles,et al.  The many roles of CD40 in cell-mediated inflammatory responses. , 1996, Immunology today.

[18]  W. Konigsberg,et al.  Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Kiener,et al.  Expression of functional CD40 by vascular endothelial cells , 1995, The Journal of experimental medicine.

[20]  J. Pober,et al.  CD40 on human endothelial cells: inducibility by cytokines and functional regulation of adhesion molecule expression. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[21]  T. Luther,et al.  Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. , 1994, The Journal of clinical investigation.

[22]  J. Francis,et al.  Assessment of hypercoagulability in patients with cancer using the Sonoclot Analyzer and thromboelastography. , 1994, Thrombosis research.

[23]  Y. Nemerson,et al.  The tissue factor pathway of blood coagulation. , 1992, Progress in hemostasis and thrombosis.

[24]  W. Kisiel,et al.  Coexisting macrophage‐associated fibrin formation and tumor cell urokinase in squamous cell and adenocarcinoma of the lung tissues , 1991, Cancer.

[25]  H. Dvorak,et al.  Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. , 1989, Biochimica et biophysica acta.

[26]  N. Semeraro,et al.  Cultured human endothelial cells generate tissue factor in response to endotoxin. , 1983, The Journal of clinical investigation.

[27]  S. Karpatkin,et al.  A new mechanism for tumor‐induced platelet aggregation. Comparison with mechanisms shared by other tumors with possible pharmacologic strategy toward prevention of metastases , 1983, International journal of cancer.

[28]  S. Karpatkin,et al.  Role of platelets in tumor cell metastases. , 1981, Annals of the New York Academy of Sciences.

[29]  S. Karpatkin,et al.  ROLE OF PLATELETS IN TUMOR CELL METASTASES , 1981, Annals of internal medicine.

[30]  W. Weston,et al.  The Endotoxin‐induced Coagulant Activity of Human Monocytes , 1975, British journal of haematology.

[31]  G. Gasic.  Role of plasma, platelets, and endothelial cells in tumor metastasis , 2004, Cancer and Metastasis Reviews.

[32]  H. Dvorak,et al.  Fibrin as a component of the tumor stroma: origins and biological significance , 2004, Cancer and Metastasis Reviews.

[33]  J. Banchereau,et al.  Immune regulation by CD40-CD40-L interactions. , 1997, Frontiers in bioscience : a journal and virtual library.

[34]  P. Hersey,et al.  Expression of the co-stimulatory molecule CD40 on melanoma cells. , 1996, International journal of cancer.

[35]  J. Fenton,et al.  The role of thrombin in tumor cell metastasis. , 1994, Invasion & metastasis.

[36]  J. Banchereau,et al.  The CD40 antigen and its ligand. , 1994, Annual review of immunology.

[37]  H. Gastpar.  Platelet-cancer cell interaction in metastasis formation: a possible therapeutic approcach to metastasis prophylaxis. , 1977, Journal of medicine.