How do platelets contribute to metastasis?

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Platelets and Metastasis In Mice and in Humans, Platelets are Important Mediators of Metastatic processGabriel Gasic, Tatiana Gasic, Carleton Stewart PNAS 61:46-52, 1968

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Transfusion of Platelet Rich Plasma Reverses Neuraminidase Effect on Metastasis

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Treatment of Mice with Anti-Platelet Serum Produces the Same Effect as Neuraminidase

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How do platelets contribute to metastasis? In many cancer patients platelet numbers are elevated. Platelets in cancer patients are activated (elevated levels of serum thrombin, von Willebrand factor, VEGF). Prostacyclin/Thromboxane A2 balance disturbed in many cancer patients. Hypercoagulable state of blood in many cancer patients Heparin (an anti-coagulant) protected against pulmonary metastasis in animal modelsHypotheis 1. Activation of clotting pathway.

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However, Clinical trials that used anti-coagulants (vitamin K antagonists such as warfarin) failed.And yet…. Retrospective analysis indicated that cancer patients that were treated with low doses of heparin before cancer surgery showed improved survival. Cancer patients treated with heparin to combat venous thromboemolism also showed improved survival.

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Activated platelets secrete cytokynes such as VEGF A, PDGF, TGFb, bFGF that promote Tumor growth and angiogenesis. Cancer patients undergoing chemotherapy experience decrease in platelet counts (thrombosytopenia) and receive platelet transfusion. BUT platelets become activated during storage (secrete P-selectin and VEGF). Transfusion of blood products carries the risk of increased cancer recurrence. Nash et al., Platelets and Cancer. Lancet Oncology 3:425, 2002

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Hypotheis 2. Platelets interact directly with tumor cells, and this interaction facilitates metastasis.Two modes of interactionPlatelets interact with tumor cells via Integrins (aIIbb3), vWF, fibronectin, fibrinogenP-selectin on platelets binds to tumor cell carbohydrate coat (sialyl Lewisa/x)Coating of tumor cells by platelets protects tumor cells from killing by immune cells, shear forces, allows them to attach, extravasate, grow and recruit blood vessels

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Selectins:E L P

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Sialyl Lewis ASialyl Lewis X

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sulfatidesSelectin Ligands

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Tumor cells upregulate sLa/x Progression to invasive phenotype of tumor cells in vitro and tumors in vivo is associated with upregulation of cell surface sLa/x Upregulation of sLa/x is a poor prognostic factor for colon, pancreas and stomach cancers Expression of sLa on colon adenocarcinomas correlates with appearance liver metastasis sLa/x on mucin-type O-glycans is highly correlated with lymphatic and venous metastasisUgorski et al., Acta Biochimica Polonica 49:303-311, 2002

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Experimental Mouse Models: Treatment of tumor cells with O-sialglycosidase (cleaves glycosylated mucins) inhibits tumor mets Treatment of tumor cells with monoclonal Ab to sLa inhibits tumor mets Heparin actually competes with sLa/x for binding to selectins also inhibits tumor metsHowever, Experiments in mice also showed that levels of sLa/x are important. When too much of sLa/x are present on tumor cell surface (presentation of sLa/x is altered), tumor cells are subject to attack by NK cells. Ohyama et al., EMBO J., 18:1516-1525, 1999

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Selectin Kos Experimental pulmonary mets are attenuated in P-KO mice.Kim et al, PNAS 95:9325, 1998

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3-D Reconstruction of Tumor-Platelet-Leukocyte Emboli in Blood Vessels of the LungBorsig et al (Varki) PNAS 98:3352, 2001Tumor Cells Platelets Leukocytes

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Heparin does not equal HeparinLow MW Heparin fraction does not have the same effect Heparin fragments generated by different heparinases exhibit different effects on tumor growth and metastasis. Fragments resulting from digestion of tumor cell surface with HepIII inhibit tumor growth and metastasis. But fragments resulting from digestion with HepI promote tumor growth!Liu et al, PNAS 99: 568-573, 2002

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Hypotheis 2. Platelets interact directly with tumor cells, and this interaction facilitates metastasis.Two modes of interactionPlatelets interact with tumor cells via Integrins (aIIbb3), vWF, fibronectin, fibrinogenP-selectin on platelets binds to tumor cell carbohydrate coat (sialyl Lewisa/x)Coating of tumor cells by platelets protects tumor cells from killing by immune cells, shear forces, allows them to attach, extravasate, grow and recruit blood vessels

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Treatment of cell lines with trypsin, hrombin or antibodies to fibronectin, vWF, aIIbb3 inhibits tumor cell binding to platelets Treatment of mice with antibodies to vWF, aIIbb3, RGDS peptides, or thrombin attenuate tumor metastasis.Karpatkin et al, J. Clin. Invest 1988 Nierodzik et al, Thromb and Haemostasis 74:282, 1995

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Seeding of metastasis is attenuated in the absence of Fibrinogen.Palumbo et al., Blood 96: 3302, 2000

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Tumor cells disappear from the lungs in Fg-/- mice!

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Targeted disruption of platelet-tumor interactions is worth clinical testing again (Varki) Heparin treatment to inhibit tumor cells association with platelets (as well as inhibiut platelet activation by thrombin) may be of great therapeutic, anti-metastatic effect Other inhibitors of platelet-tumor interactions may be helpful as well

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Last Updated: 8th March 2018

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