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Platelets and Metastasis. In Mice and in Humans, Platelets are Important Mediators of Metastatic process. Gabriel Gasic, Tatiana Gasic, Carleton Stewart PNAS 61:46-52, 1968. Transfusion of Platelet Rich Plasma Reverses Neuraminidase Effect on Metastasis. - PowerPoint PPT Presentation
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Platelets and Metastasis
In Mice and in Humans, Platelets are Important Mediators of Metastatic process
Gabriel Gasic, Tatiana Gasic, Carleton Stewart PNAS 61:46-52, 1968
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 manycancer patients.Hypercoagulable state of blood in many cancer patientsHeparin (an anti-coagulant) protected against pulmonarymetastasis in animal models
Hypotheis 1.Activation of clotting pathway.
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.
Activated platelets secrete cytokynes such asVEGF A, PDGF, TGF, bFGF that promoteTumor growth and angiogenesis.
Cancer patients undergoing chemotherapy experiencedecrease 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
Hypotheis 2.Platelets interact directly with tumor cells, and thisinteraction facilitates metastasis.
Two modes of interaction
Platelets interact with tumor cells viaIntegrins (IIb3), vWF, fibronectin, fibrinogen
P-selectin on platelets binds to tumor cellcarbohydrate coat (sialyl Lewisa/x)
Coating of tumor cells by platelets protects tumor cells fromkilling 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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sulfatides
Selecti
n Ligands
Tumor cells upregulate sLa/x
•Progression to invasive phenotype of tumor cellsin vitro and tumors in vivo is associated with upregulation of cell surface sLa/x
•Upregulation of sLa/x is a poor prognostic factorfor colon, pancreas and stomach cancers
•Expression of sLa on colon adenocarcinomascorrelates with appearance liver metastasis
sLa/x on mucin-type O-glycans is highly correlated withlymphatic and venous metastasis
Ugorski et al., Acta Biochimica Polonica 49:303-311, 2002
Experimental Mouse Models:
Treatment of tumor cells with O-sialglycosidase(cleaves glycosylated mucins) inhibits tumor mets
Treatment of tumor cells with monoclonal Ab tosLa inhibits tumor mets
Heparin actually competes with sLa/x for bindingto selectins also inhibits tumor mets
However,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
Selectin Kos
Experimental pulmonary mets are attenuated inP-KO mice.
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Kim et al, PNAS 95:9325, 1998
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3-D Reconstruction of Tumor-Platelet-LeukocyteEmboli in Blood Vessels of the Lung
Borsig et al (Varki) PNAS 98:3352, 2001
Tumor Cells Platelets Leukocytes
Heparin does not equal Heparin
1. Low MW Heparin fraction does not have the same effect
2. Heparin fragments generated by different heparinases exhibitdifferent effects on tumor growth and metastasis.
Fragments resulting from digestion of tumor cell surface withHepIII inhibit tumor growth and metastasis. But fragmentsresulting from digestion with HepI promote tumor growth!
Liu et al, PNAS 99: 568-573, 2002
Hypotheis 2.Platelets interact directly with tumor cells, and thisinteraction facilitates metastasis.
Two modes of interaction
Platelets interact with tumor cells viaIntegrins (IIb3), vWF, fibronectin, fibrinogen
P-selectin on platelets binds to tumor cellcarbohydrate coat (sialyl Lewisa/x)
Coating of tumor cells by platelets protects tumor cells fromkilling by immune cells, shear forces, allows them to attach,extravasate, grow and recruit blood vessels
Treatment of cell lines with trypsin,
hrombin or antibodies to fibronectin, vWF,
IIb3 inhibits tumor cell binding to platelets
Treatment of mice with antibodies to
vWF, IIb3, RGDS peptides,
or thrombin
attenuate tumor metastasis.
Karpatkin et al, J. Clin. Invest 1988Nierodzik et al, Thromb and Haemostasis 74:282, 1995
Seeding of metastasis is attenuated in the absence ofFibrinogen.
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Palumbo et al., Blood 96: 3302, 2000
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Tumor cells disappear from the lungs in Fg-/- mice!
Targeted disruption of platelet-tumorinteractions is worth clinical testing
again (Varki)
Heparin treatment to inhibit tumor cells associationwith platelets (as well as inhibiut platelet activation by
thrombin) may be of great therapeutic, anti-metastatic effect
Other inhibitors of platelet-tumor interactions may behelpful as well