Download Hypotheis 2. Platelets interact directly with tumor cells, and this

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
Treatment of Mice with Anti-Platelet Serum
Produces the Same Effect as Neuraminidase
How do platelets contribute to metastasis?
Hypotheis 1.
Activation of clotting pathway.
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 models
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 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
Hypotheis 2.
Platelets interact directly with tumor cells, and this
interaction facilitates metastasis.
Two modes of interaction
Platelets interact with tumor cells via
Integrins (aIIbb3), vWF, fibronectin, fibrinogen
P-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
Selectins:
E
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L
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P
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Sialyl Lewis A
Sialyl Lewis X
sulfatides
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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 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 to
sLa inhibits tumor mets
Heparin actually competes with sLa/x for binding
to 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 in
P-KO mice.
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Kim et al, PNAS 95:9325, 1998
3-D Reconstruction of Tumor-Platelet-Leukocyte
Emboli in Blood Vessels of the Lung
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Tumor Cells Platelets Leukocytes
Borsig et al (Varki) PNAS 98:3352, 2001
Heparin does not equal Heparin
1. Low MW Heparin fraction does not have the same effect
2. 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!
Hypotheis 2.
Platelets interact directly with tumor cells, and this
interaction facilitates metastasis.
Two modes of interaction
Platelets interact with tumor cells via
Integrins (aIIbb3), vWF, fibronectin, fibrinogen
P-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
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
Seeding of metastasis is attenuated in the absence of
Fibrinogen.
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Palumbo et al., Blood 96: 3302, 2000
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