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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.

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Platelets and metastasis

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


Platelets and metastasis

Transfusion of Platelet Rich Plasma Reverses

Neuraminidase Effect on Metastasis


Platelets and metastasis

Treatment of Mice with Anti-Platelet Serum

Produces the Same Effect as Neuraminidase


Platelets and metastasis

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


Platelets and metastasis

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.


Platelets and metastasis

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


Platelets and metastasis

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


Platelets and metastasis

Selectins:

E

L

P


Platelets and metastasis

Sialyl Lewis A

Sialyl Lewis X


Platelets and metastasis

sulfatides

Selectin Ligands


Platelets and metastasis

  • 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


Platelets and metastasis

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


Platelets and metastasis

Selectin Kos

Experimental pulmonary mets are attenuated in

P-KO mice.

Kim et al, PNAS 95:9325, 1998


Platelets and metastasis

3-D Reconstruction of Tumor-Platelet-Leukocyte

Emboli in Blood Vessels of the Lung

Tumor CellsPlateletsLeukocytes

Borsig et al (Varki) PNAS 98:3352, 2001


Platelets and metastasis

Heparin does not equal Heparin

Low 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


Platelets and metastasis

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


Platelets and metastasis

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


Platelets and metastasis

Seeding of metastasis is attenuated in the absence of

Fibrinogen.

Palumbo et al., Blood 96: 3302, 2000


Platelets and metastasis

Tumor cells disappear from

the lungs in Fg-/- mice!


Platelets and metastasis

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