ABSTRACT
Classic studies indicate that the formation of tumor cell-platelet complexes in the
blood stream is important in facilitating the metastatic process. Metastasis in animal
models can be inhibited by heparin, and retrospective analyses of heparin use in human
cancer have shown promise. However, most follow-up human studies using vitamin K antagonists
have failed, and conclusive proof for other previously proposed mechanisms of heparin
action is lacking. Carcinoma progression and metastasis are associated with overexpression
of sialylated fucosylated mucins. Structurally similar molecules happen to be natural
ligands for vascular adhesion molecules called the selectins. Heparin also happens
to be a good inhibitor of P-selectin, which is expressed on activated platelets or
endothelial cells. We have found that heparin blocks P-selectin-mediated interactions
of endogenous platelets with sialylated fucosylated mucins on circulating carcinoma
cells and that this reduces tumor cell survival. The use of more specific and selective
P-selectin inhibitors will some day help to dissect the relative importance of this
mechanism of heparin action in cancer. Meanwhile, we suggest that the failure of vitamin
K antagonists to improve cancer prognosis should be ignored and that heparin therapy
should be immediately revisited under this new paradigm. Unlike the suggestions in
most previous studies, we propose that heparin use should be reexplored specifically
during the interval from initial visualization of a primary tumor until just after
its definitive surgical removal. A suggested clinical trial is outlined.
KEYWORD
Carcinomas - mucins - platelets - P-selectin - heparin
