Heparin Inhibition of Selectin-Mediated Interactions during the Hematogenous Phase of Carcinoma Metastasis: Rationale for Clinical Studies in Humans

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.