Heparin and cancer revisited: Mechanistic connections involving platelets,P-selectin, carcinoma mucins, and tumor metastasis

Independent studies indicate that expression of sialylated fucosylated muci ns by human carcinomas portends a poor prognosis because of enhanced metast atic spread of tumor cells, that carcinoma metastasis in mice is facilitate d by formation of tumor cell complexes with blood platelets, and that metas tasis can be attenuated by a background of P-selectin deficiency or by trea tment with heparin. The effects of heparin are not primarily due to its ant icoagulant action. Other explanations have been suggested but not proven. H ere, we bring together all these unexplained and seemingly disparate observ ations, showing that heparin treatment attenuates tumor metastasis in mice by inhibiting P-selectin-mediated interactions of platelets with carcinoma cell-surface mucin ligands. Selective removal of tumor mucin P-selectin lig ands, a single heparin dose, or a background of P-selectin deficiency each reduces tumor cell-platelet interactions in vitro and in vivo. Although eac h of these maneuvers reduced the in vivo interactions for only a few hours, all markedly reduce long-term organ colonization by tumor cells. Three-dim ensional reconstructions by using volume-rendering software show that each situation interferes with formation of the platelet "cloak" around tumor ce lls while permitting an increased interaction of monocytes (macrophage prec ursors) with the malignant cells. Finally, we show that human P-selectin is even more sensitive to heparin than mouse P-selectin, giving significant i nhibition at concentrations that are in the clinically acceptable range. We suggest that heparin therapy for metastasis prevention in humans be revisi ted, with these mechanistic paradigms in mind.