Selectins, Heparins, and Cancer: Rationale for Clinical Trials.

Abstract

Abstract Heparin has been in use as an anticoagulant for many decades, based on its ability to enhance antithrombin activity. However, heparin is a natural product, comprising a complex polydisperse mixture of highly sulfated glycosaminoglycan chains, only a fraction of which bind antithrombin. We reported that heparin has an unrelated biological effect in inhibiting P- and L-selectin binding to their natural ligands. Meanwhile, animal studies and analyses of human clinical data suggest that heparin therapy increases survival in various cancers. In contrast, clinical trials using Vitamin K antagonists showed no major effect on survival in most studies. Thus, the heparin effect on cancer may not be due primarily to its anticoagulant function, but rather to inhibition of P- and L-selectin. Indeed, we have demonstrated that the selectins play critical roles in animal models of the hematogeneous phase of carcinoma metastasis and of the platelet-rich microthromboses typical of classical Trousseau’s syndrome. This involves interactions of selectins with pathological ligands produced by carcinoma cells, particularly sialylated, fucosylated, and sulfated mucins. The critical selectin-mediated interactions blocked by heparin occur early in the metastatic cascade. Also, inhibition occurs at concentrations in the clinically acceptable range. Furthermore, there are many other salutary actions of heparin in cancer, including adsorption of cytokines and growth factors, inhibition of thrombin generation, and inhibition of heparanases. We, therefore, suggest that heparin therapy for metastasis prevention in humans be revisited, with these new paradigms in mind. Most of the above studies used unfractionated heparin. We found that selectin-inhibiting effects of low molecular weight heparins (LMWH) are varied and that the synthetic heparinoid pentasaccharide that specifically binds antithrombin does not block at clinically relevant levels. Optimal dosing to sustain clinically acceptable levels of all these drugs in mice gave congruent results. These data suggest a rational clinical trial comparing an optimal LMWH with the pentasaccharide in the pre-/peri- and immediate post-operative periods of newly diagnosed carcinomas. Notably, heparin can also attenuate inflammatory pathologies in animal models by blocking L- and P-selectin.