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

Abstract

Independent studies indicate that expression of sialylated fucosylated mucins by human carcinomas portends a poor prognosis because of enhanced metastatic spread of tumor cells, that carcinoma metastasis in mice is facilitated by formation of tumor cell complexes with blood platelets, and that metastasis can be attenuated by a background of P-selectin deficiency or by treatment with heparin. The effects of heparin are not primarily due to its anticoagulant action. Other explanations have been suggested but not proven. Here, we bring together all these unexplained and seemingly disparate observations, 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 ligands, a single heparin dose, or a background of P-selectin deficiency each reduces tumor cell-platelet interactions in vitro and in vivo . Although each of these maneuvers reduced the in vivo interactions for only a few hours, all markedly reduce long-term organ colonization by tumor cells. Three-dimensional reconstructions by using volume-rendering software show that each situation interferes with formation of the platelet “cloak” around tumor cells while permitting an increased interaction of monocytes (macrophage precursors) with the malignant cells. Finally, we show that human P-selectin is even more sensitive to heparin than mouse P-selectin, giving significant inhibition at concentrations that are in the clinically acceptable range. We suggest that heparin therapy for metastasis prevention in humans be revisited, with these mechanistic paradigms in mind.

Role of Glycosaminoglycans in Cellular Communication

“…45 A major reason for heparin's chemoprotective effect may be through blocking of platelets that cloak circulating metastatic cancer cells by interfering with selectin-mediated interaction between platelets and neonatal mucin carbohydrates expressed by the cancer cells. 46 Wound Healing and Repair Processes. Many of the pathophysiological processes assisting the growth and spread of cancers are physiological processes, considered in a positive light in wound healing.…”

Enhanced Melanoma‐Targeted Therapy by “Fru‐Blocked” Phenyboronic Acid‐Modified Multiphase Antimetastatic Micellar Nanoparticles

“…Remarkably, a few clinical trials have demonstrated the favorable effects of low‐molecular‐weight heparin (LMWH) on human tumors 17. LMWH inhibits the adhesion between platelets and tumor cells by hindering P‐selectin on activated platelets,17, 18, 19, 20 thus inhibiting the final stage of the metastatic cascade. Moreover, d ‐α‐tocopheryl succinate (TOS), the most effective form of vitamin E analogues, can inhibit the drug resistance of tumors and increase the apoptosis of various types of cancer cells,21, 22, 23 including B16F10 melanoma cells 24.…”

The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin

“…There is a large body of evidence that P-selectin and L-selectin facilitate metastasis of tumour cells when they are still in the circulation [4,6]. Therefore, we aimed to differentiate between the contribution of tumour cell-derived VLA-4 and selectin ligands to metastasis of B16F10 melanoma.…”

“…In the early phase of hematogenous metastasis P-selectin expressed on activated platelets and endothelium contributes to platelet-rich tumour cell emboli formation resulting in protection of tumour cells from innate immune system [4,5]. Lselectin expressed by leukocytes facilitates the interaction of the tumour microemboli with the endothelium [6,7].…”