The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo

Abstract

Ample evidence suggests that many of the in vivo anti-metastatic effects by heparins reflect their actions on P-selectin-mediated binding. We hypothesized that the ability of widely used heparins and derivatives to interfere with P-selectin-dependent tumour cell interactions under flow in vitro could be used to identify anticoagulants with advanced inhibitory functions on experimental blood-borne metastasis in vivo. To test this assumption, the impact of unfractionated heparin, the low-molecular-weight heparins (LMWH) nadroparin and enoxaparin, and the synthetic pentasaccharide fondaparinux on P-selectin-dependent tumour interactions in vitro and metastasis formation in vivo were evaluated. Our data revealed that these commonly used anticoagulants widely differ in their potential to interfere with P-selectinmediated cell binding. Importantly, the superior inhibitory capacity on P-selectin function of unfractionated heparin and LMWH nadroparin as opposed to LMWH enoxaparin and synthetic heparin pentasaccharide fondaparinux strongly correlated to the inhibitory potency of each in inhibiting experimental lung metastasis in vivo. Hence, P-selectin inhibition may constitute a valuable feature to identify anticoagulants that are suitable for anticancer therapy.

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

“…However, a lack of effects of FVL has been observed as well in colon cancer tumor development in mouse liver [16] indicating that the coagulation system is not effective in all organs. Moreover, not all anticoagulants are effective inhibitors of cancer progression [17][18][19].…”

“…The anticancer properties of anticoagulants appear to be mediated by various mechanism [3,4] but blocking P-and L-selectins has major effects [17][18][19][20]. In the present study, we focussed on inhibition of thrombin formation and platelet-cancer cell complex formation by anticoagulants.…”

Heparin as an Inhibitor of Cancer Progression

“…In the majority of studies the amount of heparin applied significantly exceeded the clinically used therapeutic dose. Nevertheless, recent studies provided evidence that heparin attenuated metastasis in two different mouse models also at clinically relevant concentrations [25,26]. Taken shown to attenuate metastasis only in one study with a spontaneously metastatic mouse model, while tumor growth remained largely unaffected [27].…”

“…While the synthetic pentasaccharide -fondaparinux did not affect cancer progression, LMWH effectively attenuated metastasis at clinically tolerable levels [25,26] However, the antimetastatic activity of LMWH has been found to vary among different preparations.…”

“…Recently, different clinically used LMWH preparations have been shown to attenuate metastasis by inhibition of selectin [25,26]. heparin did not affect metastasis applied around the time of tumor cell injection [22,23].Heparin treatment of mice either 1 day before or 1 day after tumor cell injection did not affect metastasis [19,20].…”