Endothelial barrier protective properties of low molecular weight heparin: A novel potential tool in the prevention of cancer metastasis?

BACKGROUND: One of the key events in the progression of cancer metastasis is the trans-endothelial migration of circulating tumor cells. Moreover, inhibition of tumor-induced vascular permeability has been shown to inhibit metastasis in vivo. Low molecular weight heparin (LMWH) appears to confer a survival benefit in cancer but the underlying mechanisms are poorly understood. OBJECTIVE: To characterise LMWH-mediated endothelial barrier protection and to explore strategies to limit the LMWH-associated haemorrhagic risk in this setting. METHODS: Endothelial barrier function was assessed using in vitro assays of endothelial permeability and tumor cell trans-endothelial migration. Thrombin-mediated activation of PAR-1 signalling was assessed by flow cytometry and western blotting. LMWH anticoagulant activity was assessed by calibrated automated thrombography and plasma anti-factor Xa activity assay. RESULTS: LMWH tinzaparin enhanced endothelial barrier function and reduced tumor cell trans-endothelial migration (73.9±5.7% of baseline; P<.05). Tinzaparin-mediated attenuation of thrombin-induced permeability was not mediated through an inhibition of thrombin proteolytic activity. In addition, fractions of LMWH with diminished anticoagulant activity retained endothelial barrier protective properties and a marked synergistic effect on barrier function was observed using combinations of sub-anticoagulant concentrations of tinzaparin with simvastatin (which exhibits endothelial barrier protective properties in vitro), with almost complete protection against agonist-induced endothelial barrier permeability achieved (7.9±0.2% of baseline; P<.05). CONCLUSION: Collectively, these results suggest that LMWH supports endothelial barrier function in a manner which does not appear to be dependent on its anticoagulant activity. If replicated in vivo, these findings could represent a novel therapeutic approach to the suppression of metastasis.