Background: Blood-borne metastasis is critical for cancer dissemination. Crosstalk between circulating breast cancer cells (BCCs) and the coagulation system promotes metastasis. Clinical studies suggest that treatment with low molecular weight heparin (LMWH) may improve survival, by preventing thrombosis and by attenuating metastasis. Crucially, the anti-metastatic properties of LMWH are poorly understood, however endothelial von Willebrand Factor (VWF) has been implicated as a novel target of LMWH Tinzaparin.

Aims: We aim to define the biological role of the VWF-LMWH axis in BCCs dissemination including, endothelial adhesion, migration and metastasis.

Methods: Several BCCs were used in this study, including MDA-MB-231, MCF-7 and MM134-VI. Primary human endothelial cells were used to assess BCC adhesion and trans-endothelial invasion. VWF and VEGF-A levels were measured using specific ELISAs.

Results: Elevated plasma VWF levels were observed in patients with metastatic breast cancer versus healthy controls (264.7IU/dL vs 101.4IU/dL). Consequently, we assessed the ability of BCCs to induce VWF secretion from endothelial cells (EC). BCCs did not directly activate EC in isolation, however in the presence of platelets, BCCs trigger rapid EC activation and VWF secretion. VWF release was mediated by BCC-induced platelet-derived VEGF-A. Tinzaparin treatment of BCCs abolished VWF secretion. Next, we determined whether endothelial VWF may contribute to breast cancer progression. VWF multimers secreted from activated ECs mediated adhesion of BCCs under shear stress conditions. BCC adhesion to the endothelium was ablated by Tinzaparin treatment. We observed that BCCs increased vascular endothelial permeability, facilitating trans-endothelial invasion. Critically, Tinzaparin treatment enhanced endothelial barrier function  preventing BCCs invasion. VWF induced upregulation of key epithelial-to-mesenchymal invasive transition markers which were directly reversed by Tinzaparin, suggesting that LMWH may attenuate pro-metastatic changes induced in BCCs by VWF.

Conclusions: Collectively, these findings provide novel insights into anti-metastatic roles of LMWH in breast cancer and may help identify novel therapeutic targets, including VWF, to attenuate metastasis.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/delineating-the-role-of-low-molecular-weight-heparin-in-breast-cancer-metastasis/