Inhibition of metastasis in a murine 4T1 breast cancer model by liposomes preventing tumor cell-platelet interactions

Abstract

The interaction between circulating tumor cells and blood components, mainly platelets, plays an important role during metastasis. In this study, we prepared liposomes containing the platelet aggregation inhibitor Cilostazol (Cil-L). The objective of this study was to investigate the effect of this Cil-L on platelet aggregation and complex formation with murine 4T1 breast cancer cells in vitro and to determine their anti-metastatic potency in a spontaneous metastasis model of 4T1 breast cancer. Cil-L significantly inhibited the aggregation of platelets by up to 78% and completely abolished the complex formation of 4T1 tumor cells in the presence of activated platelets in vitro. Intravenous (i.v.) injection of Cil-L into mice significantly reduced the aggregability of mouse platelets by 60% measured ex vivo. To gain deeper insight into the mode of metastasis formation in a spontaneous metastasis model, 4T1 breast cancer cells were transplanted into the mammary fad pad of mice and metastasis to the mouse lungs was investigated with regard to tumor cell settlement and metastatic growth. We could demonstrate that the formation of pulmonary metastases was significantly reduced by 55% when mice were treated intravenously with 100 nmol Cil-L 6 h before tumor cell inoculation and then daily for 2 weeks. We conclude that Cil-L reduced metastasis by restricting the aggregability of mouse platelets, which probably prevents the interaction between circulating 4T1 tumor cells and platelets, making the Cil-L a useful tool for the inhibition of breast cancer metastasis in mice.

Surgical Stress Promotes the Development of Cancer Metastases by a Coagulation-Dependent Mechanism Involving Natural Killer Cells in a Murine Model

“…17,19,25,41 Platelet activation and aggregation seen after surgery could result in activation of proteaseactivated receptor signaling pathways leading to upregulation of adhesion molecules (P-selectin) on platelets. This can then interact with its ligands on tumor cells favoring cancer cell survival in the circulation by protecting them against mechanical stress and the immune system.…”

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

“…One approach to minimize these interactions has focused on the use of anticoagulation agents. Agents such as recombinant mouse tissue factor pathway inhibitor [172] and the platelet aggregation inhibitor cilostazol [173] have been found to reduce the formation of secondary metastases. Several studies suggest that heparin, a powerful P-selectin inhibitor, can attenuate tumor metastasis in mice [174] .…”

Nanobiotechnology for the Therapeutic Targeting of Cancer Cells in Blood

“…Agents such as recombinant mouse tissue factor pathway inhibitor (TFPI) and Cilostazol have been found to reduce the formation of secondary metastases. 8,9,145 Unfortunately, the use of anticoagulants may also adversely affect the normal hemostatic function of platelets in the case of bleeding. A more focused approach aims to block the signaling between platelets and CTCs.…”