Modified heparins inhibit integrin alpha(IIb)beta(3) mediated adhesion of melanoma cells to platelets in vitro and in vivo.

The adhesion of tumor cells with platelets is important in the process of tumor metastasis. A huge work has indicated that anti-adhesion is an effective strategy for metastasis inhibition. In this article, we assess the role of platelet integrin alpha(IIb)beta(3) in adhesion of melanoma cells to platelets and the effects of heparin and modified heparins on the adhesion in vitro and in vivo. We show that platelet integrin alpha(IIb)beta(3) is involved in the interaction of human melanoma A375 cells with platelets, and the high affinity epitope resides on the alpha(IIb) subunit rather than beta(3) subunit. Heparin sulfate-like proteoglycans on tumor cell surface are implicated in the adhesion of A375 cells to integrin alpha(IIb)beta(3). We also show that RO-heparin, CR-heparin, N-2,3-DS-heparin and 2,3-O-DS-heparin can significantly inhibit A375 cells binding to the CHO cells expressing integrin alpha(IIb)beta(3) under static and flow conditions, and remarkably inhibit the adhesion of A375 cells to the immobilized platelet layers under flow conditions. We find that A375 cells and B16F10 cells are arrested in the pulmonary vessels and adhered to platelets, and the initial interaction of tumor cells with platelets in lung vessel and long-term establishment of metastatic foci can be inhibited by heparin as well as CR-heparin and N-2,3-DS-heparin. These data suggest that modified heparins can inhibit tumor cell-platelet interaction mediated by platelet integrin alpha(IIb)beta(3) and modified heparins may be a potential substitute for heparin in inhibiting tumor metastasis.