Effects Of Modified Heparins On The Interaction Between Melanoma Cell And Platelets Mediated By α_IIbβ₃ Integrin

Hematogenous metastasis is a highly regulated process and a cascade of dynamic events involving many factors. The interaction between platelets and tumor cells is important in the formation of metastasis. Platelets may shield cancerous cells from high shear forces that could potentially damage the tumor cells and limit the ability of NK cells to lyse tumor cells. Furthermore, platelets facilitate the adhesion of tumor cells to the vascular endothelium, and release a number of growth factors such as platelet-derived growth factor (PDGF), angiogenic growth factor, vascular endothelial growth factor (VEGF) and angiopoietin-1, which are required for metastasis and angiogenesis. The key platelet integrinαΙΙbβ3 has been reported to involve the interaction of platelets and certain melanoma, breast, colon cancer cells through the integrin ligand on the cell surface. Therefore, inhibiting the interaction between tumor cells and integrinαΙΙbβ3 that may inhibited the binding of tumor cells with platlets , and then diminished metastatic potential.Heparin is most well known for its anticoagulant activity,heparin is widely exploited in the clinic to prevent and treat thromboembolic disease. In addition, heparin has many actions that may inhibit the metastatic process , which include inhibition of angiogenesis and tumor growth. However, the significant anticoagulant properties of heparin and its potential for bleeding complications may contraindicate its use as an anti-tumor compound. There are repots that chemically modified heparin derivatives, which have, to certain extent, reduced anticoagulant activities. In this study, we assessed the role of integrinαΙΙbβ3 in the adhesion of melanoma cells to platelets, and the impact of heparin and modified heparin to this adhesion in vitro and in vivo. We showed that platelet integrinαΙΙbβ3 involved in the interaction of human melanoma A375 cells and platelets, heparin sulfate-like proteoglycans on tumor cell surface are implicated in the adhesion of A375 cells toαΙΙbβ3-integrin. Moreover, platelet integrinαΙΙbβ3 appear to be capable of directly capturing A375 cells from the fluid stream without rolling on the immobilized platelet monolayers. RO-heparin, CR-heparin, N-2,3-DS-heparin and 2,3-O-DS-heparin can significantly inhibit the A375 cells bind to CHO cells expressing integrinαΙΙbβ3 under static and flow conditions, and remarkably inhibit the A375 cells bind to the immobilized platelet monolayers under flow conditions. In vivo, the initial interaction of tumor and platelets in lung vessel could be inhibited by heparin as well as CR-heparin and N-2,3-DS-heparin. These results suggested that some chemically modified heparins with low anticoagulant activity may be used to inhibit the metastasis which induced by the interaction between tumor cells and platelets.