Inhibition Of Modified Heparins On The Interaction Between Tumor Cells And Platelets Mediated By Fibrinogen

Malignant tumor is one of the main diseases threaten human health. Hematogenous metastasis is a complicated, multi-step process. The formation of tumor cell-platelet emboli complexes in the blood stream is an essential step during metastatic process. In the process of the formation of"microthrombus", plasma protein, adhesion molecules in the cells, especially the selectin and integrin family, play very important roles. Recent results show that fibrinogen, thrombin can mediated the interaction of tumor cells with platelets. However, how could they mediate the interaction? Are there any drug inhibit the interaction between tumor cells and platelets mediated by fibrinogen?Heparin, as anticoagulant drug widely exploited in the clinic to treat thromboembolic disease, also is used as adjuvant therapy drug with cancer patients. However, heparin anticoagulant properties and the potential of bleeding complications may contraindicate its use as an anti-metastasis compound in the clinic. As has been documented, chemically modified heparins with diminished anticoagulant activities were prepared and proved to inhibit metastasis in vitro and in vivo.In this study, we selected mouse melanoma cell line (B16F10) and human melanoma cell line (A375), and analyzed the interaction between these cell lines and fibrinogen, platelet mediated by fibrinogen under static and flow conditions. Furthermore, heparin and various modified heparins were evaluated for their ability to inhibit these interactions. The results indicate that the two cell lines can bind to fibrinogen, and adhere to platelet under static and flow conditions. Heparin and chemically modified heparins could significantly inhibit the interaction between the cell lines and fibrinogen, the interaction between the cell lines and platelets mediated by fibrinogen under static and flow conditions. Compared with the inhibition effects of the modified heparins, CR-Heparin,2/3ODS-Heparin are the better ones with their appropriate anti-adhesion activity.Then, to further investigate the mechanism of the interaction, we explored that integrinβ3,αvβ3 on the tumor cell surface andαⅡbβ3 highly espressed on the platelets play a key role, by using specific mAb, treatment with blocking mAb and flow cytometric analysis.In conclusion, the results in this study indicated that the interaction between tumor cells and platelets can be enhanced by fibrinogen, which can improve metastasis. Among the low anticoagulant heparins, RO-Heparin, CR-Heparin, 2/3ODS-Heparin and N/2/3DS-Heparin have high anti-adhesion activity. Our study will provide a valuable experimental foundation for clinical trial of low anticoagulant heparins in preventing metastasis. Also, the data presented here have provided a cue for further insight into mechanisms of the interaction between tumor cells with platelets.