Inhibitory effects of chemically modified heparin on the P-selectin-mediated adhesion of breast cancer cells in vitro.

P-selectin plays a crucial role during hematogenous metastasis, and the blockade of P-selectin binding to its ligand can attenuate metastasis in various tumor models. Heparin or chemically modified heparins with decreased anticoagulant activities exhibit marked inhibitory effects on P-selectin-mediated adhesion. Here, we prepared chemically modified heparins with reduced anticoagulant activities and investigated whether they effectively inhibited P-selectin binding to breast cancer cells under static and flow conditions. The results indicated that P-selectin binding to ZR-75-30 cells was attenuated by chemically modified heparins in a sulfation-dependent manner under static and flow conditions. Flow cytometric analysis with heparan sulfate-specific monoclonal antibody revealed that heparan sulfate-like proteoglycans on the tumor cell surface were not implicated in this process. Instead, other glycoproteins were found to serve as P-selectin ligands. These findings suggest that further detailed research involving chemically modified heparins with low or no anti-coagulant activities is warranted, and that chemically modified heparins should be considered in the treatment of metastatic breast cancer disease, with P-selectin potentially being a good target.