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Endothelial P-Selectin as a Target of Heparin Action in Experimental Melanoma Lung Metastasis

¹ Department of Dermatology, Klinikum der J. W. Goethe-Universität, Frankfurt am Main; ² RBA Dermatology, Schering AG, Berlin; ³ Department of Hematology/Oncology, Krankenhaus Nordwest, Frankfurt am Main; ⁴ Institute of Transfusion Medicine, German Red Cross Blood Center, Frankfurt am Main; and ⁵ Department of Molecular Biology, Max-Planck-Institut für Physiologische und Klinische Forschung, Bad Nauheim, Germany

Spontaneous and experimental metastasis can be effectively inhibited by the widely used anticoagulant heparin in different tumor models. At the cellular level, many of the antimetastatic effects of heparin in vivo are due to its action on P-selectin-mediated binding. Whereas previous attention has focused on P-selectin-dependent tumor-cell–platelet interactions in blood-borne metastasis, we sought to address the potential contribution of endothelial P-selectin expression to adhesive events between the microvasculature and melanoma cells in vivo. Transplantation of bone marrow from P-selectin-deficient into wild-type mice conveyed inhibition of ex-perimental melanoma metastasis. However, the extent to which bone marrow-conferred lack of platelet P-selectin expression attenuated melanoma lung metastasis was significantly less than that seen in P-selectin-deficient mice, suggesting that endothelial P-selectin expression may additionally contribute to formation of hematogenous metastases. This assumption was supported by our intravital microscopy studies, in which a significant proportion of melanoma cells were capable of directly interacting with postcapillary venules of the murine ear in a P-selectin-dependent manner. Heparin not only inhibits P-selectin-mediated melanoma cell rolling but also attenuates melanoma metastasis formation in vivo, further supporting the concept that endothelial P-selectin expression may represent an additional target of heparin action in experimental melanoma lung metastasis.

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