Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis
Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis
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DOI：
10.1158/0008-5472.can-03-1054
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发表时间：
2004-04-15
期刊：
影响因子：
11.2
通讯作者：
Gille, J
中科院分区：
文献类型：
--
作者：
Ludwig, RJ;Boehme, B;Gille, J
在不同的肿瘤模型中，广泛使用的抗凝剂肝素可以有效地抑制自发性和实验性转移。在细胞水平，肝素在体内的许多抗转移作用是由于其对P-选择素介导的结合的作用。鉴于以前的注意力集中在P-选择素依赖性肿瘤细胞血小板相互作用的血液传播的转移，我们试图解决的潜在贡献的内皮P-选择素表达之间的粘附事件的微血管和黑色素瘤细胞在体内。骨髓移植从P-选择素缺陷到野生型小鼠传达抑制实验性黑色素瘤转移。然而，在何种程度上骨髓赋予缺乏血小板P-选择素表达减弱黑色素瘤肺转移显着低于P-选择素缺陷小鼠，表明内皮P-选择素表达可能另外有助于形成血行转移。我们的活体显微镜研究支持了这一假设，其中相当大比例的黑色素瘤细胞能够以P-选择素依赖的方式与小鼠耳的毛细血管后小静脉直接相互作用。肝素不仅抑制P-选择素介导的黑色素瘤细胞滚动，而且还减弱体内黑色素瘤转移形成，进一步支持内皮P-选择素表达可能代表实验性黑色素瘤肺转移中肝素作用的额外靶点的概念。
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 experimental 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.