Endothelial E- and P-selectins promote metastasis formation by interacting with sialyl-Lewis X and A (sLeX/sLeA) on circulating tumor cells. This interaction precedes extravasation and can take place under dynamic and static conditions. Metastasis formation is often studied in xenograft models. However, it is unclear whether species differences exist in the ligand specificity of human (h) vs. murine (m) selectins and whether different ligands are functional under dynamic vs. static conditions. We systematically compared the h vs. m E- and P-selectin (ESel/PSel) binding of a range of human tumor cells under dynamic vs. static conditions. The tumor cells were categorized by their sLeA/X status (sLeA+/sLeX+, sLeA−/sLeX+ and sLeA−/sLeX−). The general biological nature of the tumor–selectin interaction was analyzed by applying several tumor cell treatments (anti-sLeA/X blockade, neuraminidase, pronase and inhibition of O/N-glycosylation). We observed remarkable differences in the static vs. dynamic interaction of tumor cells with h vs. m ESel/PSel depending on their sLeA/X status. The tumor cell treatments mostly affected either static or dynamic as well as either h- or m-selectin interaction. mESel showed a higher diversity of potential ligands than hESel. Inhibition of O-GalNAc-glycosylation also affected glycosphingolipid synthesis. Summarized, different ligands on human tumor cells are functional under static vs. dynamic conditions and for the interaction with human vs. murine ESel/PSel. Non-canonical selectin ligands lacking the sLeA/X glycan epitopes exist on human tumor cells. These findings have important implications for the current development of glycomimetic, antimetastatic drugs and encourage the development of immunodeficient mice with humanized selectins.

中文翻译：

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在静态与动态条件下，人类肿瘤细胞与人与鼠 E- 和 P-选择素结合的系统分析。

内皮 E- 和 P-选择蛋白通过与循环肿瘤细胞上的唾液酸-刘易斯 X 和 A (sLeX/sLeA) 相互作用来促进转移形成。这种相互作用先于外渗，可以在动态和静态条件下发生。通常在异种移植模型中研究转移形成。然而，尚不清楚人类 (h) 与鼠 (m) 选择素的配体特异性是否存在物种差异，以及不同的配体在动态与静态条件下是否具有功能。我们系统地比较了一系列人类肿瘤细胞在动态与静态条件下的 h 与 m E-和 P-选择素 (ESel/PSel) 结合。肿瘤细胞按其 sLeA/X 状态分类（sLeA+/sLeX+、sLeA-/sLeX+ 和 sLeA-/sLeX-）。O / N-糖基化）。我们观察到肿瘤细胞与 h 与 m ESel/PSel 的静态与动态相互作用的显着差异，这取决于它们的 sLeA/X 状态。肿瘤细胞治疗主要影响静态或动态以及 h-或 m-选择素相互作用。mESel 显示出比 hESel 更高的潜在配体多样性。抑制O-GalNAc-糖基化也影响了鞘糖脂的合成。总之，人类肿瘤细胞上的不同配体在静态与动态条件下以及与人类与鼠 ESel/PSel 的相互作用下均具有功能。人类肿瘤细胞上存在缺乏 sLeA/X 聚糖表位的非经典选择素配体。这些发现对当前糖模拟物、抗转移药物的开发具有重要意义，并鼓励开发具有人源化选择素的免疫缺陷小鼠。