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首页> 外文学位 >Receptor-mediated interactions of polymorphonuclear leukocytes with colon carcinoma cells and selectin substrates under shear.
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Receptor-mediated interactions of polymorphonuclear leukocytes with colon carcinoma cells and selectin substrates under shear.

机译：剪切作用下多形核白细胞与结肠癌细胞和选择素底物的受体介导相互作用。

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Receptor-mediated cell adhesion plays a pivotal role in diverse biological processes that occur in the vasculature including inflammation and cancer metastasis. For instance, a critical step in polymorphonuclear leukocyte (PMN) recruitment to sites of inflammation/infection is their adhesion to the activated endothelium. Also, new evidence suggests that the metastatic spread of certain types of cancers may be enhanced by PMN-tumor cell adhesive interactions. Since these cell-cell adhesive interactions take place in the fluid mechanical environment of the vasculature, it is important to characterize the molecular mechanisms mediating cell adhesion under physiologically relevant flow conditions. Therefore, we examined the effect of hydrodynamic shear on the adhesive interactions of PMNs with carcinoma cells and selectin substrates using experimental and computational methods.; The first part of the study comprises of an in vitro experimental investigation of the effect of fluid shear on the kinetics and receptor specificity of PMN-colon carcinoma cell adhesive interactions in cell suspensions using a rheometric-flow cytometric methodology. We demonstrate for the first time that L-selectin-mediated tethering is required for optimal PMN-colon carcinoma cell adhesion under high shear conditions (≥400 s -1). We also show that the L-selectin ligand on the metastatic LS174T cells is sialylated, O-linked and a protease-sensitive glycoprotein. In contrast, the non-metastatic HCT-8 cells, which do not possess the L-selectin ligand are unable to bind to PMNs under high shear conditions. Moreover, the contribution of PMN LFA-1 and Mac-1 to PMN-colon carcinoma cell stable adhesion is shown to be dependent on shear rate, shear exposure time and the ligands for the beta2 integrins.; In the second part of the study we used a computational model to simulate PSGL-1-mediated rolling of a deformable PMN on a P-selectin-coated surface under shear flow. We observed that the average rolling velocity of the cell and the cell-substrate contact area decrease with increasing membrane stiffness for shear rates ≥200 s-1. The lifetime of the P-selectin - PSGL-1 bond was found to decrease with increasing membrane stiffness at all shear rates examined.; Collectively, these findings may provide insights for the rational development of novel therapeutics to combat inflammation and cancer metastasis.
机译：受体介导的细胞粘附在包括炎症和癌症转移在内的脉管系统中发生的多种生物学过程中起着关键作用。例如，多形核白细胞（PMN）募集到炎症/感染部位的关键步骤是它们与活化内皮细胞的粘附。同样，新的证据表明，某些类型的癌症的转移扩散可能会通过PMN-肿瘤细胞粘附相互作用而增强。由于这些细胞-细胞粘附相互作用发生在脉管系统的流体机械环境中，因此重要的是表征在生理相关的流动条件下介导细胞粘附的分子机制。因此，我们使用实验和计算方法研究了流体动力剪切对PMNs与癌细胞和选择素底物之间黏附相互作用的影响。该研究的第一部分包括使用流变流式细胞术对流体剪切对细胞悬浮液中PMN-结肠癌细胞粘附相互作用的动力学和受体特异性影响的体外实验研究。我们首次证明，在高剪切条件（≥400s -1）下，PMN结肠癌细胞的最佳粘附需要L-选择蛋白介导的系链。我们还显示，转移性LS174T细胞上的L-选择蛋白配体被唾液酸化，O-连接和蛋白酶敏感性糖蛋白。相反，不具有L-选择蛋白配体的非转移性HCT-8细胞在高剪切条件下不能与PMN结合。此外，显示PMN LFA-1和Mac-1对PMN结肠癌细胞稳定粘附的贡献取决于剪切速率，剪切暴露时间和beta2整联蛋白的配体。在研究的第二部分中，我们使用计算模型来模拟PSGL-1介导的P-选择素涂层表面在剪切流作用下可变形PMN的滚动。我们观察到，当剪切速率≥200s-1时，细胞的平均滚动速度和细胞与基材的接触面积随膜硬度的增加而降低。在所有所考察的剪切速率下，发现P-选择蛋白-PSGL-1键的寿命随着膜刚度的增加而降低。总的来说，这些发现可能为合理开发新的疗法以对抗炎症和癌症转移提供见解。

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