Hang Benson, Jassem Eman, Mohammed Hanan, Wan Leo Q, Herschkowitz Jason I, Fan Jie
Department of Natural Sciences, CASL, University of Michigan-Dearborn, Dearborn, Michigan 48128, USA.
Department of Biomedical Sciences, Cancer Research Center, University at Albany-SUNY, Rensselaer, New York 12144, USA.
APL Bioeng. 2022 Dec 6;6(4):046107. doi: 10.1063/5.0115827. eCollection 2022 Dec.
Endothelial cells (ECs) possess a strong intrinsic clockwise (CW, or rightward) chirality under normal conditions. Enervating this chirality of ECs significantly impairs the function of the endothelial barrier. Malignant tumor cells (TCs) undergo metastasis by playing upon the abnormal leakage of blood vessels. However, the impact of TCs on EC chirality is still poorly understood. Using a transwell model, we co-cultured the human umbilical vein endothelial cells or human lung microvascular endothelial cells and breast epithelial tumor cell lines to simulate the TC-EC interaction. Using a micropatterning method, we assessed the EC chirality changes induced by paracrine signaling of and physical contact with TCs. We found that the intrinsic clockwise chirality of ECs was significantly compromised by the TC's physical contact, while the paracrine signaling (i.e., without physical contact) of TCs causes minimal changes. In addition, ECs neighboring TCs tend to possess a left bias, while ECs spaced apart from TCs are more likely to preserve the intrinsic right bias. Finally, we found the chirality change of ECs could result from physical binding between CD44 and E-selectin, which activates protein kinase C alpha (PKCα) and induces pseudopodial movement of EC toward TC. Our findings together suggest the crucial role of EC-TC physical interaction in EC chirality and that weakening the EC chirality could potentially compromise the overall endothelial integrity which increases the probability of metastatic cancer spread.
在正常条件下,内皮细胞(ECs)具有很强的内在顺时针(CW,或向右)手性。削弱ECs的这种手性会显著损害内皮屏障的功能。恶性肿瘤细胞(TCs)通过利用血管的异常渗漏来进行转移。然而,TCs对EC手性的影响仍知之甚少。我们使用Transwell模型,将人脐静脉内皮细胞或人肺微血管内皮细胞与乳腺上皮肿瘤细胞系共培养,以模拟TC-EC相互作用。我们使用微图案化方法,评估了TCs旁分泌信号和与TCs物理接触所诱导的EC手性变化。我们发现,TCs的物理接触显著损害了ECs固有的顺时针手性,而TCs的旁分泌信号(即无物理接触)引起的变化最小。此外,与TCs相邻的ECs往往具有向左的偏向,而与TCs间隔开的ECs更有可能保持固有的向右偏向。最后,我们发现ECs的手性变化可能源于CD44与E-选择素之间的物理结合,这会激活蛋白激酶Cα(PKCα)并诱导EC向TC的伪足运动。我们的研究结果共同表明,EC-TC物理相互作用在EC手性中起关键作用,削弱EC手性可能会损害整体内皮完整性,从而增加转移性癌症扩散的可能性。