肿瘤细胞跨内皮屏障外渗已被认为是协调转移形成的关键事件。该事件是由外渗肿瘤细胞与内皮细胞 (EC) 的相互作用引发的。因此，针对肿瘤细胞和内皮细胞之间的串扰可能是预防转移的一种有前途的治疗策略。在这项研究中，我们证明人参的主要成分之一Rh1在体外和体内均能阻碍乳腺癌（BC）细胞的侵袭并降低ECs的通透性，从而导致肿瘤细胞减弱跨内皮细胞外渗。值得注意的是，我们发现EC能够通过限制造血表达同源盒（HHEX）的核易位来诱导BC细胞的上皮间质转化（EMT）和侵袭伪足，这对于肿瘤细胞迁移和侵袭至关重要。核HHEX的减少为启动CCL20/CCR6信号轴铺平了道路，这反过来又导致内皮连接受损，揭示了肿瘤细胞和EC之间的新串扰模式。有趣的是，Rh1抑制酪蛋白激酶II亚基α（CK2α）的激酶活性，并进一步促进BC细胞中HHEX的核转位，从而导致BC细胞中趋化因子（C-C基序）配体20（CCL20）之间的串扰被破坏EC 中的趋化因子（C-C 基序）受体 6 (CCR6)。 Rh1 抑制的 CCL20-CCR6 轴增强了血管完整性并减弱了肿瘤细胞的运动性。总而言之，我们的数据表明，Rh1 作为一种有效的天然 CK2α 抑制剂，可以进一步优化为减少肿瘤细胞外渗的治疗剂。版权所有 © 2023。由 Elsevier Ltd 出版。

Tumor cell extravasation across endothelial barrier has been recognized as a pivotal event in orchestrating metastasis formation. This event is initiated by the interactions of extravasating tumor cells with endothelial cells (ECs). Therefore, targeting the crosstalk between tumor cells and ECs might be a promising therapeutic strategy to prevent metastasis. In this study, we demonstrated that Rh1, one of the main ingredients of ginseng, hindered the invasion of breast cancer (BC) cells as well as diminished the permeability of ECs both in vitro and in vivo, which was responsible for the attenuated tumor cell extravasation across endothelium. Noteworthily, we showed that ECs were capable of inducing the epithelial-mesenchymal transition (EMT) and invadopodia of BC cells that are essential for tumor cell migration and invasion through limiting the nuclear translocation of hematopoietically expressed homeobox (HHEX). The decreased nuclear HHEX paved the way for initiating the CCL20/CCR6 signaling axis, which in turn contributed to damaged endothelial junctions, uncovering a new crosstalk mode between tumor cells and ECs. Intriguingly, Rh1 inhibited the kinase activity of casein kinase II subunit alpha (CK2α) and further promoted the nuclear translocation of HHEX in the BC cells, which resulted in the disrupted crosstalk between chemokine (C-C motif) ligand 20 (CCL20) in the BC cells and chemokine (C-C motif) receptor 6 (CCR6) in the ECs. The prohibited CCL20-CCR6 axis by Rh1 enhanced vascular integrity and diminished tumor cell motility. Taken together, our data suggest that Rh1 serves as an effective natural CK2α inhibitor that can be further optimized to be a therapeutic agent for reducing tumor cell extravasation.Copyright © 2023. Published by Elsevier Ltd.