ICAM-1介导CX3CL1促进CTC-血小板簇跨椎体微血管内皮细胞外渗的机制研究

脊柱转移（SM）约占恶性肿瘤骨转移的70%，造成剧烈疼痛、瘫痪等严重后果。课题组前期研究证实椎体红骨髓中CX3CL1可以趋化循环肿瘤细胞（CTC）向脊柱迁移，但CTC到椎体微环境后如何跨内皮细胞外渗未知。粘附和跨内皮迁移是外渗的关键步骤，已知血小板与CTC聚集参与外渗。预试验发现：CX3CL1促进椎体微血管内皮细胞（MEC）与肿瘤细胞粘附，并通过提高MEC通透性增加肿瘤细胞的跨内皮迁移；添加血小板进一步加强肿瘤细胞粘附和迁移作用；粘附因子芯片结果提示CX3CL1可以提高MEC粘附因子ICAM-1表达；沉默MEC上ICAM-1表达可以抑制其参与肿瘤细胞的粘附和迁移。课题组假说：椎体红骨髓中CX3CL1通过促进MEC表达ICAM-1，结合血小板上配体后粘附CTC-血小板簇，进而增加CTC的跨内皮迁移导致CTC外渗，最终形成CTC在椎体的定植。课题期望阐明SM中ICAM-1在CTC外渗中的机制。

Spinal metastases (SM) account for about 70% of malignant tumor bone metastases, leading to paraplegia and urinary and fecal incontinence. Our preliminary work showed that CX3CL1 in the red bone marrow of the vertebral body promoted the metastasis of various tumors to the spine. However, the regulation of CX3CL1 on the extravasation of tumor cells in the vertebral microenvironment has not been reported. Adhesion and migration are the key steps to extravasation of tumor cells. We found that CX3CL1 promoted adhesion to tumor cells and permeability to increase transendothelial migration of tumor cells of vertebral microvascular endothelial cells (MEC), while addition of platelet further enhanced MEC adhesion and transendothelial migration to MEC of tumor cells. CX3CL1 promoted high expression of ICAM-1 in MEC. Silencing of ICAM-1 on MEC inhibited its adhesion to tumor cells and inhibited the transendothelial migration to MEC of tumor cells. Therefore, our study proposes that increasing expression of ICAM-1 on MEC promoted by CX3CL1 in the red bone marrow of vertebral body causes MEC to bind to platelets and adhere to CTC, thereby increasing the transendothelial migration of CTC which promoting the occurrence of spinal metastasis. This project is expected to provide a new target for the prevention of SM by elucidating the mechanism of ICAM-1 in CTC extravasation.