School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
J Cell Sci. 2023 Sep 15;136(18). doi: 10.1242/jcs.261225. Epub 2023 Sep 28.
Previous clinical studies and work in mouse models have indicated that platelets and microclots might enable the recruitment of immune cells to the pre-metastatic cancer niche, leading to efficacious extravasation of cancer cells through the vessel wall. Here, we investigated the interaction between platelets, endothelial cells, inflammatory cells, and engrafted human and zebrafish cancer cells by live-imaging studies in translucent zebrafish larvae, and show how clotting (and clot resolution) act as foci and as triggers for extravasation. Fluorescent tagging in each lineage revealed their dynamic behaviour and potential roles in these events, and we tested function by genetic and drug knockdown of the contributing players. Morpholino knockdown of fibrinogen subunit α (fga) and warfarin treatment to inhibit clotting both abrogated extravasation of cancer cells. The inflammatory phenotype appeared fundamental, and we show that forcing a pro-inflammatory, tnfa-positive phenotype is inhibitory to extravasation of cancer cells.
先前的临床研究和小鼠模型研究表明，血小板和微血栓可能使免疫细胞募集到癌转移前的生态位，从而使癌细胞有效地穿过血管壁渗出。在这里，我们通过在半透明斑马鱼幼虫中进行活体成像研究，研究了血小板、内皮细胞、炎性细胞与植入的人和斑马鱼癌细胞之间的相互作用，并展示了凝血（和血栓溶解）如何作为焦点和触发因素引发渗出。对每个谱系进行荧光标记揭示了它们在这些事件中的动态行为和潜在作用，我们通过遗传和药物敲低有贡献的参与者来测试其功能。纤维蛋白原亚基α (fga) 的 morpholino 敲低和华法林治疗抑制凝血均使癌细胞的渗出减少。炎性表型似乎是基本的，我们表明，强迫产生促炎、tnfa 阳性表型会抑制癌细胞的渗出。
