Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development.
Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development.
复制标题
DOI：
10.1158/0008-5472.can-09-4442
复制
发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Robertson GP
中科院分区：
文献类型：
--
作者：
Huh SJ;Liang S;Sharma A;Dong C;Robertson GP
目前还不清楚为什么只有少数循环肿瘤细胞被困在肺毛细血管中形成转移，免疫细胞的参与仍然不确定。本研究建立了一种新的模型，表明中性粒细胞通过物理相互作用和将循环肿瘤细胞锚定到内皮细胞来调节肺转移的发展。将人黑色素瘤细胞静脉注射到裸鼠体内，导致许多癌细胞被截留;然而，24小时后，很少有癌细胞留在肺部。相比之下，在肿瘤细胞注射后一小时注射人嗜中性粒细胞，使癌细胞保留增加约3倍。被捕获的黑色素瘤细胞产生并分泌高水平的称为IL-8的细胞因子，吸引中性粒细胞并使系留β2整合素表达增加75- 100%。黑色素瘤细胞上的ICAM-1和中性粒细胞上的β2整合素相互作用，促进锚定到血管内皮。减少黑素瘤细胞的IL-8分泌使细胞外水平降低20- 50%，使中性粒细胞上的β2整联蛋白降低约50%，并使嗜中性粒细胞介导的外渗减少25- 60%，导致束缚于内皮并滞留在肺中的黑素瘤细胞减少约50%。因此，跨内皮迁移和肺转移发展减少了约50%，表明靶向黑色素瘤细胞中的IL-8具有通过破坏与中性粒细胞的相互作用来减少转移发展的潜力。
It is unknown why only a minority of circulating tumor cells trapped in lung capillaries form metastases and involvement of immune cells remains uncertain. A novel model has been developed in this study showing that neutrophils regulate lung metastasis development through physical interaction and anchoring of circulating tumor cells to endothelium. Human melanoma cells were intravenously injected into nude mice leading to entrapment of many cancer cells; however, 24 hours later very few remained in the lungs. In contrast, injection of human neutrophils an hour after tumor cell injection, increased cancer cell retention by ~3-fold. Entrapped melanoma cells produced and secreted high levels of a cytokine called IL-8, attracting neutrophils and increasing tethering β2 integrin expression by 75-100%. ICAM-1 on melanoma cells and β2 integrin on neutrophils interacted, promoting anchoring to vascular endothelium. Decreasing IL-8 secretion from melanoma cells lowered extracellular levels by 20-50%, decreased β2 integrin on neutrophils by ~50% and reduced neutrophil-mediated extravasation by 25-60%, resulting in ~50% fewer melanoma cells being tethered to endothelium and retained in lungs. Thus, transendothelial migration and lung metastasis development decreased by ~50%, showing that targeting IL-8 in melanoma cells has the potential to decrease metastasis development by disrupting interaction with neutrophils.