Oxidative stress inhibits distant metastasis by human melanoma cells.
Oxidative stress inhibits distant metastasis by human melanoma cells.
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DOI：
10.1038/nature15726
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发表时间：
2015-11-12
期刊：
影响因子：
64.8
通讯作者：
Morrison SJ
中科院分区：
文献类型：
--
作者：
Piskounova E;Agathocleous M;Murphy MM;Hu Z;Huddlestun SE;Zhao Z;Leitch AM;Johnson TM;DeBerardinis RJ;Morrison SJ
实体癌细胞通常进入血液并全身扩散，但由于不清楚的原因，在形成远处转移方面效率很低。我们研究了不同的人类黑色素瘤，在他们的转移历史的患者和他们的能力转移NSG小鼠。所有的黑色素瘤都有高频率的细胞形成皮下肿瘤，但静脉内或脾内移植后形成肿瘤的细胞百分比要低得多，特别是在无效的转移者中。血液和内脏器官中的黑色素瘤细胞经历了在已建立的皮下肿瘤中未观察到的氧化应激。成功转移的黑色素瘤在转移过程中经历了可逆的代谢变化，增加了它们抵抗氧化应激的能力，包括增加了对叶酸途径中NADPH生成酶的依赖性。抗氧化剂促进NSG小鼠的远处转移。使用低剂量甲氨蝶呤、ALDH1L2敲低或MTHFD1敲低的叶酸途径抑制可抑制远处转移，而不会显著影响相同小鼠皮下肿瘤的生长。因此，氧化应激限制了体内黑色素瘤细胞的远处转移。
Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.