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Oxidative stress inhibits distant metastasis by human melanoma cells

2015; Nature Portfolio; Volume: 527; Issue: 7577 Linguagem: Inglês

10.1038/nature15726

1476-4687

Elena Piskounova, Michalis Agathocleous, Malea M. Murphy, Zeping Hu, Sara E. Huddlestun, Zhiyu Zhao, A. Marilyn Leitch, Timothy M. Johnson, Ralph J. DeBerardinis, Sean J. Morrison,

Cancer, Hypoxia, and Metabolism

Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg−/− (NSG) mice. We show that 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 inefficiently metastasizing melanomas. 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 on NADPH-generating enzymes in the folate pathway. Antioxidants 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 tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo. Human melanoma cells grown in mice experience high levels of oxidative stress in the bloodstream such that few metastasizing cells survive to form tumours; the rare melanoma cells that successfully metastasize undergo metabolic changes that increase their capacity to withstand this stress, and antioxidant treatments increase metastasis formation by human melanoma cells, while inhibiting antioxidant pathways had the reverse effect. Although solid cancer cells such as melanoma cells readily enter the circulation system, they are not very efficient at forming metastases at sites away from the original tumour. Sean Morrison and colleagues show that human melanoma cells grown in mice experience high levels of oxidative stress in the bloodstream, such that few metastasizing cells survive to form tumours. The rare melanoma cells that do successfully metastasize undergo metabolic changes that increase their capacity to withstand this stress. Antioxidant treatments increase metastasis by human melanoma cells, while inhibiting antioxidant pathways has the opposite effect.