Oxidative Stress Is a Limiting Factor for Metastasis

Reactive oxygen species (ROS) have been suggested to promote tumor initiation and progression by increasing mutation rates and activating oncogenic pathways, raising the possibility that antioxidants may reduce tumorigenesis. However, dietary antioxidant supplementation has been shown to increase the incidence and progression of some cancers in clinical trials and to have protumorigenic effects in mice. To evaluate the role of oxidative stress in distant metastasis, Piskounova and colleagues analyzed the metastatic potential of patient-derived human melanoma samples in immunodeficient mice. In contrast to the high rate of subcutaneous tumor formation by melanoma cells, intravenous or intrasplenic injection of melanoma cells resulted in significantly decreased formation of distant metastases. Metabolomic profiling revealed the presence of increased oxidative stress in circulating melanoma cells in the blood and metastatic nodules compared with subcutaneous tumors, as measured by elevated ROS levels and a decreased ratio of glutathione (GSH) to oxidized glutathione (GSSG) in metastasizing cells. Treatment with the antioxidant N-acetyl-cysteine (NAC) enhanced metastatic disease burden, but not subcutaneous tumor growth. The ability of melanoma cells to successfully metastasize was mediated by reversible adaptive metabolic changes that enabled cells to withstand oxidative stress, including increased expression of NADPH-regenerating enzymes and elevated flux through the folate pathway. Inhibition of the folate pathway using methotrexate or knockdown of folate pathway enzymes decreased the frequency of circulating melanoma cells and reduced metastatic burden. Consistent with these findings, Le Gal and colleagues found that NAC treatment augmented lymph node and lung metastasis in a genetically engineered mouse model of malignant melanoma, which was accompanied by a higher GSH/GSSG ratio in metastases. In addition, antioxidants enhanced the migration and invasion of malignant melanoma cells and resulted in increased RHOA activation. Together, these findings demonstrate that oxidative stress limits distant melanoma metastasis in vivo and suggest that antioxidants may enhance tumor progression.

Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015;527:186–91.

Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 2015;7:308re8.

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