Oxidative stress inhibits distant metastasis by human melanoma cells

By E. Piskounova, Michalis Agathocleous, M. Murphy, Zeping Hu, Sara E. Huddlestun, Zhiyu Zhao, A. Leitch, Timothy Johnson, Ralph J. Deberardinis, Sean J. Morrison. Nature, 2015

1,164 citations recorded by the source corpus.

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.

Subfields: Biotechnology, Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/2a38fff8e9de6c6e84da1db25d3b4f97cff4817c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biotechnology

1. Navdeep S. Chandel
2. Arthur W. Lambert
3. Guido Kroemer
4. R. Weinberg
5. D. Pattabiraman
6. Lisa M. Coussens

In Cancer Research

1. Ralph J. Deberardinis
2. M. V. Vander Heiden
3. Navdeep S. Chandel
4. Guido Kroemer
5. L. Galluzzi
6. E. White
7. D. Y. Gui
8. Alba Luengo

In Immunology

1. L. Galluzzi
2. Guido Kroemer
3. Antoni Ribas
4. Arthur W. Lambert
5. A. Dinkova-Kostova
6. W. Zong
7. J. Hayes
8. R. Weinberg

Citations in the corpus

• Mitochondrial metabolism and cancer (2017, background): “Conversely, in the presence of severe oxidative stress, ROS de facto inhibit metastatic dissemination, most likely as a direct consequence of reduced fitness and RCD or cellular senescence [159-161].”
• Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress (2018, background): “Metastasizingmelanoma cells have been shown to experience increased oxidative stress, with successful metastasis dependent on increased GSH regeneration (Piskounova et al., 2015).”
• EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “For instance, cancer cells have been shown to experience higher levels of oxidative stress both in the circulation and in the parenchyma of a distant tissue (Piskounova et al., 2015).”
• Role of Glutathione in Cancer: From Mechanisms to Therapies (2020, background): “This may be related to the findings that high levels of ROS can mitigate metastasis and tumorigenesis, for example in cancer cells detaching from the extracellular matrix [42,43].”
• Targeting Metabolism for Cancer Therapy (2017, background): “Emerging work suggests that increased serine synthesis may be particularly important for maintaining redox homeostasis during metastasis (Piskounova et al., 2015).”
• Fundamentals of cancer metabolism (2016, background): “The ability to up-regulate antioxidant proteins and increase flux through NADPH-producing metabolic pathways enables distant metastasis to occur (8).”