title: Oxidative stress inhibits distant metastasis by human melanoma cells.
abstract: 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.
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Piskounova
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Michalis
authors.initials: M
authors.lastname: Agathocleous
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Malea M
authors.initials: MM
authors.lastname: Murphy
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zeping
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Huddlestun
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: A Marilyn
authors.initials: AM
authors.lastname: Leitch
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008545:Melanoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D008727:Methotrexate / Q000494:pharmacology; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens; D009249:NADP / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000172:deficiency / Q000378:metabolism; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000975:Antioxidants; D005492:Folic Acid; D008727:Methotrexate; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D015778:Minor Histocompatibility Antigens; D009249:NADP; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000099295:Formyltetrahydrofolate Dehydrogenase; C539735:MTHFD1 protein, human