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Oxidative stress inhibits distant metastasis by human melanoma cells.

Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ - Nature (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

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.

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Clinical data on the melanomas used in this study and summary of their metastatic behavior in NSG micea) Summary of the clinical characteristics of the melanomas used in this study at the time of banking, as well as patient outcome after banking, and metastasis patterns upon transplantation of banked tumours into NSG mice. Melanomas were stratified into efficient and inefficient metastasizers. Efficient metastasizers formed distant metastases in patients and in NSG mice. Inefficient metastasizers did not form distant metastases in patients or distant macrometastases in NSG mice. They did form micrometastases in the lung, but not outside of the lung in the period of time it took for subcutaneous tumours to grow to 2 cm in diameter (when the mice had to be euthanized in these experiments27). Nonetheless, most of the inefficient metastasizers have the ability to form macrometastases if given enough time (data not shown). b) Growth rates of subcutaneous tumours in NSG mice after subcutaneous transplantation of 100 cells. Statistical significance was assessed using two-tailed Student’s t-test. c) Clinical characteristics of the patients from whom melanomas were obtained at the time of banking and upon subsequent clinical follow up. The tumours were confirmed to be melanomas by clinical dermatopathology. The tumours were independently confirmed to be melanomas after xenografting in mice by histological and flow cytometric analysis of melanoma markers (Extended data figure 1) as well as examination by a clinical dermatopathologist.
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Figure 5: Clinical data on the melanomas used in this study and summary of their metastatic behavior in NSG micea) Summary of the clinical characteristics of the melanomas used in this study at the time of banking, as well as patient outcome after banking, and metastasis patterns upon transplantation of banked tumours into NSG mice. Melanomas were stratified into efficient and inefficient metastasizers. Efficient metastasizers formed distant metastases in patients and in NSG mice. Inefficient metastasizers did not form distant metastases in patients or distant macrometastases in NSG mice. They did form micrometastases in the lung, but not outside of the lung in the period of time it took for subcutaneous tumours to grow to 2 cm in diameter (when the mice had to be euthanized in these experiments27). Nonetheless, most of the inefficient metastasizers have the ability to form macrometastases if given enough time (data not shown). b) Growth rates of subcutaneous tumours in NSG mice after subcutaneous transplantation of 100 cells. Statistical significance was assessed using two-tailed Student’s t-test. c) Clinical characteristics of the patients from whom melanomas were obtained at the time of banking and upon subsequent clinical follow up. The tumours were confirmed to be melanomas by clinical dermatopathology. The tumours were independently confirmed to be melanomas after xenografting in mice by histological and flow cytometric analysis of melanoma markers (Extended data figure 1) as well as examination by a clinical dermatopathologist.

Mentions: We obtained four efficiently (UT10, M481, M405, and M514) and four inefficiently (M597, M528, M610, and M498) metastasizing melanomas from patients. All expressed melanoma markers (Extended data figure 1). The efficiently metastasizing melanomas formed distant metastases in patients and in NSG mice after subcutaneous injection (Extended data figure 2a).


Oxidative stress inhibits distant metastasis by human melanoma cells.

Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ - Nature (2015)

Clinical data on the melanomas used in this study and summary of their metastatic behavior in NSG micea) Summary of the clinical characteristics of the melanomas used in this study at the time of banking, as well as patient outcome after banking, and metastasis patterns upon transplantation of banked tumours into NSG mice. Melanomas were stratified into efficient and inefficient metastasizers. Efficient metastasizers formed distant metastases in patients and in NSG mice. Inefficient metastasizers did not form distant metastases in patients or distant macrometastases in NSG mice. They did form micrometastases in the lung, but not outside of the lung in the period of time it took for subcutaneous tumours to grow to 2 cm in diameter (when the mice had to be euthanized in these experiments27). Nonetheless, most of the inefficient metastasizers have the ability to form macrometastases if given enough time (data not shown). b) Growth rates of subcutaneous tumours in NSG mice after subcutaneous transplantation of 100 cells. Statistical significance was assessed using two-tailed Student’s t-test. c) Clinical characteristics of the patients from whom melanomas were obtained at the time of banking and upon subsequent clinical follow up. The tumours were confirmed to be melanomas by clinical dermatopathology. The tumours were independently confirmed to be melanomas after xenografting in mice by histological and flow cytometric analysis of melanoma markers (Extended data figure 1) as well as examination by a clinical dermatopathologist.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644103&req=5

Figure 5: Clinical data on the melanomas used in this study and summary of their metastatic behavior in NSG micea) Summary of the clinical characteristics of the melanomas used in this study at the time of banking, as well as patient outcome after banking, and metastasis patterns upon transplantation of banked tumours into NSG mice. Melanomas were stratified into efficient and inefficient metastasizers. Efficient metastasizers formed distant metastases in patients and in NSG mice. Inefficient metastasizers did not form distant metastases in patients or distant macrometastases in NSG mice. They did form micrometastases in the lung, but not outside of the lung in the period of time it took for subcutaneous tumours to grow to 2 cm in diameter (when the mice had to be euthanized in these experiments27). Nonetheless, most of the inefficient metastasizers have the ability to form macrometastases if given enough time (data not shown). b) Growth rates of subcutaneous tumours in NSG mice after subcutaneous transplantation of 100 cells. Statistical significance was assessed using two-tailed Student’s t-test. c) Clinical characteristics of the patients from whom melanomas were obtained at the time of banking and upon subsequent clinical follow up. The tumours were confirmed to be melanomas by clinical dermatopathology. The tumours were independently confirmed to be melanomas after xenografting in mice by histological and flow cytometric analysis of melanoma markers (Extended data figure 1) as well as examination by a clinical dermatopathologist.
Mentions: We obtained four efficiently (UT10, M481, M405, and M514) and four inefficiently (M597, M528, M610, and M498) metastasizing melanomas from patients. All expressed melanoma markers (Extended data figure 1). The efficiently metastasizing melanomas formed distant metastases in patients and in NSG mice after subcutaneous injection (Extended data figure 2a).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

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.

Show MeSH
Related in: MedlinePlus