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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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Related in: MedlinePlus

Expression of melanoma markers by xenografted melanomasa) M405, M481, M514, M528, M498, M597, M610, and UT10 tumours were consistently positive for S100, a marker used clinically to diagnose melanoma. b) Flow cytometric analysis of xenografted tumour cells that were HLA-ABC+ and negative for mouse CD31/CD45/Ter119 showed that these cells were usually positive for Melanoma Cell Adhesion Molecule (MCAM) and Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP). Both of the tumors that lacked MCSP staining (M514 and M597) were heavily pigmented and expressed other melanoma markers (such as S100 and MCAM).
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Figure 4: Expression of melanoma markers by xenografted melanomasa) M405, M481, M514, M528, M498, M597, M610, and UT10 tumours were consistently positive for S100, a marker used clinically to diagnose melanoma. b) Flow cytometric analysis of xenografted tumour cells that were HLA-ABC+ and negative for mouse CD31/CD45/Ter119 showed that these cells were usually positive for Melanoma Cell Adhesion Molecule (MCAM) and Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP). Both of the tumors that lacked MCSP staining (M514 and M597) were heavily pigmented and expressed other melanoma markers (such as S100 and MCAM).

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)

Expression of melanoma markers by xenografted melanomasa) M405, M481, M514, M528, M498, M597, M610, and UT10 tumours were consistently positive for S100, a marker used clinically to diagnose melanoma. b) Flow cytometric analysis of xenografted tumour cells that were HLA-ABC+ and negative for mouse CD31/CD45/Ter119 showed that these cells were usually positive for Melanoma Cell Adhesion Molecule (MCAM) and Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP). Both of the tumors that lacked MCSP staining (M514 and M597) were heavily pigmented and expressed other melanoma markers (such as S100 and MCAM).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Expression of melanoma markers by xenografted melanomasa) M405, M481, M514, M528, M498, M597, M610, and UT10 tumours were consistently positive for S100, a marker used clinically to diagnose melanoma. b) Flow cytometric analysis of xenografted tumour cells that were HLA-ABC+ and negative for mouse CD31/CD45/Ter119 showed that these cells were usually positive for Melanoma Cell Adhesion Molecule (MCAM) and Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP). Both of the tumors that lacked MCSP staining (M514 and M597) were heavily pigmented and expressed other melanoma markers (such as S100 and MCAM).
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