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. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All 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 inefficient metastasizers. 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 upon NADPH-generating enzymes in the folate pathway. Anti-oxidants 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 tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

The mitochondrial dynamics in cancer and immune-surveillance

“…Elevated ROS can also promote upregulation of several oncogenic signalling pathways, such as Ras/MAPK/ERK, PI3K/Akt and IKK/KF-B, and can favour tumor cell proliferation, apoptosis-resistance and cell migration (see [112] for a review). On the contrary, at later stages of cancer progression, a controlled reduction of ROS amounts in tumor cells promotes tumor growth and metastasis formation, as in melanoma and lung cancer mouse models [114,115], this indicating an important correlation between ROS accumulation and cancer stage. Further, the pro-angiogenesis activity of tumor cells becomes crucial for their survival in a microenvironment progressively more hypoxic, for a continuous supply of nutrients and oxygen [116].…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…These ob ser va tions raise the im por tance of ROS lev els and com part men tal iza tion on their ef fect on cell sig nal ing. In deed, both mi to chon dria tar geted su per ox ide scav enger mi toTEMPO [11] and methotrex ate [194] in ter fer ing with fo late me tab o lism can de crease the oc cur rence of metas ta sis in melanoma mod els, whereas the gen eral an tiox i dant N acetyl cys teine does not [194]. In these mod els, N acetyl cys teine rather pro moted metas ta sis [194].…”

“…Both a par tial in hi bi tion and an over load of the elec tron trans port chain re sult in elec tron leak and were shown to pro mote tu mor metas ta sis in a mtROS de pen dent way [11,193]. Con versely, ox ida tive stress in hib ited dis tant metas ta sis in a melanoma model, as cir cu lat ing metasta tic cells, com pared to can cer cells of the pri mary tu mor, were char ac ter ized by de creased stores of re duced glu tathione and an up reg u la tion of NADPH gen er at ing and a down reg u la tion of NADPH con sum ing en zymes of the fo late path way [194]. These ob ser va tions raise the im por tance of ROS lev els and com part men tal iza tion on their ef fect on cell sig nal ing.…”

Coping with the metabolic stress of leaving home

“…In turn, these antioxidants can be regenerated using the reducing power from the metabolite NADPH, which is generated by multiple metabolic pathways throughout the cell. While the role of ROS in cancer is complex, several recent reports have clearly shown that cellular antioxidant systems are required for multiple steps of tumorigenesis, including tumor initiation [3] and metastasis [4], both of which require anchorage-independent growth. This suggests that the ability to detoxify ROS upon ECM detachment is a critical component of anchorage independence and essential for tumor development and progression.…”

“…This suggests that the ability to detoxify ROS upon ECM detachment is a critical component of anchorage independence and essential for tumor development and progression. Indeed, provision of exogenous antioxidants can promote anoikis resistance [1], metastasis [4], and cancer incidence [5].…”