Hypoxia-resistant profile implies vulnerability of cancer stem cells to physiological agents, which suggests new therapeutic targets

Abstract

We have previously shown that peculiar metabolic features of cell adaptation and survival in hypoxia imply growth restriction points that are typical of embryonic stem cells and disappear with differentiation. Here we provide evidence that such restrictions can be exploited as specific antiblastic targets by physiological factors such as pyruvate, tetrahydrofolate, and glutamine. These metabolites act as powerful cytotoxic agents on cancer stem cells (CSCs) when supplied at doses that perturb the biochemical network, sustaining the resumption of aerobic growth after the hypoxic dormant state. Experiments were performed in vivo and in vitro using CSCs obtained from various anaplastic tumors: human melanoma, leukemia, and rat hepatoma cells. Pretreatment of melanoma CSCs with pyruvate significantly reduces their self-renewal in vitro and tumorigenicity in vivo. The metabolic network underlying the cytotoxic effect of the physiological factors was thoroughly defined, principally using AH130 hepatoma, a tumor spontaneously reprogrammed to the embryonic stem stage. This network, based on a tight integration of aerobic glycolysis, cellular redox state, and folate metabolism, is centered on the cellular NADP/NADPH ratio that controls the redox pathway of folate utilization in purine synthesis. On the whole, this study indicates that pyruvate, FH4, and glutamine display anticancer activity, because CSCs are committed to survive and maintain their stemness in hypoxia. When CSC need to differentiate and proliferate, they shift from anaerobic to aerobic status, and the few mitochondria available makes them susceptible to the injury of the above physiological factors. This vulnerability might be exploited for novel therapeutic treatments.

Novel Pathway for Hypoxia-Induced Proliferation and Migration in Human Mesenchymal Stem Cells: Involvement of HIF-1α, FASN, and mTORC1

“…Taken together, hypoxia stimulates FASN expression via HIF‐1α/SCAP/SREBP1 pathway. Besides, several recent studies reported that alteration of cellular metabolites ratios, such as NADP/NADPH, by hypoxia has also an important role in the regulation of various stem cell functions such as cell cycle and self‐renewal activities . These findings indicate that change of cellular metabolite ratios may be another pathway, in addition to the HIF1α/SCAP/SREBP1 pathway, involved in the regulation of lipid metabolism in UCB‐hMSCs.…”

Metabolic regulation of glioma stem-like cells in the tumor micro-environment

“…Cells undergo metabolic fluctuations during differentiation under hypoxia, going between glycolysis and oxidative phosphorylation to overcome mitochondrial deficiencies [51]. It is quite possible that CSCs are able to similarly modulate redox status in order to regulate their own stem maintenance.…”

Hypoxia in Mesenchymal Stem Cell

“…Change in cellular metabolite ratios may be another pathway, in addition to the HIF1a/SCAP/SREBP1 pathway, involved in the regulation of lipid metabolism in UCB-hMSCs. Some studies reported that alteration of cellular metabolite ratios, such as NADP/NADPH, by hypoxia has also an important role in the regulation of various stem cell functions such as cell cycle and selfrenewal activities [126,127].…”