Metabolic state of glioma stem cells and nontumorigenic cells

Abstract

Gliomas contain a small number of treatment-resistant glioma stem cells (GSCs), and it is thought that tumor regrowth originates from GSCs, thus rendering GSCs an attractive target for novel treatment approaches. Cancer cells rely more on glycolysis than on oxidative phosphorylation for glucose metabolism, a phenomenon used in 2-[ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography imaging of solid cancers, and targeting metabolic pathways in cancer cells has become a topic of considerable interest. However, if GSCs are indeed important for tumor control, knowledge of the metabolic state of GSCs is needed. We hypothesized that the metabolism of GSCs differs from that of their progeny. Using a unique imaging system for GSCs, we assessed the oxygen consumption rate, extracellular acidification rate, intracellular ATP levels, glucose uptake, lactate production, PKM1 and PKM2 expression, radiation sensitivity, and cell cycle duration of GSCs and their progeny in a panel of glioma cell lines. We found GSCs and progenitor cells to be less glycolytic than differentiated glioma cells. GSCs consumed less glucose and produced less lactate while maintaining higher ATP levels than their differentiated progeny. Compared with differentiated cells, GSCs were radioresistant, and this correlated with a higher mitochondrial reserve capacity. Glioma cells expressed both isoforms of pyruvate kinase, and inhibition of either glycolysis or oxidative phosphorylation had minimal effect on energy production in GSCs and progenitor cells. We conclude that GSCs rely mainly on oxidative phosphorylation. However, if challenged, they can use additional metabolic pathways. Therefore, targeting glycolysis in glioma may spare GSCs.

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

“…Glioblastoma is a deadly brain tumor for which there are limited therapies and chemoradioresistance remains a serious problem to be conquered. Altered glucose metabolism in glioblastoma has been extensively investigated in vitro (5,24,25) and, more recently, in vivo in patients (26) and in human orthotopic glioblastoma models (27). These studies established that glucose is oxidized in the citric acid cycle in addition to confirming that there is a significant fraction of glucose that is shunted to lactate generation.…”

Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells

“…So it is believed that PKM2 plays a key role in the channeling of glucose carbons either into catabolic or into anabolic pathways [14,15]. But not all of the tumors express PKM2 only; there might be different expressing patterns and roles of PKM2 in different tumors (19,20).…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Over the last few years, a grow ing body of ev i dence has been ob tained sug gest ing that can cer ini ti at ing cells/can cer stem cells (CICs/ CSCs) dif fer in their me tab o lism from that of the bulk tu mor mass [235,236], al though there is so far no con sen sus on this [201]. Can cer cell stem ness can arise from EMT [203], but not nec es sar ily so [204].…”