For more than a century cancer cell metabolism has been viewed as something of a paradox, but newly reported research by scientists at Washington University in St. Louis shows that it might not be such an anomaly. The rate at which tumors consume glucose has been exploited by doctors as a way to diagnose and stage cancer, and has pointed to the possibility that using drugs—or even eating a sugar-free diet—to limit glucose uptake might “starve” cancer cells to death. The newly reported results, which could help to explain the apparently wasteful use of glucose by cancer cells, also raise questions about this strategy.

“We may need to rethink how best to target glucose metabolism in cancer,” said Gary Patti, PhD, the Michael and Tana Powell Professor of Chemistry in Arts & Sciences and of genetics and of medicine at the School of Medicine. “If cancer cells take up more glucose than they need, and using it wastefully is not a driver of disease, then glucose metabolism may not be as attractive of a therapeutic target as we had hoped.”

Patti, a member of Siteman Cancer Center at Barnes-Jewish Hospital and the School of Medicine, is senior author of the team’s published paper in Molecular Cell, in a paper titled “Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.”

Glucose, a common sugar in food, is one of the most important nutrients in the body. Cancer cells tend to consume it at an astounding pace. At first glance that might seem to make good sense because cancer cells have a lot of synthesis to do. After all, as tumors grow rapidly, each cell has to replicate its entire contents.

But it’s not that simple. Cancer cells don’t use the glucose very efficiently. Instead of sucking all of the energy they can out of glucose, they release most of it as a waste material, lactate. Biochemist Otto Warburg first discovered the wasteful nature of tumors in the 1920s.

“Aerobic glycolysis, also known as the Warburg effect, is characterized by a high rate of glucose fermentation to lactate irrespective of oxygen availability,” the authors explained. “This metabolic phenotype has long been associated with rapidly dividing cancer cells.” However, they continued, “… nearly a 100 years after first being described by Otto Warburg, there continues to be a lack of clarity about why proliferating cells engage in aerobic glycolysis.”

Mitochondria are tiny compartments inside cells, and what goes in and out of them is tightly controlled. So, to explain why more energy isn’t harvested from glucose, Warburg postulated that mitochondria are damaged in cancer cells. It’s now known that this isn’t true Patti noted. Mitochondria are functional and, in fact, active in most cancers. “But that leaves a persistent and vexing question unanswered: Why do cancer cells metabolize so little of the glucose they consume in mitochondria?”

Patti added, “I think what has been confounding is that there has been this notion that cancer cells prefer not to oxidize glucose in their mitochondria. Perhaps as a legacy of Warburg’s original thinking or maybe because it happens so extensively, the assumption has often been that cancer cells want to use glucose wastefully.”

All sorts of explanations have been offered as to why cancer cells might want to be wasteful with their glucose. However, Patti and his team contend that these rationalizations may be off the mark, and that cancer metabolism may not actually be as unusual as scientists thought. It’s possible that cancer cells really do want to metabolize glucose in their mitochondria, and they do so. But that’s only until they can’t.

The newly reported work showed that cancer cells only waste glucose because transport into mitochondria is too slow. “When we restrict the amount of glucose taken up by cancer cells, almost all of it makes its way into mitochondria,” Patti said. “But as glucose consumption is increased, the speed of moving glucose-derived molecules into mitochondria can’t keep up.”

An analogy might be a bathtub faucet that is delivering water faster than the drain can remove it. Eventually, the water overflows onto the floor. “This is not a radically new metabolic paradigm,” Patti said. “Most cells do prefer to oxidize glucose in mitochondria rather than excrete it as waste. Our data suggest that cancer cells are not an exception. They appear to follow the same biochemical patterns as other cells.”

Patti’s team applied metabolomics technology to make their discovery. “During the past decade, advances in the field of metabolomics and mass spectrometry have been extraordinary,” Patti noted. “We have now reached a point where measuring molecules in single cells is even possible.”

For their reported study the researchers combined metabolomics with stable isotope tracers. This allowed them to tag different parts of glucose so that they could track it inside of cells, watching the speed at which things entered mitochondria or were excreted from cells. Using this approach the scientists discovered that the normal pathways for transporting fuel were getting outpaced, or saturated, in cancer cells.

The data revealed that the amount of glucose excreted as lactate in cancer cells was not correlated with the rate of proliferation, but instead strongly correlated with the activity of the malate-aspartate-shuttle (MAS) and glycerol 3-phosphate shuttle (G3PS) in mitochondria. Taken together, the team noted, “… these findings suggest that fermentation occurs in proliferating cells under oxygenated conditions because glycolysis outpaces electron transport into mitochondria …”

Patti concluded, “To extract the maximum amount of energy from glucose, cells must transport its transformation products into mitochondria. There are certain biochemical rules that metabolism is supposed to follow. It’s been interesting to think about why tumors might be allowed to break them. However, the findings we report here demonstrate that cancer cells do follow conventional principles.”

The role of glucose fermentation in proliferating cancer cells may be analogous to that in healthy tissues during normal physiological states, such as during prolonged exercise, the team continued. “In all cases, glucose fermentation is a secondary mechanism to replenish cytosolic NADH when the mitochondrial shuttle systems are insufficient,” the investigators noted. “Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.”