By Sy Mukherjee and Clifton Leaf
October 16, 2017

Cancer cells are nasty little anarchists. They go where they shouldn’t, subvert authority, co-opt law-abiding cells around them, and break a ton of biological rules in their mindless quest for destruction.

They’re also weird. And one of the most bizarre examples of their rule breaking is how they metabolize sugar. When oxygen is readily available, as it is in the human body, normal cells break down and extract energy from glucose through a process called oxidation. By way of this biochemical machination, cells can extract 36 molecules of ATP, which is like cash money in the body. (Think of it like Bitcoin: Cells do some complex equation-solving and, as a reward, they get something they can spend.)

But cancer cells (mostly) do lots of biochemical work to get less coin. They break down glucose through an ancient 10-step process called glycolysis—which yields them a mere two molecules of ATP for every one of glucose.

With glycolysis, cells can produce energy even in the absence of oxygen, which is what our primordial slime ancestors had to do. It’s also what anaerobic bacteria and yeasts do. They derive energy from sugar by way of fermentation. But in the presence of oxygen, extracting energy from sugar by glycolysis is the equivalent of ironing your socks: It would seem to involve expending a lot of effort for little benefit.

What’s more, cancer cells need gobs of energy to fuel their mad rebellion; rapid cell division, after all, requires plenty of biochemical fuel. And cancer cells gobble up sugar like nobody’s business. (That’s why we’re often able to see tumors on a PET scan, which highlights tissues that rapidly take up an injected sugar called FDG.)

A German biochemist named Otto Warburg, back in the 1920s, was the first to observe these oddball, counterintuitive facts about cancer cells, which he blamed on a defect in their mitochondria, the cell’s energy factories (and my all-time favorite organelles). Indeed, the biochemist believed this aberrant aerobic glycolysis—which later became known as the “Warburg effect”—actually caused cancer, though it wasn’t clear how or why.

The notion was somewhat forgotten for decades, as researchers focused on other theoretical frameworks for cancer and tried to tease out the genetic mutations that transformed cells and drove the disease. But in recent years, the Warburg effect—and the broader metabolic theory of cancer—has had a reawakening. (For those wanting to learn more about it, my friend Travis Christofferson has written an excellent book on the subject.)

Still, as much as the cancer research community has rekindled interest in the metabolic aspects of the disease, there are two big questions that have kept some from embracing it whole hog. The first is why? Why would cancer cells, which require so much energy, evolve to adapt such an inefficient process? And the second is how? By what mechanism would aerobic glycolysis drive the cancer process (or is it, rather, a side effect of the malignant transformation of a cell)?

The first question remains a mystery. But as to the second, a new study published by three Dutch research groups has revealed the possible missing molecular link—or at least a candidate for one of them. Working in the model system of yeast, the teams, after a nine-year effort, identified a connection between a key sugar molecule in the glycolytic pathway (fructose-1,6-bisphosphate) and a critical gene called ras, that’s central to a cell’s ability to proliferate and survive. Ras, importantly, is a so-called oncogene—a gene that, when mutated, can help turn a cell malignant. Mutated forms of ras are found in as many as half of all cancers.

In the paper, published online Friday in the journal Nature Communications, the authors report that a “reciprocal” interaction between ras and the identified sugar molecule “may lock cancer cells in a vicious cycle causing both persistent stimulation of cell proliferation and continued maintenance of overactive glycolysis. This would explain the close correlation between the proliferation rate and aggressive character of cancer cells and their fermentation hyperactivity.”

It’s a “vicious cycle of continued stimulation of cancer development and growth,” said one of the study’s senior authors, Johan Thevelein, in a follow-up press statement—an interaction that seems to “explain the correlation between the strength of the Warburg effect and tumor aggressiveness.”

The finding is a provocative one, surely, and one that may have implications for the diets of cancer patients. For the rest of us, this study is one more piece of evidence about the dangers of excessive sugar consumption. And now, there’s a potential mechanism of action to explain it.

Clifton Leaf, Editor in Chief, FORTUNE
@CliftonLeaf
clifton.leaf@fortune.com

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