One of the hallmarks of cancer is a change in cellular metabolism, a series of chemical reactions so fundamental to life that their alteration makes cancer cells seem creepily malevolent.

Healthy cells take in blood sugar (glucose molecules), which they break down to extract energy. This happens in two phases—one phase that takes place in the cytoplasm and a subsequent phase that occurs inside cellular compartments called mitochondria.

Cancer cells are thought to mostly skip the mitochondrial phase, compensating for the energy they forgo by revving up the first phase and breaking down glucose rapidly to secrete large quantities of lactate—a form of partially digested glucose that has long been regarded as a "waste product."

Some parts of this hypothesis must be true because cancer cells do soak up more glucose than healthy cells; this increased glucose uptake is significant enough to be the basis of an imaging technique used to diagnose cancer in the clinic.

On the other hand, it has been hard to understand how cells could discard most of the energy and substance that can be produced from glucose, like royal food testers taking only one bite of each "dish."

In a new study published in Nature Chemical Biology researchers describe the surprising results of a seemingly simple experiment. Originally undertaken to test a new methodology, their findings unexpectedly challenged this notion of cancer metabolism.

By studying lactate, they showed that cancer cells can run their energy production differently than thought. They have the ability to import the "waste product" lactate into the mitochondria where the rest of the glucose energy can then be extracted.

To study metabolism in an unbiased way, they puts tags (isotope labels) on nutrients so that they can track what becomes of them when they are metabolized by cells.

It didn't turn out as expected. "We saw thousands of labeled signals," author said. "Nearly every lipid in the cell ended up tagged. It was very unexpected and exciting." The cells weren't just extracting extra energy from lactate, they were then using its atoms to make other important building blocks essential to cancer cell growth.

"It's a big transition," author said. "We're going from saying something is thrown away to saying that it makes effectively an entire class of molecules in cancer cells."

Since the finding was so startling, the team ran a series of experiments to ensure that the lactate was actually going into the mitochondria. The experiments not only confirmed that lactate can be transported into the mitochondria, but also demonstrated that an enzyme within the mitochondria metabolizes lactate to produce energy and cellular building blocks.

So why waste effort converting glucose into lactate if it is just going to be transported into the mitochondria anyway?

When cells metabolize glucose in the cytoplasm, it produces electrons. They have to put the electrons somewhere, or the tightly regulated metabolic reactions cannot continue. Healthy cells move the electrons into the mitochondria, but cancer cells make electrons so fast that they can't keep up. This forces cancer cells to stick the electrons on lactate and excrete it, or so it was thought.

"We think what we have found is a work around. Cancer cells stick electrons on lactate, but that doesn't mean the precious nutrient has to be wasted. "It's a case of having your cake and eating it too," author said.

https://medicine.wustl.edu/news/