With Johan Thevelein, PhD, at the Laboratory of Molecular Cell Biology at KU Leuven and the VIB Center for Microbiology
By Sarah DiGiulio
Whether or not there's a link between how much sugar we eat and cancer has long been a topic of interest among cancer biologists and others caring and designing treatments for patients with cancer. A new study reveals some key data on the matter and answers important questions, according to the researchers.
"It was previously known that cancer cells have an elevated rate of sugar breakdown compared to regular human cells and prefer fermentation over respiration," Johan Thevelein, PhD, Professor and Head of the Laboratory of Molecular Cell Biology at KU Leuven and Group Leader at the VIB Center for Microbiology, Flanders, Belgium, told Oncology Times—meaning that tumors convert much higher amounts of sugar into lactic acid than noncancerous human cells convert sugar into carbon dioxide.
"This behavior of cancer cells is bizarre because fermentation produces about 15 times less energy than respiration and, since cancer cells multiply much faster than regular human cells, they actually need much more energy than regular cells," Thevelein added.
The key finding from the group's new research conducted over 9 years is the identification of the mechanism by which the elevated rate of sugar breakdown stimulates tumor growth.
"Our conclusion is that the beneficial effect of sugar-poor diets may not be a hype or a phantom, but may have a real scientific basis," Thevelein said.
"The key finding is that an intermediate compound in the sugar breakdown pathway (fructose 1,6-bisphosphate) is a potent activator of the Ras proteins, which are important controllers of cell proliferation in human cancer cells," he explained.
The group first conducted experiments in yeast cells because they have the same preference for fermentation over respiration as cancer cells—and then conducted experiments in cancer cells to show that the same mechanism was occurring. The experiments took a much closer look at cancer cells under a much finer microscope than many practicing oncologists may deal with on a daily basis, but they have important implications for patients undergoing treatment highlighting the risk of stimulating cancer with high sugar feeding, Thevelein said. The paper shows a clear link between sugar breakdown and the Ras protein, an oncogenic driver, he explained.
Here's what else Thevelein told Oncology Times about the findings—which were published online ahead of print in Nature Communications (2017; doi:10.1038/s41467-017-01019-z)—as well as what practicing cancer care providers need to know.
1. What is the Warburg effect—and why is your research that set out to better understand this phenomenon important?
"The Warburg effect is the preference of cancer cells for fermentation over respiration. It was discovered by the German biochemist Otto Warburg about 80 years ago. Up to the appearance of our paper, it had remained unclear whether the Warburg effect was merely a symptom of cancer or whether it could also play a role in stimulation of the cancer.
"This Warburg effect is also present in yeast cells (where it is called the Crabtree effect). When you add sugar to yeast cells, they will ferment it to ethanol (and make beer, wine, etc.) in spite of aerobic conditions. The fermentation pathway for sugar breakdown in yeast and human cells is the same except for the last step: in yeast, ethanol is the final product, [whereas] in mammalian or cancer cells lactic acid is the final product.
"We have been doing research on the mechanisms by which yeast cells sense nutrients for 30 years, and we have elucidated the glucosesensing network in great detail. Now, it turns out that an important part, the activation of Ras by fructose 1,6-bisphosphate, is conserved between yeast and mammalian and cancer cells."
2. Do the findings have any implications for whether or not sugar in the diet might cause cancer—or whether a lower-sugar diet could help prevent cancer?
"No, we certainly do not claim that sugar can cause cancer in healthy people or that sugar-poor diets may reduce the risk of cancer. Regular human cells have proper mechanisms to break down sugar in a controlled manner through respiration, and they can also properly handle an occasional switch to fermentation, as happens for instance in muscle cells.
"It has to be mentioned, however, that there is a clear link between obesity and a higher risk of getting cancer—and this applies to multiple types of cancer. Why this link exists is unknown. Obesity can disturb the proper release of insulin from the beta cells of the pancreas, and insulin of course is crucial for proper control of glucose levels in the blood. However, at this moment there is no scientific evidence to link obesity to susceptibility to cancer in this way."
3. What is the bottom line that oncologists and cancer providers should know about your work? Does it have implications for how they should care for patients with cancer?
"Sugar can stimulate the aggressiveness of cancer, and that should be taken into account in providing sugar to cancer patients, especially high levels of rapidly used sugars like glucose.
"There are some reports in the scientific literature that [suggest] sugar-poor diets may be beneficial for cancer patients, helping them to recover, for instance, during chemotherapy. However, this is a controversial issue since there was no scientific evidence up to now for a mechanism linking sugar breakdown to cancer.
"This is what we have provided with our paper: a clear mechanistic link between sugar breakdown and a protein, Ras, that is very well known for its oncogenic potency.
"When cancer patients need an energy-rich diet to strengthen their health in order to better support the burden of chemotherapy, it might be advisable to avoid high-sugar diets and use other energy-rich diets instead. This is an area that now clearly needs more extensive clinical investigation."