High-fructose corn syrup, a sweetener made from corn starch, is widely found in common foods. Due to its widespread use, the consumption of fructose has increased over the past five decades.
“If you go through your pantry and look for the items that contain high-fructose corn syrup, which is the most common form of fructose, it is pretty astonishing,” said Gary Patti, PhD, professor of genetics and of medicine at the Washington University School of Medicine. “Almost everything has it. It’s not just candy and cake, but also foods such as pasta sauce, salad dressing and ketchup,” he said. “Unless you actively seek to avoid it, it’s probably part of your diet.”
It has been suggested previously that fructose promotes the growth of some tumors directly—by serving as a fuel. Now, new research from the Patti lab shows that dietary fructose promotes tumor growth in animal models of melanoma, breast cancer, and cervical cancer after being converted in the liver.
This work is published in Nature in the paper, “Dietary fructose enhances tumor growth indirectly via interorgan lipid transfer.”
Fructose does not directly fuel tumors. The authors note that the cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). However, the liver converts fructose into usable nutrients for cancer cells. Primary hepatocytes did express KHK-C, they write, “resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs).”
“The idea that you can tackle cancer with diet is intriguing,” said Patti. “When we think about tumors, we tend to focus on what dietary components they consume directly. You put something in your body, and then you imagine that the tumor takes it up. But humans are complex. What you put in your body can be consumed by healthy tissue and then converted into something else that tumors use.”
“Our initial expectation was that tumor cells metabolize fructose just like glucose, directly utilizing its atoms to build new cellular components such as DNA. We were surprised that fructose was barely metabolized in the tumor types we tested,” said Ronald Fowle-Grider, PhD, a postdoctoral fellow in Patti’s lab. “We quickly learned that the tumor cells alone don’t tell the whole story. Equally important is the liver, which transforms fructose into nutrients that the tumors can use.”
Using metabolomics, the researchers uncovered that the mechanism includes an increase in the availability of circulating lipids in the blood. “We looked at numerous different cancers in various tissues throughout the body, and they all followed the same mechanism,” Patti said.
The researchers fed tumor-bearing animals a diet rich in fructose, then measured how quickly their tumors grew. The researchers found that added fructose promoted tumor growth without changing body weight, fasting glucose, or fasting insulin levels.
“We were surprised to see that it had a rather dramatic impact. In some cases, the growth rate of the tumors accelerated by two-fold or even higher,” Patti said. “Eating a lot of fructose was clearly very bad for the progression of these tumors.”
When Fowle-Grider attempted to repeat a version of this test by feeding fructose to cancer cells isolated in a dish, the cells did not respond. “In most cases they grew almost as slowly as if we gave them no sugar at all,” Patti said.
Using metabolomics, they identified elevated levels of a variety of lipid species, including lysophosphatidylcholines (LPCs). Additional dish tests showed that liver cells that were fed fructose release LPCs.
More specifically, they write, in co-culture experiments, “hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumor growth.”
“Over the past few years, it’s become clear that many cancer cells prefer to take up lipids rather than make them,” Patti noted. “The complication is that most lipids are insoluble in blood and require rather complex transport mechanisms. LPCs are unique. They might provide the most effective and efficient way to support tumor growth.”
“It will be exciting to better understand how dietary fructose influences cancer incidence. But one take-home message from this current study is that if you are unfortunate enough to have cancer, then you probably want to think about avoiding fructose. Sadly, that is easier said than done,” Patti said.
Aside from dietary intervention, the study authors said that this research could help us develop a way to prevent fructose from driving tumor growth therapeutically, using drugs.
“An implication of these findings is that we do not have to limit ourselves to therapeutics that only target disease cells,” Patti said. “Rather, we can think about targeting the metabolism of healthy cells to treat cancer. This has worked with mice in our study, but we would like to take advantage of our observations and try to improve the lives of patients.” The study authors are working with clinical partners at WashU Medicine to explore a clinical trial related to fructose in the diet.
