Research Reveals How Fructose in Diet Enhances Tumor Growth

Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener in beverages and ultra-processed foods. New research from Washington University in St. Louis shows that dietary fructose promotes tumor growth in animal models of melanoma, breast cancer and cervical cancer. However, fructose does not directly fuel tumors, according to the study published Dec. 4 in the journal Nature.

Instead, WashU scientists discovered that the liver converts fructose into usable nutrients for cancer cells, a compelling finding that could open up new avenues for care and treatment of many different types of cancer.

“The idea that you can tackle cancer with diet is intriguing,” said Gary Patti, the Michael and Tana Powell Professor of Chemistry in Arts & Sciences and a professor of genetics and of medicine at the School of Medicine, all at WashU.

“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,” Patti said. “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 the study’s first author, Ronald Fowle-Grider, 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 — a method of profiling small molecules as they move through cells and across different tissues in the body — the researchers concluded that one way in which high levels of fructose consumption promote tumor growth is by increasing the availability of circulating lipids in the blood. These lipids are building blocks for the cell membrane, and cancer cells need them to grow.

“We looked at numerous different cancers in various tissues throughout the body, and they all followed the same mechanism,” Patti said.

The corn syrup era

Scientists have long recognized that cancer cells have a strong affinity for glucose, a simple sugar that is the body’s preferred carbohydrate-based energy source.

In terms of its chemical structure, fructose is similar to glucose. They are both common types of sugar, with the same chemical formula, but they differ in how the body metabolizes them. Glucose is processed throughout the whole body, while fructose is almost entirely metabolized by the small intestine and liver.

Both sugars are found naturally in fruits, vegetables, dairy products and grains. They are also added as sweeteners in many processed foods. Fructose, in particular, has penetrated the American diet over the last few decades. It is favored by the food industry because it is sweeter than glucose.

Prior to the 1960s, people consumed relatively little fructose compared with today’s numbers. A century ago, an average person consumed just 5-10 pounds of fructose per year. To put it in familiar terms, that is roughly equal to the weight of a gallon of milk. In the 21st century, that number has increased to be as high as the equivalent of 15 gallons of milk.

“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 Patti, who is also a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and the Center for Human Nutrition at WashU 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.”

Cancer’s appetite for fructose

Given the rapid rise in the consumption of dietary fructose over recent decades, the WashU researchers wanted to know more about how fructose impacts the growth of tumors.

Patti and Fowle-Grider began their investigation by feeding tumor-bearing animals a diet rich in fructose, then measuring 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.”

But the next step in their experiments initially stumped them. 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.

So, Patti and Fowle-Grider went back to looking at changes in the small molecules in the blood of animals fed high-fructose diets. 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.

“Interestingly, the cancer cells themselves were unable to use fructose readily as a nutrient because they do not express the right biochemical machinery,” Patti said. “Liver cells do. This allows them to convert fructose into LPCs, which they can secrete to feed tumors.”

A defining characteristic of cancer is uncontrolled proliferation of malignant cells. Each time a cell divides, it must replicate its contents, including membranes. This requires a substantial amount of lipids. While lipids can be synthesized from scratch, it is much easier for cancer cells to simply take lipids up from their surrounding environment.

“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.”

Avoiding fructose

Interestingly, over the same period of time when human fructose consumption has surged, a number of cancers have become increasingly more prevalent among people under the age of 50. This raises the question whether the trends are linked. With $25 million in support from Cancer Grand Challenges, Patti recently teamed up with Yin Cao, an associate professor of surgery at WashU Medicine, and other investigators from around the world, none of whom were involved in this study, to investigate possible connections.

“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.

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This research was funded in part by the National Institutes of Health (NIH) (R35 ES028365)