Fructose in Diet Linked to Enhanced Tumor Growth

Fructose consumption has risen dramatically over the last five decades, owing primarily 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 demonstrates that dietary fructose enhances tumor formation in animal models of melanoma, breast cancer, and cervical cancer. However, a study published on December 4 in the journal Nature found that fructose does not directly drive malignancies.

Instead, WashU researchers discovered that the liver transforms fructose into nutrients that cancer cells can need, a compelling result that could pave the way for new cancer treatments and therapies.

“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 tool for monitoring tiny molecules as they travel through cells and tissues in the body, the researchers determined that excessive fructose consumption promotes tumor growth by increasing the availability of circulating lipids in the blood. These lipids are the building components of the cell membrane, and cancer cells require them to proliferate.

“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

Cancer cells have long been known to have a strong affinity for glucose, a simple sugar that the body uses as its primary carbohydrate-based energy source.

Fructose has a similar molecular structure to glucose. They are both common sugars with the same chemical formula, but they are metabolized differently by the body. Glucose is digested throughout the body, whereas fructose is mostly metabolized by the small intestine and liver.

Both sugars occur naturally in fruits, vegetables, dairy products, and grains. They are also used as a sweetener in many processed goods. Fructose, in particular, has permeated the American diet during the previous few decades. It is popular in the food business because it is sweeter than glucose.

Prior to the 1960s, people consumed significantly less sugar than they do now. A century ago, the average person ingested only 5-10 pounds of fructose per year. That is roughly equivalent to the weight of a gallon of milk. In the twenty-first century, the figure has risen to the equivalent of fifteen 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 the Siteman Cancer Center at Barnes-Jewish Hospital 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 dramatic increase in dietary fructose consumption over the last few decades, WashU researchers wanted to learn more about how fructose affects tumor formation.

Patti and Fowle-Grider began their experiment by providing fructose-rich diets to tumor-bearing rats and analyzing how quickly their tumors grew. The researchers discovered that additional fructose increased tumor growth without affecting 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.”

However, the next phase in their tests initially confused them. When Fowle-Grider sought to replicate this test by feeding fructose to cancer cells isolated in a dish, they did not respond. “In most cases they grew almost as slowly as if we gave them no sugar at all,” Patti told me.

So, Patti and Fowle-Grider returned to studying alterations in small molecules in the blood of animals fed high-fructose diets. Using metabolomics, they discovered higher amounts of a number of lipid species, including lysophosphatidylcholines. Additional dish testing revealed that liver cells fed fructose produce 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.”

Cancer is defined by the uncontrolled expansion of malignant cells. When a cell divides, it must copy its contents, including membranes. This demands a significant amount of lipids. While lipids can be generated from scratch, cancer cells find it far easier to absorb lipids from their 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, as human fructose consumption has increased, a number of malignancies have become more common among persons under the age of 50. This begs the question of whether the trends are connected.

Patti recently collaborated with Yin Cao from WashU Medicine and other researchers from around the world, none of whom were engaged in this work, to look at potential linkages.

“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 stated that this research could help us establish a therapeutic method to prevent fructose from causing tumor growth utilizing medications.

“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.”

For more information: Gary Patti, Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer, Nature (2024). DOI: 10.1038/s41586-024-08258-3. www.nature.com/articles/s41586-024-08258-3