In recent decades, there has been a remarkable surge in fructose consumption, largely driven by the extensive use of high-fructose corn syrup as a sweetener in beverages and highly processed edibles. Groundbreaking research from Washington University in St. Louis has now unearthed a disturbing link: dietary fructose appears to accelerate tumor growth in animal models of melanoma, breast cancer, and cervical cancer. However, as reported in the December 4th issue of the journal Nature, fructose doesn’t directly power tumors.
Rather, the scientists at WashU made a startling discovery. The liver plays a pivotal role, converting fructose into nutrients that cancer cells can utilize, potentially opening novel pathways for cancer care and treatment across multiple types.
“Exploring the idea that diet could combat cancer is truly captivating,” remarks Gary Patti, the Michael and Tana Powell Professor of Chemistry in Arts & Sciences and a professor in genetics and medicine at the School of Medicine, WashU.
Patti elaborates, “When we consider tumors, our focus often narrows to what dietary elements they directly ingest. We assume that what we consume is directly taken up by the tumor. But humans are complex organisms. What enters our bodies can be metabolized by healthy tissues and then transformed into something beneficial for tumors.”
Ronald Fowle-Grider, the study’s first author and a postdoctoral fellow in Patti’s lab, adds, “Our initial presumption was that tumor cells would metabolize fructose like glucose, using its atoms to construct new cellular components such as DNA. But we were taken aback when we found that fructose was scarcely metabolized in the tumor types we examined. It quickly became evident that the tumor cells alone don’t tell the whole story; the liver, which transforms fructose into nutrients tumors can use, is equally crucial.”
Employing metabolomics – a technique for profiling small molecules as they journey through cells and across different tissues in the body – the researchers deduced that high fructose intake promotes tumor growth by increasing the availability of circulating lipids in the blood. These lipids serve as building blocks for cell membranes, essential for cancer cell proliferation.
“We examined numerous cancers in various body tissues, and they all adhered to the same underlying mechanism,” Patti notes.
Scientists have long recognized cancer cells’ strong affinity for glucose, the body’s primary carbohydrate-based energy source. Structurally, fructose resembles glucose; both are common sugars with identical chemical formulas but differ in how the body processes them. Glucose is metabolized throughout the body, while fructose is predominantly metabolized by the small intestine and liver.
Both sugars occur naturally in fruits, vegetables, dairy products, and grains and are added to many processed foods as sweeteners. Fructose, in particular, has permeated the American diet over the past few decades, favored by the food industry for its enhanced sweetness compared to glucose.
Before the 1960s, fructose consumption was relatively meager compared to present levels. A century ago, an average person consumed merely 5 – 10 pounds of fructose annually, roughly equivalent to the weight of a gallon of milk. In the 21st century, that figure has skyrocketed to as much as the equivalent of 15 gallons of milk.
“If you rummage through your pantry and search for items containing high-fructose corn syrup – the most prevalent form of fructose – it’s truly astonishing,” says Patti, who is also a research member of the Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and the Center for Human Nutrition at WashU Medicine.
He continues, “Almost everything has it. It’s not just confectionery and cakes; it’s also in foods like pasta sauce, salad dressing, and ketchup. Unless you deliberately avoid it, it’s likely part of your diet.”
Given the sharp rise in dietary fructose consumption in recent decades, the WashU researchers were compelled to explore its impact on tumor growth.
Patti and Fowle-Grider initiated their study by feeding tumor-bearing animals a fructose-rich diet and then gauging the rate of tumor growth. They discovered that additional fructose hastened tumor growth without altering body weight, fasting glucose, or fasting insulin levels.
“We were astonished to observe such a pronounced effect. In some instances, the tumor growth rate doubled or even exceeded that,” Patti states. “Clearly, a high fructose intake was detrimental to these tumors’ progression.”
However, the next phase of their experiments initially baffled them. When Fowle-Grider attempted to replicate a version of the test by feeding fructose to isolated cancer cells in a dish, the cells showed little response. “In most cases, they grew almost as slowly as if we provided no sugar at all,” Patti says.
So, Patti and Fowle-Grider redirected their attention to changes in the small molecules in the blood of animals on a high-fructose diet. Using metabolomics, they detected elevated levels of various lipid species, including lysophosphatidylcholines (LPCs). Further dish tests revealed that liver cells fed fructose release LPCs.
“Interestingly, cancer cells themselves lack the biochemical machinery to readily use fructose as a nutrient,” Patti explains. “Liver cells possess this ability, enabling them to convert fructose into LPCs, which they can secrete to nourish tumors.”
A defining trait of cancer is the uncontrolled proliferation of malignant cells. Each cell division demands replication of cell contents, including membranes, which requires a significant amount of lipids. While lipids can be synthesized de novo, it’s far easier for cancer cells to absorb them from their surroundings.
“Over the past few years, it’s become evident that many cancer cells prefer to uptake lipids rather than synthesize them,” Patti observes. “The complication is that most lipids are insoluble in blood and require complex transport mechanisms. LPCs are unique; they may offer the most efficient means to support tumor growth.”
Coincidentally, during the same period when human fructose consumption soared, there has been an increasing prevalence of certain cancers among those under 50. This has led to speculation about a possible connection. With $25 million in support from Cancer Grand Challenges, Patti recently joined forces with Yin Cao, an associate professor of surgery at WashU Medicine, and other international investigators, none of whom were involved in this study, to probe potential links.
“It will be exciting to gain a deeper understanding of how dietary fructose influences cancer incidence,” Patti says. “But one key takeaway from this current study is that if you’re unfortunate enough to have cancer, you might want to consider avoiding fructose. Alas, that’s easier said than done.”
Beyond dietary intervention, the study authors suggest that this research could pave the way for developing drug-based therapies to prevent fructose from fueling tumor growth.
“An implication of these findings is that we don’t have to confine ourselves to therapeutics that target only diseased cells,” Patti contends. “Rather, we can contemplate targeting the metabolism of healthy cells to treat cancer. This approach worked in our mouse studies, and we hope to translate our observations to improve patient lives.”
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