Researchers at Weill Cornell Medicine and Baylor College of Medicine have shown that consuming even a modest amount of high-fructose corn syrup (HFCS)—the primary sweetener in sugar-sweetened beverages (SSBs)—promotes the growth of intestinal tumors in mouse models, independently to any link with obesity and metabolic syndrome. The studies, headed by Jihye Yun, PhD, assistant professor of molecular and human genetics at Baylor, also identified the mechanism by which fructose can fuel cancer growth, a finding that could feasibly lead to new therapeutic strategies. Yun is co-corresponding author of the researchers’ published paper in Science.

“This study revealed the surprising result that colorectal cancers utilize high-fructose corn syrup, the major ingredient in most sugary sodas and many other processed foods, as a fuel to increase rates of tumor growth,” commented Lewis Cantley, PhD, co-corresponding author and professor of cancer biology in medicine and director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “While many studies have correlated increased rates of colorectal cancer with diet, this study shows a direct molecular mechanism for the correlation between consumption of sugar and colorectal cancer.”

The researchers describe their studies and findings in a report titled, “High-fructose corn syrup enhances intestinal tumor growth in mice.”

Increasing consumption of SSBs has been paralleled by a global “epidemic” of obesity, and also by an increase in the rate of colorectal (CRC) incidence among young and middle-aged adults, “suggesting a potential link between SSBs, obesity, and CRC development,” the authors wrote.

Studies have indicated that excessive consumption of SSBs causes obesity, and that obese men in particular are at an increased risk of CRC. However, it’s not clear whether SSBs contribute directly to tumor formation. “Two important confounders are obesity and metabolic syndrome, which can indirectly affect tumor development by changing a myriad of physiologic and endocrine systems in multiple organs,” the team pointed out.

To investigate any direct link between HFCS and cancer, the team turned to a genetically engineered mouse model in which the adenomatous polyposis coli (APC) gene has been deleted. These APC–/ animals are predisposed to develop intestinal tumors. “APC is a gatekeeper in colorectal cancer,” Yun explained. “Deleting this protein is like removing the brakes of a car. Without it, normal intestinal cells neither stop growing nor die, forming early-stage tumors called polyps. More than 90% of colorectal cancer patients have this type of APC mutation.”

To determine the physiological effects of ad lib HFCS consumption the researchers gave APC-deficient mice and normal control (Con) mice free access to water that was sweetened with 25% HFCS, which is composed of both glucose and fructose in a 45:55 ratio. Both APC-deficient and control animals with ad lib access to HFCS became obese within two months, and the control mice also developed metabolic syndrome. The researchers then syringe-fed another group of APC-deleted mice with a daily amount of the HFCS-sweetened water that was equivalent to a human drinking just one can of sweetened soda per day. “This modest amount of HFCS (~3% of total daily caloric intake) is calorically equivalent to human consumption of less than 12 ounces of SSB (~20 g of HFCS) per day,” the researchers wrote.

While these animals didn’t become obese or develop metabolic syndrome, after two months they had developed larger and higher-grade tumors than the tumors developing in control mice given unsweetened water. “Although the total number of tumors was similar, HFCS treatment significantly increased the number of large adenomas (>3 mm in diameter) and high-grade tumors in the HFCS group compared to the Con group,” they commented. Interestingly, similar results were obtained in a different mouse model that develops tumors in the colon rather than in the small intestine. “These results suggest that the chronic intake of modest amounts of HFCS in liquid form facilitates tumor growth in the setting of APC deficiency independent of obesity and the metabolic syndrome.”

Yun said the findings point to an independent relationship between HFCS and tumor progression. “These results suggest that when the animals have early stage of tumors in the intestines—which can occur in many young adult humans by chance and without notice—consuming even modest amounts of high-fructose corn syrup in liquid form can boost tumor growth and progression independently of obesity.” This observation might also explain why increased consumption of sweet drinks and other foods with high sugar content during the past 30 years is correlating with an increase in colorectal cancers in 25- to 50-year-olds in the United States, Cantley further noted.

The team next investigated the mechanism by which HFCS might promote tumor growth. They found that the APC–/ mice that had been syringe-fed the moderate amount of the HFCS had high levels of fructose and glucose in their colons, and that their tumors could effectively utilize both types of sugar. “We observed that sugary drinks increased the levels of fructose and glucose in the colon and blood, respectively and that tumors could efficiently take up both fructose and glucose via different routes.”

The fructose also appeared to be retained by the tumors, the authors stated. “Furthermore, the amount of fructose reaching the liver and serum was reduced in tumor-bearing APC−/− mice compared to WT mice, implying that fructose is trapped by the tumors instead of being transported to the liver and blood.”

Interestingly, while glucose and fructose have the same calorific value and similar structures, they are metabolized differently, the scientists stated. Using techniques including radiolabelling to trace the fate of glucose and fructose in the APC-deficient mouse model, they found fructose was being converted to fructose-1 phosphate in the mouse tumors. This altered tumor cell metabolism and generated fatty acids, which supported tumor growth.

“Most previous studies used either glucose or fructose alone to study the effect of sugar in animals or cell lines,” Yun said. “We thought that this approach did not reflect how people actually consume sugary drinks because neither drinks nor foods have only glucose or fructose. They have both glucose and fructose together in similar amounts … Our findings suggest that the role of fructose in tumors is to enhance glucose’s role of directing fatty acids synthesis. The resulting abundance of fatty acids can be potentially used by cancer cells to form cellular membranes and signaling molecules, to grow or to influence inflammation.”

The researchers next modified their APC-deficient model mice to lack genes coding either for the enzyme KHK (ketohexokinase, or fructokinase), which is involved in fructose metabolism, or fatty acid synthase (FASN), a key enzyme in fatty acid synthesis. Significantly, animals deficient in either of the two enzymes didn’t develop the larger tumors seen in the original APC-deficient mice, even when fed the same, moderate amount of HFCS. “This study revealed the surprising result that colorectal cancers utilize high-fructose corn syrup, the major ingredient in most sugary sodas and many other processed foods, as a fuel to increase rates of tumor growth,” Cantley said. “While many studies have correlated increased rates of colorectal cancer with diet, this study shows a direct molecular mechanism for the correlation between consumption of sugar and colorectal cancer.”

Sugar-sweetened beverages (SSBs) containing a mixture of glucose (Glu) and fructose (Fru), flow through the gastrointestinal tract after consumption. Goncalves et al., show that Glu and Fru are directly absorbed by intestinal tumors, and daily dosing of SSBs accelerates tumor growth. This growth promoting effect is dependent on the enzyme, ketohexokinase (KHK), which produces fructose 1-phosphate (F1P) from Fru, and results in the depletion of adenosine triphosphate (ATP). Both of these metabolic changes promote the conversion of Glu to the building blocks needed for tumor growth. [Vincent Dittmer]
The team concluded that their results demonstrate that HFCS contributes to intestinal tumorigenesis in mice by accelerating glycolysis and de novo lipogenesis. “These effects are independent of obesity and metabolic syndrome,” they stated. “HFCS in liquid form rapidly increases the levels of fructose and glucose in the intestinal lumen and serum, respectively, which allows intestinal tumors to take up these sugars for their growth.”

“Our findings also open new possibilities for treatment,” Yun commented. “Unlike glucose, fructose is not essential for the survival and growth of normal cells, which suggests that therapies targeting fructose metabolism are worth exploring. Alternatively, avoiding consuming sugary drinks as much as possible instead of relying on drugs would significantly reduce the availability of sugar in the colon.”

The researches do acknowledge that further research will be needed to determine whether their mouse results can be extrapolated to humans. Nevertheless, they state, “Together these findings suggest that therapeutic targeting of fructose metabolism may merit investigation as a strategy for slowing the progression of CRCs.”

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