High-fructose corn syrup promotes colon tumor growth in mice

NEW YORK (March 21, 2019)--Consuming the equivalent of one can of soda per day caused mice predisposed to colon cancer to develop larger tumors, according to a study by Weill Cornell Medicine and NewYork-Presbyterian investigators.

The study, published March 22 in the print issue of Science, shows how high-fructose corn syrup fuels the growth of colon tumors in these mice and demonstrated a potential strategy to block this excess tumor growth. Though more study is needed to demonstrate whether high-fructose corn syrup promotes colon tumor growth in humans, the findings might have implications for cancer treatment or prevention.

"The study shows that colorectal polyps feed on high fructose corn syrup and explains the molecular mechanism by which this drives the growth of the tumor," said co-senior author Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian. "While our work was conducted in mice, our findings build on mounting evidence that sugar fuels cancer growth."

Investigators say that, based on their findings, people with colon cancer or those at high risk should avoid sugary drinks.

"If you are predisposed to getting polyps, you should not be drinking any sugar-sweetened beverages," said lead author Dr. Marcus D. Goncalves, an assistant professor of medicine at Weill Cornell Medicine and an endocrinologist at NewYork-Presbyterian/Weill Cornell Medical Center. "If you have colorectal cancer, you could be feeding your tumor by drinking high-fructose corn syrup."

Consumption of soda and other beverages sweetened with high-fructose corn syrup has increased dramatically since the 1980s, the investigators said. During that same period, rates of obesity and metabolic syndrome, along with colorectal cancer among young and middle-aged adults, have also risen. Observational studies suggest people who eat more sugar-sweetened foods and those who have obesity have a higher risk of colon cancer. But it has been hard to disentangle the effects of diet and complex conditions like obesity in colon cancer.

Other observational studies have linked diets high in processed meat and low in fiber to increased colon cancer risk, while high-fiber diets loaded with fruits and vegetables and low in red meat have been associated with reduced risk. Though these types of studies can't prove that diet causes colon cancer, there are good reasons to suspect it might contribute.

Now, Dr. Cantley, Dr. Goncalves and their colleagues provide more direct evidence that sugar promotes colon tumor growth. To do this, they squirted a small dose of high-fructose corn syrup each day for eight to nine weeks into the mouths of mice genetically engineered to develop colon tumors. This dose is the mouse equivalent of drinking one soda per day, which about half of Americans do, Dr. Goncalves said. These mice did not become obese or develop metabolic syndrome. The investigators then compared the tumors that developed in the sugar-fed mice with tumors in mice with the same predisposition to colon tumors but no added sugar in their diet. They found that the sugar-fed mice developed more large tumors compared with the control mice.

"We were not able to show that giving high-fructose syrup causes new tumors because these mice develop tumors even on normal diets free of added sugar," Dr. Goncalves cautioned. "But when you give them this additional sugar, the tumors grow much bigger."

To understand why, they looked at what happens when mice are fed high-fructose corn syrup. Consuming the sweetener delivers an excess of both glucose and fructose to the colon of the mice. By using isotope-labeled sugars, Dr. Cantley and his team showed colon tumors readily take in both sugars. An enzyme called ketohexokinase (KHK) changes the fructose into fructose-1-phosphate, which makes it easier for the tumor to use glucose for energy. This also promotes the production of fats necessary for tumors to grow. Both the fats and the fructose-1-phosphate promote more tumor growth. Preliminary studies on the effects of added table sugar, also known as sucrose, led to a similar degree of glucose and fructose exposure in the gut; the investigators speculate that sucrose could also drive tumor growth in this model.

"We expect that consuming beverages or processed foods with added sucrose is likely to have the same effect as consuming drinks with high-fructose corn syrup, since sucrose has a similar composition of fructose and glucose to high-fructose corn syrup," Dr. Cantley said.

Deleting the gene for KHK or a gene called fatty acid synthase, which is responsible for producing fats that are essential for making the membranes that surround new cancer cells, in mice genetically engineered to develop colon tumors prevents the tumor growth-promoting effects of high-fructose corn syrup.

"Our study showed two genetic ways to reverse the high-fructose corn syrup's effects, by manipulating glucose metabolism," Dr. Cantley said.

This may suggest that drugs targeting KHK or fat production in tumor cells may help reverse the tumor-growing effects of these sugars in people. One potential way to determine whether this would be effective is to randomize patients to receive a KHK-blocking drug, which is currently in phase 2 clinical trials for fatty liver disease. Another approach would be to test whether a very low-sugar diet, like the ketogenic diet, slows tumor growth, Dr. Goncalves said. He and colleagues from Weill Cornell Medicine's Clinical and Translational Science Center have created a ketogenic diet that is less than 3 percent carbohydrate and has no sugar, which he thinks could be helpful for patients undergoing cancer therapy. Dr. Goncalves cautioned that the dietary approach would work best with treatments such as chemotherapy or radiation.

"It's the ability of diet to enhance traditional therapy that I believe holds the most promise," he said.

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Dr. Cantley is a founder of and holds equity in Agios Pharmaceuticals and Petra Pharmaceuticals and is a member of the scientific advisory board for these companies. Petra provides financial support for his laboratory research. Dr. Cantley is also a member of the scientific advisory boards of Cell Signaling Technologies and EIP and holds equity in these companies.

This study was initiated by Drs. Jihye Yun and Goncalves when they were postdoctoral fellows in Dr. Cantley's laboratory and completed after they became faculty members at Baylor College of Medicine in Houston and Weill Cornell, respectively.

Weill Cornell Medicine

Weill Cornell Medicine is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of Weill Cornell Medicine -- faculty from Weill Cornell Medical College, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Physician Organization--are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Located in the heart of the Upper East Side's scientific corridor, Weill Cornell Medicine's powerful network of collaborators extends to its parent university Cornell University; to Qatar, where Weill Cornell Medicine-Qatar offers a Cornell University medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell Medicine faculty provide comprehensive patient care at NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian Lower Manhattan Hospital, NewYork-Presbyterian Queens and NewYork-Presbyterian Brooklyn Methodist Hospital. Weill Cornell Medicine is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

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