{"id":27591,"date":"2021-10-29T12:00:00","date_gmt":"2021-10-29T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2021\/fructose-promotes-obesity-colorectal-cancer"},"modified":"2024-11-03T15:14:11","modified_gmt":"2024-11-03T15:14:11","slug":"does-too-much-fructose-help-colorectal-cancers-grow","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/does-too-much-fructose-help-colorectal-cancers-grow\/","title":{"rendered":"Does Too Much Fructose Help Colorectal Cancers Grow?"},"content":{"rendered":"

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A microscopic cross section of villi, finger-like structures that line the intestines.<\/p>\n

Credit: Used with permission from Amy Engevik, Ph.D., Medical University of South Carolina<\/p>\n<\/div>\n<\/figcaption><\/figure>\n<\/div>\n

A new study suggests that excess consumption of fructose can promote both obesity and colorectal cancer.<\/p>\n

Conducted largely in mice, the study found that large amounts of the sweetener, which is present in both table sugar and high-fructose corn syrup (HFCS), increased how long both normal and cancer cells in the intestines<\/a> live. <\/p>\n

In normal mice, this increased cell survival led to more nutrients being absorbed, leading to weight gain. And in mice prone to develop cancer, the increased cell survival led the animals to develop larger tumors and more anemia<\/a>, a common tumor-related complication.<\/p>\n

Findings from the study, which was funded in part by NCI, appeared August 18 in Nature<\/em>.<\/p>\n

The researchers, led by Marcus Goncalves, M.D., Ph.D., of Weill Cornell Medicine, are launching human studies to see if a similar phenomenon occurs in people.<\/p>\n

\u201cBut this mouse study is really important, because it establishes a molecular mechanism for why fructose can drive tumor growth,\u201d said Kristine Willis, Ph.D., of NCI\u2019s Division of Cancer Biology<\/a>, who was not involved with the study.<\/p>\n

How Could Fructose Increase Tumor Growth?<\/h2>\n

In 2019, Dr. Goncalves and his colleagues published a study showing that feeding HFCS to mice prone to developing intestinal tumors could increase the size and aggressiveness of colorectal tumors<\/a>. They also found that blocking the uptake of that particular sweetener by the body\u2019s cells could prevent such growth.<\/p>\n

But the details of the \u201cwhy\u201d behind these results remained a mystery. In the new work, the researchers thoroughly examined what was happening on the cellular level in the intestines after HFCS consumption. <\/p>\n

They first looked at what happened to intestinal cells in normal mice fed a diet including large amounts of HFCS. The team focused on villi: finger-like protrusions of the intestinal lining. Villi increase the surface area of the intestinal lining and maximize the amount of nutrients that can be absorbed after a meal.<\/p>\n

The HFCS caused the villi to grow in length. Normal mice fed HFCS had villi that were around 25%\u201340% longer than those in mice that weren\u2019t fed the sweetener. <\/p>\n

When the mice were then fed a high-fat diet in addition to excess fructose, it caused them to gain far more weight than mice only fed a high-fat diet.<\/p>\n

High-Fructose Corn Syrup Metabolism at the Cellular Level<\/h2>\n

Further experiments showed that the overabundance of HFCS kept the cells at the tips of the villi alive longer. Normally, the cells at the tip of a villus<\/a>, where oxygen levels are lower (called hypoxia<\/a>), die off. They\u2019re then replaced by new cells that are produced at the base of the villus and migrate up to the tip. <\/p>\n

But by increasing cell survival at the villi tips, and with new cells continuing to be made, the villi inevitably got longer, they found.<\/p>\n

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Excess fructose causes cells at the tips of villi to live longer than they should. With new cells continuing to be made, the villi get longer.<\/p>\n

Credit: Used with permission from Dr. Marcus Goncalves, Weill Cornell Medicine<\/p>\n<\/div>\n<\/figcaption><\/figure>\n<\/div>\n

The researchers then turned to human colorectal cancer cell lines<\/a> to see whether excess fructose would affect their ability to grow and survive in low-oxygen conditions. Hypoxia is a common occurrence in the middle of tumors and can limit their growth. <\/p>\n

As with the mouse intestinal cells, the researchers found that adding fructose to colorectal cancer cells grown in a low-oxygen environment didn\u2019t increase the rate at which they grew but helped the cells survive longer than cells to which fructose wasn\u2019t added. <\/p>\n

But why does fructose increase cell survival when oxygen levels are low? In further experiments in colorectal cancer cells, the researchers found that the sweetener caused a chain of cellular reactions, which resulted in lowered activity of a protein<\/a> called PKM2.<\/p>\n

PKM2 is involved in cellular metabolism<\/a>. When PKM2 activity is low, as can happen under stressful conditions like hypoxia, cells adjust their metabolism so that they can stay alive.<\/p>\n

So in order to survive, \u201cthe tumor wants to find the best way it can to inhibit PKM2,\u201d explained Dr. Goncalves.<\/p>\n

Several additional experiments showed that preventing fructose from inhibiting PKM2 could stop both villi and colorectal cancer cells from thriving in a low-oxygen environment. For example, when they gave HFCS-fed normal mice a drug called TEPP-46, which turns PKM2 back on, their villi didn\u2019t elongate and they didn\u2019t gain weight.<\/p>\n

When the researchers then fed excess HFCS to mice predisposed to develop colorectal cancer, the mice developed bigger tumors and became more anemic\u2014a complication associated with worse survival in both mice and people\u2014than mice not fed the sweetener. Treating mice fed large amounts of HFCS with TEPP-46 slowed tumor growth.<\/p>\n

The ability of a drug to activate PKM2 even in the presence of fructose, both stopping weight gain and slowing tumor growth stimulated by HFCS is exciting, said Dr. Willis. <\/p>\n

\u201cThere\u2019s huge potential there,\u201d she said. \u201cIf this translates to humans, does that then represent a possible avenue of treatment for obesity as well as colorectal cancer?\u201d<\/p>\n

What Happens in Humans?<\/h2>\n

Dr. Goncalves and his colleagues are getting ready to launch a follow-up study in people. To date, it remains controversial whether substantial amounts of the HFCS that people consume in their diets can reach the colon, or whether most of it gets absorbed higher in the digestive tract<\/a>, he explained. The mouse digestive tract is much shorter than the human version, relative to size, making it easy for HFCS to reach the colon in mice.<\/p>\n

The team will recruit people with colon cancer scheduled to undergo surgery to have their tumors removed. Before surgery, they\u2019ll eat a meal containing HFCS to which a heavy isotope of fructose has been attached. After the tumors are removed, this \u201clabel\u201d will allow the researchers to measure how much of the fructose made it into the cancer cells.<\/p>\n

This work will, the team hopes, help answer the question of whether fructose from HFCS can reach tumors in the human colon. If so, Dr. Goncalves said, \u201cthe next step is: how do we intervene?\u201d he added. Several drugs that target PKM2 or related molecules are currently under development for other conditions. <\/p>\n

\u201cThese could [potentially] be repurposed to reduce or shorten villi and hopefully prevent tumor growth,\u201d he said.<\/p>\n

Metabolism can differ vastly from one person to another, Dr. Goncalves explained. So many mechanisms\u2014not just related to PKM2\u2014likely drive both obesity and colorectal cancer. <\/p>\n

\u201cBut exposure to fructose is one component of the diet that’s modifiable, and we think plays a role,\u201d he said. \u201cThere’s still a lot more work to do in terms of [understanding] how big of an effect it has, and if we can use drugs to try to prevent it from happening.\u201d<\/p>\n

His lab also studies cachexia<\/a>, a loss of body weight and muscle mass that often occurs in people with advanced cancer. People with cachexia have the reverse problem from that seen in this study: their villi shrink, Dr. Goncalves explained. That leads to the intriguing question of whether fructose could actually be a treatment for cachexia, to help people maintain weight and strength.<\/p>\n

They\u2019ve started studying this approach in mice. \u201cIf you give cachexic animals fructose, will they absorb [nutrients] better and ultimately maintain their body weight?\u201d he asked.<\/p>\n