Past research suggests both the ketogenic diet and calorie restriction appear to stunt tumor growth by lowering blood glucose and insulin levels since both diets are very low in sugar. But new research suggests sugar isn’t the only nutrient that may predict tumor growth.
“When we compared tumor growth in a mouse model, we got different effects with different diets even though they were both low in glucose, which meant another factor must be at play,” lead author Matthew Vander Heiden, Director of the Koch Institute for Integrative Cancer Research at MIT, tells Inverse.
They found that pancreatic tumor growth slowed in the mice following the caloric-restricted diet, but did not in mice following a keto diet. They attributed this to an imbalance in saturated and unsaturated fats caused by a low-fat, low-sugar diet.
Essentially, the caloric-restricted diet appeared to take away the building blocks of cancer cells.
What you should know first — In humans, calorie restriction refers to consuming fewer calories below what is normally eaten — without depriving your body of essential nutrients.
Animal studies, and a few human trials, suggest this eating pattern can improve health, extend longevity, and reduce the effects of disease. This is thought to happen because caloric restriction influences processes related to inflammation and sugar metabolism, among others.
The keto diet involves eating meals high in fat, moderate proteins, and low in carbohydrates. In people, it’s associated with rapid weight loss but it’s unclear what its long-term effects on health are. Because it is high in saturated fat, doctors warn it can lead to unwanted repercussions like heart disease.
When scientists study how these diets influence mice, they put them on the mouse diet versions. Keto typically involves eating a type of chow broken down into mostly fat, some protein, and a few carbs. Mice on calorie-restricted diets have access to food in limited time windows.
Why the discovery was made — It all comes down to the raw materials cells need to replicate.
Cells have a membrane that separates their inner workings from the outside environment. For those membranes to work properly, they have to be composed of both saturated and unsaturated fats.
“... the kinds of fat you eat in your diet matters because that influences how much fat your body is tasked with making.”
But in a low-calorie diet, fewer fats are available to cells in the body, so your body has to create saturated fat — the only kind it can create — and then desaturates some of that. This provides the body with both saturated and unsaturated fat, which cells need in order to duplicate.
“It's a quirk of mammalian metabolism that we make fat and then desaturate that fat later,” Vander Heiden says. “It creates a situation where the kinds of fat you eat in your diet matters because that influences how much fat your body is tasked with making.”
The human body performs this desaturation process using an enzyme called stearoyl-CoA desaturase. The enzyme inserts a double bond into saturated fat molecules to create unsaturated fat. Low-sugar diets impair the enzyme’s ability to do this.
But if you’re eating a high-fat ketogenic diet, you end up getting enough fat from your diet to make up for the sluggish enzyme. The enzyme doesn’t need to work as hard because your body doesn’t have to create as much of its own fat — the cancer cells already have everything they need to duplicate.
“... diet could make our therapies better or worse.”
With a low-sugar, low-fat diet, the sluggish enzyme can’t keep up with desaturation, which leads to an imbalance in unsaturated and saturated fat. This imbalance appears to prevent tumors from growing.
“But if you eat a keto diet, you end up with enough fat that it doesn’t matter because you rescue the effects,” says Vander Heiden.
He and his team saw this play out in their mice. When mice followed the mouse version of a keto diet, fatty acids in their blood increased. Meanwhile, a calorie-restricted diet reduced almost all fatty acids.
The scientists believe that when glucose intake is low — meaning if your diet is keeping your blood sugar low because you’re eating a very small amount of sugars including carbohydrates and lactose — this difference in fat appears to determine how many resources tumor cells have to replicate.
This is why the researchers believe the low-fat, low-sugar nature of a caloric restricted diet slowed tumor growth, while the keto diet did not.
Why it matters — Almost 10 million people die of cancer every year. The prognosis is often grim for certain types, including pancreatic cancer, which don’t cause symptoms until the cancer has already spread. Understanding how to better manage tumor growth is critical for advancing cancer treatment.
“We aren’t going to cure cancer just with diet alone, but there’s a lot of reason to think diet has an effect on cancer growth,” says Vander Heiden. “And it’s important to think about because diet could make our therapies better or worse.”
A diet that suppresses tumor growth in some people could eliminate a barrier that therapies have to compete with when attempting to slow or stop the spread of cancer. It could also lead to new treatments.
“The number one thing this research taught us is that if we can understand the mechanism of how diet can affect cancer, we can look into therapeutic approaches that may be able to take advantage of these changes,” Vander Heiden says.
What’s next — Vander Heiden says what scientists discover in mouse models should never be directly applied to humans. Instead, early research like this is the first step that can inform further research in humans.
In other words, we can’t say for certain that a calorie-restricted diet will definitely slow tumor growth in people. But it is a promising step that now needs to be tested in clinical trials. Vander Heiden explains that gaining a better understanding of the mechanisms behind the process — like the kind gained through this study — is essential for moving forward.
“There are a lot of people who give advice on this topic which is why we decided to study it,” he says. “People make decisions on bad data and if we can get better information, we can design clinical trials that can give patients data-driven advice. Hopefully, this will be step one in that process.”
Abstract: Dietary interventions can change metabolite levels in the tumor microenvironment, which might then affect cancer cell metabolism to alter tumor growth. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumor progression by lowering blood glucose and insulin levels, we found that only CR inhibits the growth of select tumor allografts in mice, suggesting that other mechanisms contribute to tumor growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumors. Upregulation of stearoyl-CoA desaturase (SCD), which synthesizes monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumor SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumor growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumor SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumors, and changing the KD fat composition to increase tumor saturated fatty acid levels cooperates with decreased tumor SCD activity to slow tumor growth. These data suggest that diet-induced mismatches between tumor fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumor growth.