There is some accumulating evidence that dietary interventions might help to slow the growth of tumors, and scientists at MIT now report on rodent research that suggests how those diets affect cancer cells, and also offers up an explanation of how restricting calories might slow tumor growth. The study examined the effects of a calorically restricted (CR) diet and a ketogenic diet (KD) in mice with pancreatic tumors. The results showed that while both diets reduce the amount of sugar available to tumors, only the calorie restricted diet reduced the availability of fatty acids, and it was this that was linked to a slowdown in tumor growth.
The scientists stress that their findings don’t indicate that cancer patients should try to follow either diet, rather, the results could prompt new research to determine how dietary interventions might be combined with existing or emerging drugs to help patients with cancer. “There’s a lot of evidence that diet can affect how fast your cancer progresses, but this is not a cure,” says Matthew Vander Heiden, MD, PhD, director of MIT’s Koch Institute for Integrative Cancer Research and senior author of the team’s report in Nature. “While the findings are provocative, further study is needed, and individual patients should talk to their doctor about the right dietary interventions for their cancer.”
Lead author Evan Lien, PhD, and colleagues describe their results in a paper titled, “Low glycaemic diet alter lipid metabolism to influence tumour growth.”
Vander Heiden, who is also a medical oncologist at Dana-Farber Cancer Institute, says his patients often ask him about the potential benefits of various diets, but there is not enough scientific evidence available to offer any definitive advice. Many of these dietary questions relate to either a calorie-restricted diet, which reduces calorie consumption by 25–50%, or a ketogenic diet, which is low in carbohydrates and high in fat and protein.
Previous studies have suggested that a calorically restricted diet might slow tumor growth in some contexts, and such a diet has been shown to extend lifespan in mice and in many other animal species. A smaller number of studies exploring the effects of a ketogenic diet on cancer have produced inconclusive results.
“A lot of the advice or cultural fads that are out there aren’t necessarily always based on very good science,” Lien said. “It seemed like there was an opportunity, especially with our understanding of cancer metabolism having evolved so much over the past 10 years or so, that we could take some of the biochemical principles that we’ve learned and apply those concepts to understanding this complex question.”
Cancer cells consume a great deal of glucose, so some scientists have hypothesized that either the ketogenic diet or calorie restriction might slow tumor growth by reducing the amount of glucose available. “Dietary interventions can change metabolite levels in the tumor microenvironment, which might then affect cancer cell metabolism to alter tumor growth,” the authors noted. However, they also pointed out, “Low glycemic diets are often presumed to inhibit tumor growth by lowering blood glucose and insulin levels, but whether changes in other nutrients also contribute is less understood.”
For the newly reported studies, the researchers investigated and compared the effects of a normal diet, a calorie-restricted diet, and a ketogenic diet, in mice carrying pancreatic tumors. They found that calorie restriction had a much greater effect on slowing tumor growth than the ketogenic diet, and this prompted them to think that glucose levels might not be playing a major role in tumor growth slowdown. “Interestingly, only CR inhibits tumor growth in this model,” they wrote. “Although CR mice consume 40% fewer calories and have reduced body weights, tumor growth is still inhibited even when normalized to animal body weights.”
To investigate the potential mechanism underlying the effects of CR on cancer growth, the team analyzed tumor growth and nutrient concentration in mice with pancreatic tumors. They found that in both the ketogenic and calorie-restricted mice, glucose levels went down. But in the calorie-restricted mice, lipid levels also went down, while in mice on the ketogenic diet lipid levels went up. “A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumors,” the team noted.
Lipid shortages impair tumor growth because cancer cells need lipids to construct their cell membranes. Normally, when lipids aren’t available in a tissue, cells can make their own. As part of this process, they need to maintain the right balance of saturated and unsaturated fatty acids, which requires an enzyme called stearoyl-CoA desaturase (SCD). This enzyme is responsible for converting saturated fatty acids into unsaturated fatty acids.
The team’s experiments showed that while calorie-restricted and ketogenic diets reduced SCD activity, mice on the ketogenic diet had lipids available to them from their food, so they didn’t need to use SCD. Mice on the calorie-restricted diet, however, couldn’t get fatty acids from their diet or produce their own. In these mice, tumor growth slowed significantly, compared to mice on the ketogenic diet. “Not only does caloric restriction starve tumors of lipids, it also impairs the process that allows them to adapt to it,” Lien noted. “That combination is really contributing to the inhibition of tumor growth.”
In addition to their mouse research, the researchers also looked at human data. Working with co-author Brian Wolpin, MD, an oncologist at Dana-Farber Cancer Institute, the team looked at the relationship between dietary patterns and survival times in pancreatic cancer patients. “The interaction between dietary fat composition and low glycemic tumor SCD inhibition to cause an imbalance between saturated and unsaturated fatty acids provides a mechanism by which low glycemic diets influence tumor growth,” the team wrote. “To begin to assess if low glycemic diet effects on lipid metabolism might influence human tumor growth, we evaluated associations between dietary patterns and survival time in 1,165 patients with pancreatic cancer in two large prospective cohorts: the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS),” they explained.
From this human data, the scientists found that the type of fat consumed appears to influence how patients on a low-sugar diet fare after a pancreatic cancer diagnosis, although the researchers also acknowledged that the data are not complete enough to draw any conclusions about the effect of diet. “A dietary pattern lower in carbohydrates and higher in fat and protein was associated with longer survival time,” they wrote. “ … this association was modestly stronger for low-carbohydrate dietary patterns in which the fat and protein components were plant-based instead of animal-based.”
Although the study did show that calorie restriction has beneficial effects in mice, the researchers say they do not recommend that cancer patients follow a calorie-restricted diet, which is difficult to maintain and can have harmful side effects. However, they believe that cancer cells’ dependence on the availability of unsaturated fatty acids could be exploited to develop drugs that might help slow tumor growth.
One possible therapeutic strategy could be inhibition of the SCD enzyme, which would cut off tumor cells’ ability to produce unsaturated fatty acids. “The purpose of these studies isn’t necessarily to recommend a diet, but it’s to really understand the underlying biology,” Lien pointed out. “They provide some sense of the mechanisms of how these diets work, and that can lead to rational ideas on how we might mimic those situations for cancer therapy.”
The researchers plan to study how diets with a variety of fat sources—including plant or animal-based fats with defined differences in saturated, monounsaturated, and polyunsaturated fatty acid content—alter tumor fatty acid metabolism and the ratio of unsaturated to saturated fatty acids. “Although more work is needed to understand mechanisms by which distinct dietary fat compositions affect human tumor growth and metabolism, the fact that plant-derived lipids contain more unsaturated fatty acids than animal-derived lipids is provocative,” they noted in their paper. “… this study shows how diet can alter tumor metabolite availability and influence cancer cell metabolism to affect growth. A better understanding of dietary effects on tumor metabolism and progression might lead to orthogonal strategies to mimic the effects of a particular diet and provide guidance for how to incorporate dietary interventions to improve the care of patients with cancer.”