What we commonly term “good fatty acids,” or polyunsaturated fatty acids (PUFAs), are essential for human health, and are considered to be important as part of a healthy eating plan. Among these, the omega-3 (n-3) PUFA, DHA (docosahexaenoic acid), is crucial to brain function, vision, and the regulation of inflammatory phenomena. DHA has also been linked with a reduction in the incidence of cancer, and a multidisciplinary team of researchers at the University of Louvain (UCLouvain) has now identified a biochemical mechanism, known as ferroptosis, that allows DHA and other related fatty acids to slow the development of tumors.
Their studies in mice showed that administration of an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet. Reporting on their studies in Cell Metabolism (“Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects”), the team, headed by Olivier Feron, PhD, professor, concluded: “These data point out dietary PUFA as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches.”
Whether and how different nutrients might contribute to the biosynthetic, bioenergetics, and antioxidant needs of cancer cells has been extensively studied in the last decade, the authors explained. Scientists are also now looking increasingly at whether diet may influence cancer progression through changes in tumor cells’ access to and utilization of nutrients, whether that be through restricted access, or the supplementation of specific nutrients. Dietary omega-3 PUFAs have in particular attracted attention for their potential anticancer effects. “Outcomes of PUFA administration in tumor-bearing mice are indeed promising,” the team continued. However, they pointed out, “… clinical validation of potential benefits is still in its infancy …”. And interpreting studies carried out to date can also be confusing because the study protocols may use different PUFAs, in different amounts, and with different administration routes.
In 2016, Feron’s UCLouvain team, which specializes in oncology, discovered that cells in an acidic microenvironment (acidosis) within tumors replace glucose with lipids as an energy source in order to multiply. In collaboration with UCLouvain’s Cyril Corbet, PhD, Feron demonstrated in 2020 that these same cells are the most aggressive and acquire the ability to leave the original tumor to generate metastases. Meanwhile, Yvan Larondelle, PhD, a professor in the UCLouvain faculty of bioengineering, whose team is developing improved dietary lipid sources, proposed to Feron that they combine their skills in a research project, led by PhD candidate Emeline Dierge, to evaluate the behavior of tumor cells in the presence of different fatty acids.
The results of the team’s studies showed that these acidotic tumor cells responded in diametrically opposite ways, depending on the fatty acid they were absorbing. “We soon found that certain fatty acids stimulated the tumor cells while others killed them,” the researchers explained. And in particular, they found, DHA literally poisons these cancer cells.
For their study, UCLouvain researchers used a 3D tumor cell culture system, called spheroids. In the presence of DHA, spheroids first grew and then imploded. “We found that n-3 but also remarkably n-6 PUFAs induced cell death in 2D-grown acid-adapted cancer cells and within the acidic compartment of 3D tumor spheroids, they wrote. Tumor-bearing mice fed a DHA-enriched diet also demonstrated far slower tumor development than mice on a conventional diet. “… we documented in mice that an n-3 LC-PUFA-rich diet led to a significant delay in tumor growth when compared with an MUFA-rich diet.”
The team’s analyses showed that DHA acts on tumor cells via a phenomenon called ferroptosis, a type of cell death that is linked to the peroxidation of certain fatty acids. The greater the amount of unsaturated fatty acids in the cell, the greater the risk of their oxidation. Normally, in the acidic compartment within tumors, cells store these fatty acids in lipid droplets, a kind of bundle in which fatty acids are protected from oxidation. But in the presence of a large amount of DHA, the tumor cell is overwhelmed and cannot store the DHA, which oxidizes and leads to cell death.
By using a lipid metabolism inhibitor that prevents the formation of lipid droplets, researchers were able to observe that this phenomenon is further amplified, which added confirmation that the identified mechanism was responsible for tumor inhibition. “Altogether, these data identify dietary LC-PUFA as an adjuvant modality to take advantage of acidosis-driven induction of ferroptosis in tumors,” the team concluded. “Mechanistically, we provide evidence that ferroptosis, an iron-dependent, non-apoptotic form of cell death associated with oxidized lipids, is promoted when acidic cancer cells fail to buffer the enhanced uptake of PUFAs and expose themselves to the detrimental effects of peroxidation.”
Importantly, they pointed out, the work also provides evidence that how much bioactive n-3 LC-PUFAs are needed in the tumor may be reduced by taking advantage of the co-administration of DGAT inhibitors. “… an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet, an effect further accentuated by administration of DGATi or ferroptosis inducers.”
The overall findings could open the door to new, combined treatment possibilities. “The well-established link between tumor acidosis and disease progression, including through increased invasiveness, drug resistance, and immune escape, makes dietary n-3 LC-PUFA supplementation a particularly relevant strategy to be implemented,” the authors suggested.
For an adult, they further noted, “it’s recommended to consume at least 250 mg of DHA per day. But studies show that our diet provides on average only 50 to 100 mg per day. This is well below the minimum recommended intake.”