Thanks to our deeper understanding of the underlying biology and molecular mechanisms that govern cancer, we are gaining important ground in tackling the myriad mediators of this disease. Research continues to unravel the complex interactions and interplay between mutated cells and their surrounding biological landscape, stromal cells and inflammatory cells, and extracellular matrix proteins as key components of the tumour microenvironment, and the many socioeconomic factors that make up the macroenvironment.
Delving into the tumour microenvironment, dietary interventions have been shown to change metabolite levels which can influence cancer cell metabolism to alter tumour growth. Over the past decade, in particular, we have gained molecular insights into how diet can affect this disease, where restricting calories may put the brakes on cancer growth, and excessive calorie intake could act as an accelerator of disease progression.
Diet as an anti-cancer ‘co-worker’
Mounting evidence points to the influence of fasting or fasting-mimicking diets (FMDs) on a range of alterations in growth factors and in metabolite levels that can ultimately reduce the capacity of cancer cells to adapt, survive, and grow.
In an elegant Opinion article (Nat Rev Cancer. 2018 Nov;18(11):707-719), the authors discussed the biological rationale for using these diets as an experimental approach in minimizing cancer treatment-emergent adverse events as well as more effectively preventing and treating this disease. They also highlight the caveats of these strategies, and update on some of the clinical studies that have explored the biological activity of FMDs in cancer patients undergoing treatment.
But there is still not enough scientific evidence to offer definitive advice to our patients regarding the potential benefits of various diets including calorically restricted as well as ketogenic diets. Now, results from a recent study led by investigators at the Massachusetts Institute of Technology, Cambridge, MA, USA, shed important new light on the subject (Nature. 2021 Nov;599(7884):302-307).
While low glycaemic diets have been suggested to inhibit tumour growth in preclinical model by lowering blood glucose and insulin levels, possible alterations in other nutrients have not been well described. At the preclinical level, several diets are now emerging as experimental strategies that might stall cancer growth and even potentiate anticancer medicines in combination with standard therapies.
Lien and colleagues sought to achieve a better understanding of how diet can alter tumor metabolite availability and influence cancer cell metabolism to affect growth. They studied the molecular activity of a low-calorie diet and a ketogenic diet and how they affect tumour progression in PDX1-cre mouse models of pancreatic cancer.
While both diets led to a similar reduction in blood-glucose levels, they discovered that only the calorically restricted diet impaired the growth of specific tumors. By measuring the availability of fatty-acid molecules in the plasma component of blood and in the tumours, the MIT team discovered that in the calorie-restricted mice, lipid levels were reduced, but increased in mice on the ketogenic diet. This observation points to the role of certain fatty acids in the deceleration of cancer growth.
Going beyond the glucose
Since cancer cells require high levels of lipids to construct their own cell membranes, shortages of these fatty acids slow growth. When they are not available in a tissue, cells can make their own. This relies on striking the right balance of saturated and unsaturated fatty acids. The major orchestrator of this process is the stearoyl-CoA desaturase (SCD) enzyme that converts saturated fatty acids into unsaturated ones.
Results showed that both calorie-restricted and ketogenic diets reduced SCD levels. Mice on the latter had available lipids from their diet and therefore did not require SCD. In the mice receiving the calorie-restricted diet, that could not get fatty acids or produce their own, the investigators observed a significant slowdown in disease growth compared to mice on the ketogenic regimen.
Incorporating dietary interventions to improve outcomes for our patients?
While this study advances important insights into how low glycaemic diets can alter lipid metabolism and slow tumour growth in patient derived xenograft, the authors rightly caution that calorie-restricted diets are by no means recommended for all cancer patients since they are difficult to maintain and tolerate, and associated weight loss could limit treatment options.
They conclude by suggesting that a deeper understanding of dietary effects on tumour metabolism and progression might lead to strategies that mimic the effects of a given diet, and steer next step directions towards potentially incorporating dietary components in the development of cancer therapies.
Drawing on the results of this particular study, cancer cell dependency on the availability of unsaturated fatty acids could perhaps be exploited to develop future therapies that may more effectively slow tumour growth.