BCAAs and tumour growth: A*STAR study suggests benefits of low dietary intake
The researchers are from A*STAR's Singapore Bio-imaging Consortium (SBIC), and the team was led by SBIC deputy director and head of the Laboratory of Metabolic Medicine (LMM) Dr Han Weiping and LMM research scientist Dr Russell Ericksen.
They came to this conclusion after having worked with Duke University, the National Cancer Centre Singapore (NCCS) and the University of Rhode Island on a six-year study that entailed pre-clinical and clinical research, which included metabolomics and transcriptomic analyses of human tumours and cancer cell lines, as well as a mouse model of liver cancer.
They also reported that BCAAs in tumours could be targeted for cancer prevention and treatment, and found that some cancers significantly suppressed BCAA catabolism — or breakdown — resulting in BCAAs accumulating in tumours and activating mTOR, a pro-oncogenic pathway.
In the academic paper, published in the journal Cell Metabolism, they wrote: "We use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive loss of BCAA catabolism promotes tumour development and growth.
"In human hepatocellular carcinomas and animal models of liver cancer, suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumours…the degree of enzyme suppression strongly correlated with tumour aggressiveness, and was an independent predictor of clinical outcome.
"Dietary BCAA intake in humans also correlated with cancer mortality risk. The loss of BCAA catabolism in tumours confers functional advantages, which could be exploited by therapeutic interventions in certain cancers."
Animal testing
As essential amino acids, BCAAs are absorbed from food and not naturally produced by the body. Based on this, the research team investigated the impact of dietary BCAA intake on tumour development and growth by using a common mouse model of liver cancer.
They fed the mice either normal or high levels of BCAAs, and after five to eight months, observed that the mice on high-BCAA diets had experienced a "potent increase" in tumour count and size (20% to 40% incidence).
The researchers also noted that after five months, "of the tumours that did develop, the largest were from mice fed high-BCAA diets".
However, this diet did not lead to any significant change in mice that had not already developed tumours, suggesting that the effects of a high-BCAA diet are specific to cancer.
On the other hand, the mice that had been given a pharmacological compound to promote BCAA catabolism and the mice on a low-BCAA diet experienced limited tumour growth.
Additionally, the liver masses of diethylnitrosamine-injected mice on the high-BCAA diet were heightened after five and eight months, but the same was not seen in non-injected mice.
Thus, the researchers wrote that "dietary BCAAs may influence liver tissues predisposed to tumorigenesis, but have minimal impact on healthy liver tissues".
They also assessed the impact of dietary BCAA restriction on tumour burden by putting mice on a diet with a 50% reduction in BCAA content.
Subsequently, they observed that all the injected mice on a low-BCAA diet survived the study duration, whereas only 70% of the mice on regular or high-BCAA diets survived.
The mice on a low-BCAA diet were also found to have "significantly smaller tumours and reduced liver BCAA content".
These results suggest that BCAA accumulation can regulate the development of liver tumours, and tumour progression could be limited and overall survival improved by dietary intervention.
The human element
To further explore the impact of dietary BCAA intake on tumour development, the research team also analysed the National Health and Nutrition Examination Survey (NHANES) III cohort, which provided detailed medical and nutritional information.
Their analysis found that high dietary BCAA intake was linked to high overall cancer mortality risk in humans; this result was consistent with the mouse study.
Based on dietary protein recommendations of 10% to 35% of total kcal intake per person, they set the threshold for low BCAA intake at 1.73% and for high BCAA intake at 3.89%.
The researchers then found that among the biggest consumers of BCAAs, those aged 50 to 66 had a 200% higher risk of death from cancer compared to the smallest consumers in the same age group.
They wrote: "When evaluated as continuous substitutive variables, isocalorically replacing 3% of energy from BCAAs with either carbohydrate or fat decreased cancer mortality risk by more than 50%.
"While the effect of substituting BCAAs with non-BCAA protein could not be accurately evaluated due to high co-linearity between the variables, non-BCAA protein intake was associated with only a modest change in cancer mortality risk.
They added that these associations were not significant among seniors, possibly due to their higher basal protein requirements.
The researchers concluded: "Overall, we find that BCAA catabolism is a metabolic pathway potently and robustly altered in certain cancers.
"Not only can this pathway be examined and utilised for its diagnostic and prognostic value, but dietary and pharmacologic interventions may effectively modulate tumour development and growth while minimally affecting normal and regenerating tissues."
Future opportunities
Lead researcher Dr Han said in a statement that the study "presents opportunities for the development of prevention and therapeutic intervention strategies" for a number of common and fatal cancers, adding that the team hoped to see the study "eventually lead to new drugs and therapies that benefit patients".
NCCS senior consultant and medical oncologist, associate professor Toh Han Chong added that the study was key to improved understanding of BCAAs in liver cancer and potentially, other cancers.
"The finding that dietary BCAAs regulate cellular metabolism uncovers new factors in the cause of liver cancer, and potentially new drug targets," Toh added.
The research team will continue to work with the NCCS to further investigate BCAAs' underlying mechanisms in regulating hepatocellular carcinoma, as well as to test the efficacy of drug compounds may result in improved treatments and outcomes for cancer patients.
