The Study

Woolf et al. (2015) studied the effects of a ketogenic diet (KD) on malignant glioma growth and progression using a mouse model. Malignant gliomas are aggressive brain tumors with usually negative survival prognosis, despite current available treatments. Currently, patients with glioblastomas multiforme, the most common and aggressive type of glioma, have a life expectancy of only 12 to 18 months and less than 10% survive 5 years following the diagnosis.

The main hypothesis for the present study is that KD might be useful to control malignant tumors, as cancer cells demand glucose, having a glycolysis rate that can be up to 200 times higher than that of normal cells. This happens even in the absence of oxygen, as glycolysis is coupled with glucose fermentation in cancer cells.

Methods

Cancer cells causing gliomas were implanted in 10-week old female mice. For 3 days after this surgery, they were fed with normal mouse food. After that, they were separated in two groups, one continuing to be fed with normal mouse food and one fed using a very low carbohydrates KD mix (3% carbohydrates, 72% fats and 15% protein). The growth of the tumors, as well as many other molecular parameters involved in cancer progression, were then monitored for 21 days.

Results

Animals fed KC had a statistically significant increase in blood β HB levels (a “ketone body” from KD) and decreased blood glucose both 7 and 14 days post-implantation. Main hallmarks of cancer were monitored throughout this study. Key modulators of the tumor hypoxic response were significantly reduced in KD-fed mice, meaning that hypoxia was reduced in the tumor. Tumor hypoxia, a situation where the tumor is deprived in oxygen, is known to play a key role in many processes associated with cancer, such as increased glycolysis, tumor growth and spreading of cancer cells to other parts of the body. Furthermore, the expression of genes specifically involved in the spreading process of cancer cells elsewhere in the body was also reduced in KD-fed mice. Many other proteins in the tumor microenvironment were also modified in KD-fed mice, leading to a decrease of the tumor microvasculature. The amount of edema around the tumor, a frequent cause of morbidity and mortality in patients with gliomas, was also reduced in KD-fed mice. Taken together, all these changes contributed to the reduction of the growth and the progression rate of the tumor.

Conclusion

Diet-based therapeutic approaches, such as KD, are the only therapeutic approaches that simultaneously target multiple hallmarks of cancer such as energy metabolism, inflammation, hypoxia, angiogenesis and invasion, whereas, the majority of chemical treatments usually target a single aspect of the cancer. Furthermore, the KD does not present the same harmful side effects than many of these chemical cancer treatments. As such, the authors conclude that KD might be a promising effective therapeutic approach for patients with gliomas that can be combined with other treatments in order to increase their effects and also the survival prognosis of the patients. The authors highlight that “these results taken together suggest a potential utility of the KD as an adjuvant treatment for brain tumors …”

It is not yet clear from this study whether the KD directly causes all of these changes in the tumor, or if some may be a result of changes in the tumor and/or tumor microenvironment that results from the KD. Notwithstanding this, the authors state “it is clear that the overall result has powerful anti-tumor effects in our preclinical model of glioma.”

Study Editor

Marie-Christine Brotherton holds a Ph.D. in Cellular and Molecular Biology with specific expertise in Parasitology, Proteomics, Drug Resistance and Genomics. She also holds a MBA with a major in Corporate Social and Environmental Responsibility. She has strong experience with the scientific publication process, including author guidelines requirements, as well as with the medical and social/environmental fields. She can be reached by email at marie-christine.brotherton.1@ulaval.ca

Citation

Woolf, E. C., Curley, K. L., Liu, Q., Turner, G. H., Charlton, J. A., Preul, M. C., & Scheck, A. C. (2015). The ketogenic diet alters the hypoxic response and affects expression of proteins associated with angiogenesis, invasive potential and vascular permeability in a mouse glioma model. PloS one10(6), e0130357.