Might Cancer Be a Metabolic Disease?

A Q&A with Thomas N. Seyfried, PhD, Professor of Biology, Boston College
Q: As a geneticist, you know that the genomic makeup of cancers recently has captivated much of the scientific community with new knowledge and new treatments. And yet, cancer outcomes remain dismal for many patients. You have written about cancer from a very different perspective. Why do you consider cancer to be a metabolic disease, and how might we look at different therapeutic options under that rubric?
A: Over 1,600 people die each day from cancer in the U.S., according to recent data from the American Cancer Society (Siegel et al., 2018). The failure to manage cancer has been due in large part to the dogmatic belief that cancer is a constellation of genetic diseases. Accumulating evidence, however, indicates that cancer is primarily a mitochondrial metabolic disease involving disturbances in energy production through respiration and fermentation (Seyfried et al., 2014).
The disturbances in tumor cell energy metabolism are linked to abnormalities in the structure and function of mitochondria that disrupt ATP synthesis through oxidative phosphorylation (OXPhos) (Seyfried, 2015; Seyfried & Shelton, 2010). Consequently, all cancer can be considered a single disease with a common pathophysiological mechanism involving dysfunction of mitochondrial OxPhos. As reactive oxygen species (ROS) arise from defects in mitochondrial OxPhos, the gene mutations observed in various cancers and all other recognized cancer hallmarks are considered downstream effects, and not causes, of the initial disturbance of cellular energy metabolism (Seyfried, 2012; Seyfried et al., 2014).
Arising from this metabolic basis of cancer, cancer growth and progression can be best managed following a whole-body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies (Seyfried et al., 2017). Normal cells transition to ketone bodies for energy under low glucose conditions. Ketone body metabolism thus protects the brain against hypoglycemia. Tumor cells, on the other hand, cannot effectively use ketone bodies for energy due to their dysfunction in OxPhos. Therapeutic fasting and calorie restricted ketogenic diets lower cancer-provoking glucose and insulin-like growth factor (IGF-1) levels, while elevating ketone bodies (Marsh et al., 2008; Mukherjee et al., 2004; Mukherjee et al., 2002). The metabolic transition from glucose to ketone bodies reduces tumor angiogenesis and inflammation while enhancing tumor cell apoptosis.
The Press-Pulse therapeutic paradigm used with the Glucose/Ketone Index will facilitate the non-toxic management and prevention of cancer (Meidenbauer et al., 2015; Seyfried et al., 2017). In addition to glucose, tumor cells can obtain significant energy from the fermentation of amino acids, especially glutamine. The simultaneous restriction of glucose and glutamine, while under therapeutic ketosis, offers an opportunity for long-term cancer management without toxicity. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment and prevention strategy will require fine-tuning to match the therapy to an individual’s unique physiology.
The efficacy of metabolic therapy for management of malignant cancer is seen in preclinical models and in humans with various cancers (Elsakka et al., 2018; Iyikesici et al., 2017; Seyfried et al., 2014; Seyfried et al., 2017; Shelton et al., 2010; Toth & Clemens, 2016). It is anticipated that metabolic therapies targeting glucose and glutamine while increasing therapeutic ketosis will significantly improve quality of life and overall survival for most cancer patients.

Editor’s note: If you are curious to learn more about this unusual perspective on cancer, we invite you to follow these links or send us your questions via our ASK Cancer Commons service:

1. Is Cancer a Metabolic Disease?
2. Mitochondrial metabolism and cancer
3. Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer

 
References:
Elsakka, A.M.A., Bary, M.A., Abdelzaher, E., Elnaggar, M., Kalamian, M., Mukherjee, P. & Seyfried, T.N. (2018). Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up.. Front Nutr, 5, 20.
Iyikesici, M.S., Slocum, A.K., Slocum, A., Berkarda, F.B., Kalamian, M. & Seyfried, T.N. (2017). Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer. Cureus, 9, e1445.
Marsh, J., Mukherjee, P. & Seyfried, T.N. (2008). Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma. Clin Cancer Res, 14, 7751-62.
Meidenbauer, J.J., Mukherjee, P. & Seyfried, T.N. (2015). The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer. Nutr Metab (Lond), 12, 12.
Mukherjee, P., Abate, L.E. & Seyfried, T.N. (2004). Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res, 10, 5622-9.
Mukherjee, P., El-Abbadi, M.M., Kasperzyk, J.L., Ranes, M.K. & Seyfried, T.N. (2002). Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model. Br J Cancer, 86, 1615-21.
Seyfried, T.N. (2012). Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. John Wiley & Sons: Hoboken.
Seyfried, T.N. (2015). Cancer as a mitochondrial metabolic disease. Front Cell Dev Biol, 3, 43.
Seyfried, T.N., Flores, R.E., Poff, A.M. & D’Agostino, D.P. (2014). Metabolic therapy: a new paradigm for managing malignant brain cancer. Carcinogenesis, 35, 515-27.
Seyfried, T.N. & Shelton, L.M. (2010). Cancer as a metabolic disease. Nutr Metab (Lond), 7, 7.
Seyfried, T.N., Yu, G., Maroon, J.C. & D’Agostino, D.P. (2017). Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr Metab (Lond), 14, 19.
Shelton, L.M., Huysentruyt, L.C. & Seyfried, T.N. (2010). Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model. Inter. J. Cancer. , 127, 2478-85.
Siegel, R.L., Miller, K.D. & Jemal, A. (2018). Cancer statistics, 2018. CA Cancer J Clin, 68, 7-30. (https://doi.org/10.3322/caac.21387)
Toth, C. & Clemens, Z. (2016). Halted Progression of Soft Palate Cancer in a Patient Treated with the ..     . Paleolithic Ketogenic Diet Alone: A 20-months Follow-up. American Journal of Medical Case Reports, 4, 288-292. (doi: 10.12691/ajmcr-4-8-8).