This blog post was part of a draft for a comprehensive review paper on the ketogenic diet in the treatment of cancer.

After Otto Warburg, Thomas Seyfried is the most important and influential scientist for having put carbohydrate-restricted diets and in particular the ketogenic diet “on the map” in current cancer research, starting with seminal research in 2003 [1] and continuing to the present [2]. His influence on the reception of the ketogenic diet in the popular press has been profound. Seyfried’s papers are extensively cited and his views discussed in many recent and important reviews [3–6] as well as in the clinical trial literature [7,8]. Thus, while his views on cancer metabolism lie far outside the mainstream of cancer research, they have some influence among those interested in the use of the ketogenic diet for cancer, and it may be useful to readers to address some of the core features of these views here. As authors of a recent, major review write:

Some tumor entities are not able to properly respire due to a dysfunctional OXPHOS system. …Tumors with dysfunctional mitochondria or decreased mitochondrial activity seem to compensate their energy requirements by aerobic fermentation. Replacing glucose by ketone bodies requires that the tumors have functional mitochondria to be able to use ketone bodies efficiently for growth and survival [3].

Given its prominence in the field, if largely disregarded in most cancer metabolism research, it will be useful to now briefly critically evaluate this theory in light of available evidence.

Following Warburg [9], Seyfried claimed that cancer (and human glioblastoma multiforme in particular) have a mitochondrial respiratory defect and are therefore dependent on glucose to generate ATP. This concept formed the basis of his advocacy for the ketogenic diet for cancer, which, by restricting glucose and providing ketones in its place, would selectively cause cancer cells (which would then have no available energy substrate due to defective mitochondria) to die, while normal cells, which could use ketones, would be spared [10].

Recently, in a paper entitled “Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?”, Seyfried defended his view that cancer and in particular glioblastoma have impaired capacity mitochondrial respiration, writing:

A multitude of findings support the notion that oxidative phosphorylation is defective in GBM. Based on the biological principle that mitochondrial structure determines mitochondrial function, these multiple mitochondrial abnormalities, which can be of genetic and/or environmental origin, will compromise effective energy production through oxidative phosphorylation [italics ours][2].

Thus, Seyfried argues that their respiratory capacity should be impaired by virtue of the structural changes observed via electron microscopy. This then, according to Seyfried, underlies the basic science rationale behind using the ketogenic diet for glioblastoma multiforme [2].

However, a weakness of this suggestion should be immediately obvious: Seyfried does not provide evidence that this structural change actually leads to a functional change in respiration, i.e. that morphological changes in cancer mitochondria lead to a respiratory defect in the mitochondria. Seyfried’s evidence is strictly circumstantial, and he cites no direct evidence for his proposed mechanism. Indeed, contra Warburg and Seyfried, several investigators have shown that respiration is not defective in many cancer cells, with Sidney Weinhouse providing what many have considered to the definitive statements on the topic first in direct response to Warburg in 1956 [9,11], then six years after Warburg’s death in 1976 [10,12]. More recently, investigators have shown that lactate dehydrogenase A knockdown stimulates mitochondrial respiration, while complementation with the human ortholog LDH-A rescued the Warburg phenotype [13], suggesting that mitochondrial respiration is not defective but merely inactivated. Likewise, a paper published in 1983 showed that glioblastoma cells widely vary in their enzyme activity, with many having relatively low glycolytic activity compared to the brain and some having relatively high mitochondrial enzyme activity compared to the brain; in most cases, both glycolytic and mitochondrial enzyme activity was significantly depressed, but no pattern of metabolic enzyme expression could be gleaned, by tumor or in general, to the disappointment of investigators [14]. Another paper concluded that metabolic diversity with a sliding scale of dependence on oxidative phosphorylation and glycolysis, rather than a single metabolic phenotype, was the rule in glioma cell lines [15]. Still others suggest heterogeneity of metabolic phenotypes within a single cancer [16] and a higher degree of metabolic plasticity in cancer cells than in healthy cells [17].

Although Seyfried provides an intriguing and apparently sound series of arguments in his textbook explaining why the experiments supporting some the above findings are flawed, as well as interpretations of other experiments that would seem to contradict them [10], direct evidence for his view remains equivocal and relies on a particular and unresolved interpretation of a small body of scientific literature.

Glycolytic modulation

Perhaps more importantly, Seyfried’s theory of defective mitochondrial respiration as the cause of cancer is not necessary for glucose restriction to be efficacious in cancer. While Warburg and Seyfried’s explanation of the Warburg effect—that it is the cause of cancer—is not based on strong evidence and is at odds with the views of most cancer biologists, the existence and potential therapeutic importance of the effect itself is not in question. That therapeutic relevance will be the focus of the remainder of this discussion on the ketogenic diet for cancer.

The upregulation of glycolysis in the presence of oxygen is now understood to be an important feature of cancer cell proliferation, because such upregulation increases the activity of biosynthetic pathways that branch off of glycolysis, especially the pentose phosphate pathway, thereby enabling cancer cells to rapidly build biomolecules and proliferate [18]. According to this understanding, while glucose restriction would not selectively kill cancer cells unable to use alternative sources of energy substrate (as posited by the Warburg-Seyfried hypothesis), it might inhibit cancer metabolism sufficiently to provide an additional and adjunctive benefit when combined with conventional cancer treatments. The therapeutic implication well-known: drugs that directly inhibit glycolysis have also been shown to provide therapeutic benefit in preclinical studies [19]. A ketogenic diet, which might mimic the effect of such drugs on glycolytic flux, might therefore reverse components of the Warburg phenotype and inhibit tumor proliferation.

Correspondingly, observational studies suggest that fasting and average hyperglycemia and diets with high glycemic load might increase cancer mortality (see section Epidemiology). Animal models also seem to suggest a similar effect [1,20]. Moreover, a recent study has demonstrated that hyperglycemia drives intestinal barrier dysfunction in mice, that this intestinal barrier dysfunction is associated with changes in relevant immune cell localization, and that blood glucose levels are associated with microbial product influx in humans [21]. Because impaired intestinal barrier activity might predispose to cancer [22], together these findings suggest that glycolytic inhibition and a ketogenic diet in particular may have cancer-preventive properties, consistent with anticancer findings from animal longevity studies [23,24].

The effect of glucose in enhancing tumorogenesis was apparently confirmed by a retrospective cohort analysis showing high vs. random blood glucose levels associating with reduced survival in esophageal and lung squamous cell carcinoma patients but no difference in lung adenocarcinoma patients. Knockdown of the target gene that predicted protection from oxidative stress also slowed growth. Correspondingly, a diet that lowered blood glucose, the ketogenic diet, also caused slowed growth. However, the key experiment that would have linked the mechanism of GLUT1 expression to the efficacy of the ketogenic diet, i.e. showing that the ketogenic diet did not affect tumor growth in GLUT1 knockdowns xenografts, was not reported [25].

However, several lines of evidence substantially complicate the simple view that high blood glucose levels are directly causal in tumor growth. First, in a single-arm crossover study that provided parenteral glucose or lipid to twelve colorectal cancer patients with liver metastases and observed the impact on uptake of [18]2-fluoro-2-deoxy-D-glucose (FDG) using PET, while metastases predictably had a much greater uptake of FDG than healthy tissue, there was no difference between lipid and glucose boluses in FDG uptake in tumor metastases. Intriguingly, and in contrast to the null findings in metastases, normal liver tissue showed an increase of 60% in FDG uptake [26]. This suggests that additional available glucose is on average not readily taken up by colon cancer metastases but that normal tissue might be more flexible than tumor tissue. On the basis of current evidence, it is unclear whether other cancer types would show similar or different findings.

In another study examining the impact of parenteral nutrition on tumor cell proliferation as measured by thymidine labeling index, with seven subjects with gastrointestinal cancers in each group, the glucose-based formula caused a 32.2% increase in growth, while the lipid-based formula caused a 24.3% decrease, but these results were not statistically significant [27].

But perhaps more problematically for the claim that high blood glucose fuels cancer (based as it is almost entirely on correlations in animal models and observational studies): it has been widely known at least since Gerald Reaven’s work on the metabolic syndrome that glucose dysregulation is highly correlated with many gross metabolic disturbances [28], mediated by insulin resistance [29], and with an inflammatory phenotype [30]. Because few studies reporting to demonstrate a relationship between hyperglycemia and cancer control for these other metabolic and inflammatory markers, it is difficult to know whether the association between elevated blood glucose and cancer is causal or is instead indicative of a confounding biological variable (or variables) or both. In other words, is cancer caused or exacerbated by elevated blood glucose per se, or is the cause some other pathway that is altered in the profoundly metabolically dysregulated state that itself causes hyperglycemia? In future installments, we will discuss some of these possibilities in turn.

1.        Seyfried, T.N.; Sanderson, T.M.; El-Abbadi, M.M.; McGowan, R.; Mukherjee, P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br. J. Cancer 2003, 89, 1375–82.

2.        Seyfried, T.N.; Shelton, L.; Arismendi-Morillo, G.; Kalamian, M.; Elsakka, A.; Maroon, J.; Mukherjee, P. Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma? Neurochem. Res. 2019.

3.        Weber, D.D.; Aminzadeh-Gohari, S.; Tulipan, J.; Catalano, L.; Feichtinger, R.G.; Kofler, B. Ketogenic diet in the treatment of cancer – Where do we stand? Mol. Metab. 2019.

4.        Poff, A.; Koutnik, A.P.; Egan, K.M.; Sahebjam, S.; D’Agostino, D.; Kumar, N.B. Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma. Semin. Cancer Biol. 2019, 56, 135–148.

5.        Sremanakova, J.; Sowerbutts, A.M.; Burden, S. A systematic review of the use of ketogenic diets in adult patients with cancer. J. Hum. Nutr. Diet. 2018, 31, 793–802.

6.        Oliveira, C.L.P.; Mattingly, S.; Schirrmacher, R.; Sawyer, M.B.; Fine, E.J.; Prado, C.M. A Nutritional Perspective of Ketogenic Diet in Cancer: A Narrative Review. J. Acad. Nutr. Diet. 2018, 118, 668–688.

7.        van der Louw, E.J.T.M.; Olieman, J.F.; van den Bemt, P.M.L.A.; Bromberg, J.E.C.; Oomen-de Hoop, E.; Neuteboom, R.F.; Catsman-Berrevoets, C.E.; Vincent, A.J.P.E. Ketogenic diet treatment as adjuvant to standard treatment of glioblastoma multiforme: a feasibility and safety study. Ther. Adv. Med. Oncol. 2019, 11.

8.        Santos, J.G.; Da Cruz, W.M.S.; Schönthal, A.H.; Salazar, M.D. alincour.; Fontes, C.A.P.; Quirico-Santos, T.; Da Fonseca, C.O. Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma. Oncol. Lett. 2018, 15, 1263–1270.

9.        Warburg, O. On the origin of cancer cells. Science (80-. ). 1956, 123, 309–314.

10.      Seyfried, T.N. Cancer as a metabolic disease : on the origin, management, and prevention of cancer; John Wiley & Sons, 2012; ISBN 9780470584927.

11.      Weinhouse, S.; Warburg, O.; Burk, D.; Schade, A.L. On respiratory impairment in cancer cells. Science (80-. ). 1956, 124, 267–272.

12.      Weinhouse, S. The Warburg hypothesis fifty years later. Z. Krebsforsch. Klin. Onkol. Cancer Res. Clin. Oncol. 1976, 87, 115–126.

13.      Fantin, V.R.; St-Pierre, J.; Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006, 9, 425–34.

14.      Lowry, O.H.; Berger, S.J.; Carter, J.G.; Chi, M.M.; Manchester, J.K.; Knor, J.; Pusateri, M.E. Diversity of metabolic patterns in human brain tumors: enzymes of energy metabolism and related metabolites and cofactors. J. Neurochem. 1983, 41, 994–1010.

15.      Griguer, C.E.; Oliva, C.R.; Gillespie, G.Y. Glucose metabolism heterogeneity in human and mouse malignant glioma cell lines. J. Neurooncol. 2005, 74, 123–33.

16.      Miccheli, A.; Tomassini, A.; Puccetti, C.; Valerio, M.; Peluso, G.; Tuccillo, F.; Calvani, M.; Manetti, C.; Conti, F. Metabolic profiling by 13C-NMR spectroscopy: [1,2-13C2]glucose reveals a heterogeneous metabolism in human leukemia T cells. Biochimie 2006, 88, 437–48.

17.      Berridge, M. V; Herst, P.M.; Tan, A.S. Metabolic flexibility and cell hierarchy in metastatic cancer. Mitochondrion 2010, 10, 584–8.

18.      Heiden, M.G. Vander; Cantley, L.C.; Thompson, C.B. Understanding the warburg effect: The metabolic requirements of cell proliferation. Science (80-. ). 2009, 324, 1029–1033.

19.      Martinez-Outschoorn, U.E.; Peiris-Pagés, M.; Pestell, R.G.; Sotgia, F.; Lisanti, M.P. Cancer metabolism: A therapeutic perspective. Nat. Rev. Clin. Oncol. 2017, 14, 11–31.

20.      Iguchi, T.; Takasugi, N.; Nishimura, N.; Kusunoki, S. Correlation between mammary tumor and blood glucose, serum insulin, and free fatty acids in mice. Cancer Res. 1989, 49, 821–5.

21.      Thaiss, C.A.; Levy, M.; Grosheva, I.; Zheng, D.; Soffer, E.; Blacher, E.; Braverman, S.; Tengeler, A.C.; Barak, O.; Elazar, M.; et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science (80-. ). 2018, 359, 1376–1383.

22.      Fasano, A. Zonulin and its regulation of intestinal barrier function: The biological door to inflammation, autoimmunity, and cancer. Physiol. Rev. 2011, 91, 151–175.

23.      Newman, J.C.; Covarrubias, A.J.; Zhao, M.; Yu, X.; Gut, P.; Ng, C.P.; Huang, Y.; Haldar, S.; Verdin, E. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metab. 2017, 26, 547-557.e8.

24.      Roberts, M.N.; Wallace, M.A.; Tomilov, A.A.; Zhou, Z.; Marcotte, G.R.; Tran, D.; Perez, G.; Gutierrez-Casado, E.; Koike, S.; Knotts, T.A.; et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab. 2017, 26, 539-546.e5.

25.      Hsieh, M.-H.; Choe, J.H.; Gadhvi, J.; Kim, Y.J.; Arguez, M.A.; Palmer, M.; Gerold, H.; Nowak, C.; Do, H.; Mazambani, S.; et al. p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas. Cell Rep. 2019, 28, 1860-1878.e9.

26.      Bozzetti, F.; Gavazzi, C.; Mariani, L.; Crippa, F. Glucose-based total parenteral nutrition does not stimulate glucose uptake by humans tumours. Clin. Nutr. 2004, 23, 417–421.

27.      Rossi-Fanelli, F.; Franchi, F.; Mulieri, M.; Cangiano, C.; Cascino, A.; Ceci, F.; Muscaritoli, M.; Seminara, P.; Bonomo, L. Effect of energy substrate manipulation on tumour cell proliferation in parenterally fed cancer patients. Clin. Nutr. 1991, 10, 228–232.

28.      Meigs, J.B.; Wilson, P.W.F.; Nathan, D.M.; D’Agostino, R.B.; Williams, K.; Haffner, S.M. Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. Diabetes 2003, 52, 2160–2167.

29.      Reaven, G.M. Role of insulin resistance in human disease. (Banting Lecture 1988). Diabetes 1988, 37, 1595–607.

30.      Dandona, P.; Aljada, A.; Chaudhuri, A.; Mohanty, P.; Garg, R. Metabolic syndrome: A comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005, 111, 1448–1454.

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