Whether the publications of nutritional guidelines, which the DGE, DACH, DKG and comparable institutions periodically undertake, are rather the cause or the consequence of this unjustified discrediting remains to be seen. What is important at this point is to state that the ketogenic diet is a conclusive and consistent nutritional therapy that should be the foundation of every cancer therapy. The following paper provides evidence and pleads for an urgently needed paradigm shift in the assessment of the ketogenic diet: so that we – in the sense of the patient – can finally escape the mental prison of nutritional ideology.

Just recently, a series of dogmatic theses (heart-lipid hypothesis, cholesterol hypothesis, high-carb-low-fat thesis), which until then had been the basis of the official dietary recommendations as a scientific canon of values, were dismantled by the very journalistic organ that had itself contributed significantly to the cementing of these very dogmas over the last 40 years: the New York Times. The dismantling was initiated in 2002 by the seminal essay by Gary Taubes: What if It’s All Been a Big Fat Lie? But the institutionalised nonsense was finally buried on 23 June 2014 with the groundbreaking essay by Bryan Walch in NYT Magazine: Eat Butter. Scientists labeled fat the enemy. Why they were wrong.

The cost to the health of millions of people of this decades-long collective misdirection and misguidance about nutrition can be glimpsed in the pandemic development of obesity, cardiovascular disease, diabetes and cancer. If we succeeded in clearly and verifiably working out the processes of cancer that can be influenced by nutritional therapy, we would be able to derive sensible therapy proposals not only for the area of nutrition, but also for a future biological, not least also orthodox medical cancer therapy.

The root of chronic diseases

In my opinion, the vast majority of chronic and chronic-degenerative diseases, including cancer, have their main causes in the following triad: 1. western diet and lifestyle, 2. environmental toxins, 3. emotional stress.1 Overfeeding and poisoning, not least also iatrogenically caused, play the central role in chronic processes. It is worth remembering here that Waltraud Fryda pointed out the role of adrenaline as an insulin antagonist in connection with diabetes and cancer as early as the early 1980s. Prolonged stress leads to depletion of the adrenaline pool and thus initially to what she calls the symptom of decompensated adrenaline deficiency diabetes. As a consequence, a derailment of the sugar metabolism is also a possible starting point for malignant diseases.2 In contrast, numerous studies show that only 5 – 10 % of tumour incidents are genetically caused.3 But even here, the question must be asked whether such genetic damage is not already a consequence of triad damage from earlier generations.

In recent decades, interest in tumour metabolism has increased exorbitantly, especially in the sugar metabolism of tumours. Science and the pharmaceutical industry see tumour metabolism as a new starting point for targeted therapy, after other targets such as cell division, angiogenesis or surface receptors have so far failed to achieve the desired success. The focus of this research is on three levels: the inhibition of the most important metabolic pathways in tumour cells (glycolysis, pentose phosphate pathway, glutaminolysis), a better understanding of the signalling pathways regulating the aforementioned metabolic pathways (PI3K/AKT, mTOR, TIGAR, LKB1/AMPK, HIF-1, hexokinases, c-Myc, etc.), and the microenvironment of the tumour cells. ) as well as the microenvironment of the cancer cell (pH, O2, antioxidant capacity, toxin load, ROS, immunological niche, etc.), keyword: niche pressure.

Fine tuning the Warburg hypothesis

An important starting point for research aimed at the sugar metabolism of the tumour and its signalling pathways is, of course, the Warburg hypothesis. According to this hypothesis, mitochondria suffer a loss of function and the affected cells are therefore forced into a forced fermentation metabolism (aerobic glycolysis). Acquired mitochondriopathy would thus be a decisive reason, if not the cause, for the development of cancer. Post-war developments and the scathing dictum of Robert Weinberg, a US molecular geneticist known for his six (later seven) hallmarks of cancer, long prevented a broader reception of Warburg’s findings in the Anglo-Saxon world. Only in the last two decades, and not least due to more modern methods of analysis, which confirm Warburg’s theses to a large extent, has this situation changed. Diagnostically, the dependence of cancer cells on an increased glucose uptake has proven useful for the detection of tumours and their progress monitoring with the help of positron emission tomography, as can be seen in Fig. 1. Radioactively labelled (18F)-fluorodeoxyglucose (FDG) is infused, a sugar that accumulates in the tumour tissue but cannot be further degraded by it (FDG-PET).4 Therapeutic consequences have not yet been drawn from this, at least not in Germany, with a few exceptions such as the University Hospital in Würzburg. On the contrary: glucose infusions are still primarily preferred for tumour patients as therapeutically effective for their nutrition.

Fine tuning

Despite all the enthusiasm about the long overdue renaissance of the Warburg hypothesis, we must not leave out constructive criticism of Warburg’s findings if we want to oppose the general scepticism from a professional point of view. Recent findings require a fine tuning of his hypotheses, but this does not detract from the pioneering nature of his groundbreaking work. Many of the more recent findings have only become possible due to the explosive development in the penetration of biochemical details in recent decades. For example, Heine rightly remarks that Warburg did not differentiate sufficiently between aerobic and anaerobic glycolysis.6 However, Warburg not only did not differentiate sufficiently with regard to fermentation, but also erred in other details, which in part lends justification to DKG’s criticism.

Warburg assumed damage to the respiratory chain as the cause of malignant processes (de-differentiation caused by an acquired mitochondriopathy). However, this is only one case of several possible causes, since the malignant process and thus the initiation of aerobic glycolysis can also be caused by the cancer cell itself. The mitochondriopathy is then the consequence, not the cause, of the malignant transformation.7 Overall, we can attribute the complexity of the Warburg effect to three causes:

• the uncoupling of fermentation and oxidation with aerobic glycolysis, originating from the tumour cell.
• the blockade of the citrate cycle controlled by the TC
• Mitochondriopathy as a disturbance of the OxPhos chain.

I would like to deliberately avoid using the term mutation at this point, because hardly any medical doctor, biologist or biochemist nowadays knows that mutation was brought into play as a fighting term by the Dutch biologist Hugo Marie de Vries against the discoveries of the pleomorphists, who co-dominated the biology scene at least until the end of the 1930s. The monomorphists, who adhered to Social Darwinism, used the concept of “degeneracy” (mutation) to pursue a Weinberg-style scientific neutralisation strategy against dissenters at the time. The lack of dogma history at universities unfortunately leads to the unquestioned and habitual use of such terms. In my opinion, Heine therefore speaks much more correctly of the “genetic fixation of the Warburg effect in tumour cells”.6 This “behaviour” of the tumour cell is therefore an inherent prerequisite of the cancer stem cell to be able to adapt to changed milieu conditions (niche pressure) to ensure survival and has nothing to do with “degeneration”. It corresponds to what Enderlein called the “antartic law” (striving to secure the milieu) of microbes.

Metabolic Tumor Typing

Another aspect was noticed by Warburg himself during his lifetime due to the high ammonia release and openly discussed in the 1950s. It is of not insignificant importance for the differentiation of tumours via their metabolic pathway – or for a therapeutic strategy to be derived from it. Warburg initially assumed that the large amounts of lactate he found were produced exclusively by fermentation. Later, however, he discovered that a not inconsiderable part of the lactic acid produced was the waste product from the breakdown of glutamine. Compared to fermentation, glutaminolysis provides considerably more energy and also provides substrates for the synthesis of nucleic and fatty acids. This naturally raises the question of why a tumour cell then ferments at all. The solution to the riddle lies in the fundamental advantage of fermentation as the most original and primitive form of energy metabolism compared to glutaminolysis: its absolute robustness and frugality. It functions even under hypoxic conditions, whereas glutaminolysis always requires oxygen and mitochondria. From the point of view of a tumour stem cell, the last resort that saves survival is therefore always fermentation.

With a view to niche pressure, metabolic and signalling pathways of tumour cells, Florian Schilling has developed a diagnostic toolbox in which he has further developed the already known tumour typing, i.e. the question of the original population of tumour cells and their differentiation via antigenic and genetic characteristics, into metabolic tumour typing.7 In doing so, he has pursued the following questions: Which tumour type has which nutrient requirement? Which signalling pathways are impaired or altered in favour of the tumour? What milieu conditions underlie the specific tumour processes? And last but not least: What type of origin does the tumour have? In other words: What type of stem cell tumour (omni-, multi-, pluripotent) and what proportion of the total fraction of the tumour do they have, respectively how high is the proportion of clonal daughter cells?

If we take a closer look at the classification of tumour metabolic types, experience shows that four metabolic types can be distinguished from this perspective and differentiated by the frequency of their occurrence as follows:

• Aerobes (about 5 %)
• mild fermenters (Warburg-light: fermentation in combination with glutaminolysis, about 60 %)
• massive fermentations (classic Warburg type, about 20 %)
• Glutaminolysis (about 15 %)

Both subclasses of aerobic fermenters together reach about 80 % of tumours compared to the 20 % of oxygen-dependent ones. But before one hastily argues away from Warburg and the glucose question here because of 20 %, one should ask oneself whether this kind of quite tempting metabolism is really advantageous for the tumour cell. After all, it has access to all nutrient classes (proteins, fats, carbohydrates) through oxidative phosphorylation. But for one thing, even the “aerobe” still needs fermentation. But because the fermentation mode is mandatory for proliferating cells, aerobic tumours have to make considerable concessions at this point in terms of their division rate and resistance. This in turn makes them easier to attack than fermenters.

In addition, it should be noted that all proliferation-capable stem cells – and thus also tumour stem cells – already ferment physiologically more strongly in resting mode, since in the cell division process mediated by growth factors they shut down their oxygen radical-producing aerobic metabolism and switch to fermentation mode in order to protect the DNA from accumulating ROS and at the same time provide appropriate intermediate substrates for nucleotide synthesis via the switch to the pentose phosphate pathway (PPW). The higher the stem cell fraction of a tumour, the more fermentation-heavy it is. And since only the sugar-hungry and malignant stem cell fraction of a tumour is capable of emigration and metastasis, and sometimes the formation of new tumours, sugar generally plays a key role in malignant processes.8 An extreme special case of aerobic tumours is often used as an argument against KD, as it can occur in non-solid malignant cells (e.g. leukaemia cells). In this case, the tumour indeed also uses fats, although these are not predominantly used for the synthesis of ATP via the partially decoupled combustion, but for the generation of heat energy in the cytochrome oxidase.

Preliminary conclusion

From these remarks it becomes clear that in the past one has concentrated too much on seven hallmarks of the tumour that have risen to date (self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, avoidance of immunosurveillance). In my opinion, the most important hallmark, which is now recognised as the eighth hallmark, was overlooked for a long time – not least thanks to the Weinberg neutralisation strategy of the Warburg hypothesis: namely the tumour metabolism itself. In this context, however, the metabolic heterogeneity of tumour metabolism and the complexity of the Warburg effect should not obscure the fact that fermentation is still the “biological signature of the tumour”. 9 It is the all too obvious return of the cancer cell to the most primal, primitive and at the same time most stable of all energy metabolisms. It ensures its survival. But this dependence on sugar is also the tumour’s decisive Achilles’ heel. And why on earth should a nutrient that plays such a key role in tumourigenesis not be included in therapeutic considerations?

I gratefully accept the concept of genetic fixation of the Warburg effect in tumour cells proposed by Heine as quite compatible with the observations of pleomorphism also in the changes of signalling pathways in the metabolism of cancer cells, since it allows us to understand what is happening as a predisposed reaction of the tumour cell and not as a wild degeneration. All the signalling pathway changes point to a single

Goal: the predominance of the oxygen-independent sugar mode as the archaic metabolic pathway that ensures the survival and growth of the tumour. The fact that tumours can also do other things at the same time does not change this fundamental insight. Even in the case of aerobes or those tumours that predominantly carry out glutaminolysis, the cancer cell retreats into the archaic fermentation mode as a survival reaction to niche pressure (toxins, hypoxia, ROS, etc.). Let’s make life difficult for it and limit its most important fuel: sugar – with the help of the ketogenic diet.

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Literature:

1. Vgl. hierzu: Mutter J (2012): Grün essen!: Die Gesundheitsrevolution auf Ihrem Teller. VAK Verlag
2. Fryda W (1980): Diagnose: Krebs. Selbstverlag, Neuauflage 2003/4
3. Pfetzer N (2011): Identifizierung und Testung spezifischer Inhibitoren des Energiestoffwechsels von Tumorzellen. Dissertation, Julius-Maximilian-Universität Würzburg
4. Cairns R et al. (2011): Regulation of cancer cell metabolism. Nature Reviews
5. Abbildung mit freundlicher Genehmigung von Dr. Rainer Klement. Klement R (2014): Kalorien, Kohlenhydrate und Krebs. Spezialausgabe, Carb Smart Magazine
6. Heine H (2013): Von der Entzündung zum Krebsgeschehen. Teil II: Der Warburg-Effekt – Vorausset- zung zum Verständnis des Tumorstoffwechsels. Die Naturheilkunde 2013, Heft 6. (Heine 2013)
7. Schilling F (2014): Tumorstoffwechsel – Metabolic Tumor Typing Internes unveröffentlichtes Arbeitsmanuskript. (Schilling 2014)
8. Schilling F (2013): Biologische Tumortherapie, Teilnehmerskript zum Tumorseminar in Zypern (Schilling 2013)
9. Seyfried T (2012): Cancer as a Metabolic Disease. On the Origin, Management, and Prevention of Cancer. Wiley Verlag