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Page 2 of 12 Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78

Keywords: Cancer metabolism, endocrine pancreas, adrenals, GABA, stem cells, differentiated cells

INTRODUCTION
Since the early observations of Warburg on cancer metabolism showing the lactic acid increase even in
[3]
[1,2]
the presence of oxygen (Warburg effect) , until the seminal works of Mazurek and Eigenbrodt and
[4]
Eigenbrodt et al. on pyruvate kinase (PK) M2 blockade in tumors, much progress has been made on
[5,6]
metabolic rewiring processes in cancer . An increasing number of works are interestingly gathered
[7]
in special issues on cancer metabolism . However, they deserve to be included in a more general frame
proposing a mechanistic explanation for metabolic rewiring processes in cancer. In parallel, there is great
interest for diets, natural products and life styles that would decrease cancer incidence. Presumably, the
idea is that a diet might influence metabolism and the epigenetic control of genes that have been implicated
in cancer incidence. It is for example shown that a simple dietetic mixture: curcuma and poly unsaturated
[8]
fatty acid, gives protection against a carcinogen (Dimethyl Benz Anthracene) in animal models . There
are several observations linking nutrition and cancer, reminding that nutrition has evidently metabolic
consequences that may change the incidence of diseases, including cancer.

Paradoxically, even viral or cellular oncogenes that initially pointed toward a viral or genetic cause for
cancer, reinforced the metabolic cancer model, because the genes that were up-regulated by the viral or
cellular oncogenes encoded for proteins supporting the different steps of signaling pathways similar to
the one activated by insulin, via tyrosine kinase receptors. With insulin signaling, glycolytic metabolism
evidently came back on the stage. However, a general frame that would explain the metabolic rewiring
process in cancer, its effects on stem cells and differentiated cells remained to be proposed; this was started
in previous works [9-13] and is continued in this presentation.

A surprisingly low number of metabolic “switch compounds” control the direction of major metabolic
pathways in a network of enzymes that support the different metabolic finalities reached by a cell in response
to its receptors. The cascades of signals that follow coordinate the enzymes and the pathways direction
towards a specific metabolic finality responding to a physiological situation. Schematically, the finalities to
reach are: (1) the catabolic production of nutrients (glucose and ketone bodies) when food gets scarce; (2) the
production of energy, with a possible selection of the energetic source (glucose, fatty acids, eventually ketone
bodies); (3) the anabolic synthesis of new constituents for new mitotic cells, which requires energy and the
substrates for making these constituents. In addition, anabolic hormones increase glycogen and lipid tissue
stores when food is available. These metabolic finalities are controlled by the ON or OFF status of major
enzymes, activated or inhibited by phosphorylation via their respective protein kinases or phosphatases,
themselves controlled by “switchboard” kinases and phosphatases activated by specific receptors. In previous
works we have analyzed the phosphorylation status of key enzymes in given physiological situations
covering the finalities considered. A coherent set of phosphorylation of these enzymes was associated to the
action of catabolic hormones (glucagon, epinephrine and cortisol). The phosphorylation status was opposite
for anabolic hormones such as insulin or IGF. The conclusion was that in cancer, enzymes such as PK and
pyruvate dehydrogenase (PDH) remained phosphorylated and blocked in their catabolic configuration,
even if the cell had switched from catabolism to anabolism; as if the action of a switch board phosphatase
had failed. In such condition, the cell had to rewire its metabolic pathways in order to by-pass the PK and
PDH “bottle necks”, the resulting metabolism was favorable to its development at the detriment of other
differentiated cells that become their nutritional reservoir; this perverted finality seems to be a starter for
cancer. We shall first consider the status of major control switches, for the three major metabolic finalities
and then analyze the unique hybrid configuration of these switches in cancer, showing how pathways are
reconnected in mitotic stem cells, or in differentiated cells. It will become apparent that a non-coherent