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Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78 Page 3 of 12

mixed hormonal signal is received by new mitotic cells with new receptors, while differentiated cells with
desensitized insulin receptors, resistant to insulin, will respond preferentially to catabolic hormones and
to growth hormone (GH). We have in earlier works considered that a failure of the endocrine pancreas,

would explain the aberrant hybrid hormonal signaling that supports cancer metabolism. Indeed, insulin
secreting beta cells in the pancreas possess a major GABA control system that normally turns off glucagon
releasing alpha cells and somatostatin releasing delta cells, when beta cells release insulin and GABA. The
released GABA also closes via auto receptors of beta cells, the release of insulin. Thus a GABA deficiency
would not only fail to turn off glucagon release when insulin is released, sending a dual hybrid glucagon-
insulin message, but also maintain a steady leakage of insulin that desensitizes with time, insulin receptors.
New mitotic stem cells with new insulin receptors, not yet desensitized for insulin will then respond to both
insulin and glucagon, while other differentiated cells constantly submitted to an insulin leakage become
resistant to insulin. The stem cells will have to rewire their metabolic pathways in response to the hybrid
message; they gain a special metabolic advantage over differentiated cells that are simply plundered, since
they only respond to the catabolic component of the hybrid message.

The carcinogenic mechanism proposed considers that stem cells committed to repair tissues after a variety
of injuries and differentiated cells develop different metabolic features, if there is an associated GABA failure
in the endocrine pancreas [9,10] . The pancreatic GABA deficiency hypothesis that fully explained the observed
metabolic rewiring in cancer was initially published in reference 9; the hypothesis was confirmed and
strengthened by a set of epidemiological observations that were gathered in reference 10. These observations
also included the more controversial role of some pesticides that may affect GABA, a point that was not
particularly appreciated. The metabolic advantage given to stem cells by the pancreatic deficiency blocks
their differentiation and maintains their mitotic capacity; while differentiated cells are plundered. Inevitable
mutations follow, while the immune system becomes unable to eliminate a geometrically increasing number
of altered stem cells, a selection of the most aggressive and metabolically successful population starts cancer.
Presumably, this metabolic trigger for carcinogenesis starts years before cancer appears, correcting the
GABA pancreatic failure, or neutralizing eventual auto-antibodies against glutamate decarboxylase (GAD),
or suppressing its inhibition, might delay or avoid cancer. When cancer is declared present therapies might
be backed-up by a metabolic treatment aiming to reverse the rewiring process that gave to tumor cells their
metabolic advantage.

METABOLIC SWITCHES ORIENT PATHWAYS TOWARDS DIFFERENT METABOLIC FINALITIES
We represented in Figure 1, the endocrine pancreas, with its beta, alpha and delta cells that secrete
respectively insulin, glucagon and somatostatin (STH). The GABA release from beta cells inhibits alpha
and delta cells (via GABA A receptors) when insulin is released; and puts an end to insulin release (via
GABA B auto receptors). GABA also inhibits epinephrine release from adrenals. We describe with different
colors the pathways that operate for the different metabolic finalities that a cell is susceptible to reach, and
give in the corresponding colored boxes the status (increase +, decrease -, or 0 not relevant ) of the selected
switches. First finality: The production of nutrients; triggered by catabolic hormones, glucagon, epinephrine,
and cortisol (yellow pathways and yellow box Figure 1). When food gets scarce, the pancreas senses the
drop of blood glucose, hyperpolarized beta cells retain GABA, no longer spilled over alpha cells and their
relative depolarization triggers the release of glucagon. The action of glucagon on liver glucagon Gs coupled
receptors, or that of epinephrine on beta adrenergic receptors in muscles, stimulates adenylate cyclase and
the synthesis of cAMP. The latter, activates PKA serine kinase then Src tyrosine kinase, eliciting in fine, via
specific protein kinases, the phosphorylation of a set of enzymes that are ON or OFF after phosphorylation.
Glycogen phosphorylase a, is ON, supporting glycogenolysis, while PK and PDH are OFF closing the entry
of the citric acid cycle, this spares oxaloacetate (OAA) at the start of the neoglucogenic pathway; pyruvate
carboxylase (Pcarb) and phosphoenolpyruvate carboxykinase (PEPCK) are both activated. The blockade of
PK by phosphorylation, avoids a reconversion of phosphoenolpyruvate (PEP) into pyruvate (PYR). Muscle