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Page 10 of 12 Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78

CONCLUSIONS AND PERSPECTIVES
An overview of the carcinogenic mechanism proposed, considers that stem cells receive an anabolic message:
“divide and make the constituents for new cells” in order to replace altered cells by whatever cause. These
stem cells will then have to synthesize fatty acids and lipids for making new membranes. Fatty acid synthesis
automatically closes via malonyl CoA, their beta oxidation, and shuts the fatty acid source of acetyl CoA.
Since there is an associated pancreatic GABA failure, there is a catabolic message sent in parallel to insulin,
and glucagon cuts the glycolytic supply of acetyl CoA as well, by eliciting the phosphorylating of PK and
PDH. Normally this occurs in neoglucogenesis and should be reversed by the anabolic insulin message; but
here, this does not occur. Insulin did stimulate via IP3 and calcium the PDE that hydrolyses cAMP, which
boosted glycolysis by increasing Fruc2-6 bisP, and calcium did stimulate glucose uptake by incorporating
transporters in the membrane, but the end of glycolysis remains OFF, closing the glycolytic supply of acetyl
CoA. The persistent blockade of the de-phosphorylation of PK and PDH and their inhibition, comes from
an elevated DAG that maintains the stimulation of PKC and CPI 17 inhibitor of PP1, which fails to activate
PK and PDH. What kept DAG elevated is again a consequence of the GABA failure. Indeed, the GABA
deficiency increases epinephrine release as well, which turns off STH and thus activates GH; the latter will
stimulate ATGL, which increases DAG that stimulates PKC, closing the glycolytic source of acetyl CoA.
Since the two sources of acetyl CoA, from fatty acids, and from glycolysis are blocked, the mitotic stem cell
will have to get acetyl CoA from ketone bodies, reconverted into acetyl CoA by the reversible ketogenic
pathway. This is possible if liver cells are maintained in catabolism to form ketone bodies. Well, this is
again a consequence of the GABA failure, because a persistent leakage of insulin desensitizes their insulin
receptors, rendering differentiated cells resistant to insulin, while responding to glucagon. Adipocytes
provide fatty acids that will form in the liver these ketone bodies. As for the muscles, which are also
insulin resistant, they receive the catabolic message through epinephrine and cortisol, the beta oxidation
of fatty acids operates in muscles, but since the citric acid cycle Krebs cycle “turns” in muscles, acetyl CoA
condenses with OAA coming via PEPCK and forms citrate, rather than ketone bodies. In muscles an intense
proteolysis takes place, they provide amino acids to stem cells for making their proteins, and to liver for
neoglucogenesis. The adipocytes respond preferentially to the catabolic component of the hybrid pancreatic
message (they become insulin resistant) and provide fatty acids to liver and muscle. The amino acids
processed by the transamination chain form pyruvate, and lactic acid is released by stem cells and muscles.
In liver, a large part of this pyruvate feeds the neoglucogenic route.

Thus, the new mitotic stem cells that have not been chronically desensitized for insulin receive the dual
hybrid message and the metabolic advantage they gain over the differentiated cells that are plundered, opens
the road for these stem cells to cancer. Their differentiation is blocked, their number increases geometrically,
inevitable mutations select the most aggressive population, the immune system fails to eliminate such cells.

A comment of some perspectives might be useful; the finding that diabetes type 1 result from the auto-
immune destruction of beta cells by anti-GAD antibodies is certainly a major discovery, particularly if
we consider that GABA is an essential regulator in the endocrine pancreas. These anti-GAD antibodies
were detected in most cases, and were even implicated in type 2 diabetes. An interesting attempt to
prevent diabetes using a “GAD vaccination” for preserving beta cells, did not yet give the expected results.
Presumably, the network of anti-GAD antibodies and anti-idiotype antibodies is an equilibrium that is
difficult to displace. There is still some condition to be found and hopefully a preventive vaccination will
someday become efficient. This question is particularly relevant here, since we suspect that the GABA
deficiency of beta cells in the pancreas is the starting point of a metabolic rewiring process of stem cells
and differentiated cells that leads to the carcinogenic transformation of stem cells. Hence, preserving the
[19]
pancreatic GABA ergic system may not only prevent diabetes but presumably cancer as well. It would be
interesting to look for eventual anti-GAD antibodies in cancer as it was done for diabetes. One may also