A possible primary cause of cancer: deficient cellular interactions in endocrine pancreas

Abstract

BackgroundCancer is a devastating type of disease. New and innovative ways to tackle cancers that have so far proved refractive to conventional therapies is urgently needed. It is becoming increasingly clear that, in addition to conventional therapeutics targeting by small molecules, that tumor cell metabolism presents new opportunities to target selectively specific cancer cell populations. Metabolic defects in cancer cells can be manifested in many ways that might not be readily apparent, such as altering epigenetic gene regulation for example.The complex rewiring of metabolic pathways gives tumor cells a special advantage over differentiated cells, since they deplete body stores as fuel for their growth and proliferation. Tumor metabolism looks simpler when we consider that some enzymatic switches are in a neoglucogenic direction thereby depleting body stores. However, these pathways may be inadequately switched on by catabolic hormones (glucagon, epinephrine and cortisol) in a specific situation where anabolism is activated by, for example insulin released from beta pancreatic cells or IGF, inducing mitosis and synthesis that are powered by glucose catabolism. Such a hybrid metabolic situation would be reached if a pancreatic beta cell mechanism, mediated by GABA, failed to silence neighboring alpha cells and delta cells. The inhibitory transmitter GABA hyperpolarizes alpha and delta cells via their GABA A receptors, and blocks the release of glucagon and somatostatin. Alternatively, an anomaly of alpha cell channels, would lead to a similar situation. Whatever is the alteration, anabolism fails to silence catabolism and enzymatic switches controlled by kinases and phosphatases adopt an inadequate direction, leading to a hybrid metabolic rewiring found in cancer. It is daring to formulate such a hypothesis as this. However, it is quite possible that the starting point in cancer is an alteration of the endocrine pancreas, suppressing the mechanism by which beta cells silence the neighboring alpha and delta cells, with GABA and Zn2+.

Nutrition-dependent GABA deficiencies in endocrine pancreas causes cancer as shown for betel nut consumers and for diets with low vitamin B6

“…Blockade of GABA receptors is also a risk. Most of the nutritional conditions examined that disrupted this pancreatic GABAergic control system were associated with cancer, in agreement with the hypothesis 3,32 . Niacin suppressed pellagra and vitamin B 1 suppressed Beriberi.…”

“…Epinephrine inhibits pancreatic delta cells and does the job for GABA, which is deficient. Thus, epinephrine decreases somatostatin release from delta cells and increases the actions of growth hormone and Insulin like growth factor (IGF) 3 . We know that IGF activates the tyrosine kinase receptors and boosts the action of insulin, triggering the mitogenic MAPK pathway.…”

“…The blockade of alpha and delta cells by beta cells becomes gradually less efficient. Glucagon and somatostatin are then released even when insulin secretion operates 2,3 . A hybrid mixed metabolism gradually takes over; it associates glucagonmediated effects, mobilizing body stores via catabolic hormones, and insulin actions that mediate anabolism, particularly in mitotic cells that renew tissues.…”

Altered Controls Transforming Normal Metabolism into Carcinogenic

“…It is precisely what one may fear if there is a failure of the pancreatic GABA control switch that may have many causes: pesticides, inhibitors of GAD, low GAD cofactor vitamin B6, or anti GAD auto-antibodies that are known to provoke diabetes [7,8]. As we shall see, a failure of this switch, explains the observed phosphorylation of enzymes in tumors, the metabolic rewiring and advantage gained by tumor cells over differentiated cells.…”

“…Whereas, mitotic stem cells display a dual response, with a blocked PDH associated to an increase of fatty acid and lipid synthesis; the subsequent increase of malonyl-CoA blocks their mitochondrial fatty acid carnityl transporter. Hence, the only way for these cells to get their acetyl-CoA is to convert ketone bodies into acetyl-CoA and thus to live at the expense of differentiated cells resistant to insulin but responding to glucagon [2,[7][8][9], this advantage starts their carcinogenic transformation.…”