The metabolic advantage of tumor cells

1- Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases

Acetylcholine release and the cholinergic genomic locus

Choline acetyltransferase and vesicular acetylcholine-transporter genes are adjacent and coregulated. They define a cholinergic locus that can be turned on under the control of several factors, including the neurotrophins and the cytokines. Hirschprung's disease, or congenital megacolon, is characterized by agenesis of intramural cholinergic ganglia in the colorectal region. It results from mutations of the RET (GDNF-activated) and the endothelin-receptor genes, causing a disregulation in the cholinergic locus. Using cultured cells, it was shown that the cholinergic locus and the proteins involved in acetylcholine (ACh) release can be expressed separately ACh release could be demonstrated by means of biochemical and electrophysiological assays even in noncholinergic cells following preloading with the transmitter. Some noncholinergic or even nonneuronal cell types were found to be capable of releasing ACh quanta. In contrast, other cells were incompetent for ACh release. Among them, neuroblastoma N18TG-2 cells were rendered release-competent by transfection with the mediatophore gene. Mediatophore is an ACh-translocating protein that has been purified from plasma membranes ofTorpedo nerve terminal; it confers a specificity for ACh to the release process. The mediatophores are activated by Ca2+; but with a slower time course, they can be desensitized by Ca2+. A strictly regulated calcium microdomain controls the synchronized release of ACh quanta at the active zone. In addition to ACh and ATP, synaptic vesicles have an ATP-dependent Ca2+ uptake system; they transiently accumulate Ca2+ after a brief period of stimulation. Those vesicles that are docked close to Ca2+ channels are therefore in the best position to control the profile and dynamics of the Ca2+ microdomains. Thus, vesicles and their whole set of associated proteins (SNAREs and others) are essential for the regulation of the release mechanism in which the mediatophore seems to play a key rol

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

BACKGROUND: Cancer 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 Zn(2+)

Metabolic rewiring of stem cells and differentiated cells in cancer: the hypothetical consequences of a GABA deficiency in endocrine pancreas

The carcinogenic mechanism proposed considers that stem cells committed to repair tissues and differentiated cells, acquire different metabolic properties, if there is an associated GABA deficiency suppressing a control system of the endocrine pancreas. This control system mediated by GABA, released with insulin, normally turns off glucagon and somatostatin release when insulin is released. A consequence of the GABA deficiency in pancreas and adrenals is a hybrid insulin-glucagon-somatostatin message, received by new mitotic stem cells displaying then a hybrid metabolic rewiring. This gives them a selective metabolic advantage over differentiated cells that become insulin resistant and only receive the glucagon- somatostatin part of the hormonal message. Indeed, their insulin receptors are desensitized by the persistent leakage of insulin resulting from the GABA deficiency that fails to close the insulin release mechanism. Thus differentiated cells are simply rewired to be plundered by stem cells. The metabolic advantage gained by stem cells blocks their own differentiation and maintains their mitotic capacity. Inevitable mutations of mitotic cells follow, the immune system is unable to eliminate a geometrically increasing number of altered stem cells, a selection of the most aggressive but metabolically successful population takes place when cancer is declared

VIII. Judaïsme talmudique et rabbinique

Liber Maurice, Lévi Israël. VIII. Judaïsme talmudique et rabbinique. In: École pratique des hautes études, Section des sciences religieuses. Annuaire 1921-1922. 1920. pp. 45-46

VIII. — Judaïsme talmudique et rabbinique

Liber Maurice, Lévi Israël. VIII. — Judaïsme talmudique et rabbinique. In: École pratique des hautes études, Section des sciences religieuses. Annuaire 1924-1925. 1923. pp. 46-49

VIII. Judaïsme lalmudique et rabbinique

Liber Maurice, Lévi Israël. VIII. Judaïsme lalmudique et rabbinique. In: École pratique des hautes études, Section des sciences religieuses. Annuaire 1922-1923. 1921. pp. 52-55

VIII. — Judaïsme talmudique et rabbinique

Lévi Israël, Liber Maurice. VIII. — Judaïsme talmudique et rabbinique. In: École pratique des hautes études, Section des sciences religieuses. Annuaire 1925-1926. 1924. pp. 37-38

VIII. Judaïsme lalmudique et rabbinique

Liber Maurice, Lévi Israël. VIII. Judaïsme lalmudique et rabbinique. In: École pratique des hautes études, Section des sciences religieuses. Annuaire 1922-1923. 1921. pp. 52-55