Abstract
This review summarizes experimental and clinical data in support of the hypothesis that the known risk factors for Pancreatic Ductal Adenocarcinoma (PDAC), smoking, psychological stress, alcohol consumption, diabetes and pancreatitis-, create hyperactivity of the neurotransmitters norepinephrine and epinephrine in the pancreas. Smoking, psychological stress and alcohol sensitize the nicotinic acetylcholine receptors (nAChRs) that regulate the synthesis and release of PDAC stimulating stress neurotransmitters norepinephrine and epinephrine by nerves of the symapthicus, the adrenal gland and by pancreatic cancer cells and their epithelial precursor cells while simultaneously desensitizing the nAChRs that govern the synthesis and release of the PDAC inhibiting neurotransmitter g-aminobutyric acid (GABA). Experimental data generated in vitro and in animal models emphasize a key role of Gs-coupled β-adrenergic and PGE2 receptors in the activation of multiple signaling pathways by stress neurotransmitters in PDAC. The clinical behavior of PDAC confirms that sympathetic nerves that release stress neurotransmitters are important mediators of PDAC progression. Emerging experimental evidence suggests that lessons learned from the long-term management of cardiovascular disease, which is governed by sympathicus hyperactivity, can be successfully utilized to improve survival rates of PDAC patients and to prevent the development of PDAC in individuals at risk.
Highlights
Cancer of the exocrine pancreas is the fourth leading cause of cancer deaths in developed countries, with a mortality >95% within one year of diagnosis [1]
A recent study using the same ethanol concentration over a 7- day exposure period in Pancreatic Ductal Adenocarcinoma (PDAC) cells Panc1 and BXPC-3 and in immortalized pancreatic duct epithelial cells reported significant induction in the protein expression of nicotinic acetylcholine receptors (nAChRs) with subunits α3, α5, and α7. This response was accompanied by significant increases in the synthesis and release of norepinephrine and epinephrine by the cells, increased levels of intracellular cyclic adenosine monophosphate (cAMP) and activated protein kinase A (PKA) associated with increases in phosphorylated Extracellular Signal Regulated Kinases (ERK), AKT, Src and Cyclic Adenosine Response Element Binding Protein (CREB) and enhanced proliferation and migration [79]
The data compiled in this review support the hypothesis that adaptive changes of the autonomic nervous system induced by smoking, chronic psychological stress and habitual ingestion of liquorstrength alcohol play a key role in the development, progression and resistance to therapy of PDAC and occur mostly via protein induction associated with sensitization (α7nAChR) or desensitization (α4nAChR) of nAChRs that regulate the synthesis and release of stress neurotransmitters and g-aminobutyric acid (GABA), resulting in hyperactivity of Gs-mediated cAMP signaling
Summary
Cancer of the exocrine pancreas is the fourth leading cause of cancer deaths in developed countries, with a mortality >95% within one year of diagnosis [1]. In vitro studies have shown that binding of acetylcholine, nicotine or NNK to nAChRs with subunits α3, α5, and α7 jointly stimulated cell proliferation and migration of PDAC cells and immortalized pancreatic duct epithelial cells by activating the synthesis and release of norepinephrine and epinephrine [19].
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