Figure 3. Working model of the regulation of pancreatic ductal adenocarcinoma by neurotransmitters, their receptors and downstream effectors.

Chronic exposure to nicotinic agonists in tobacco products and in the human environment cause nAChR changes analogous to those in the nicotine-addicted brain (compare with Figure 2). The resulting predominance of stimulatory adenylyl cylase-dependent signaling and relative deficiency in inhibitory GABA leads to the selective activation of cell proliferation, migration and angiogenesis while inhibiting apoptosis. In addition, psychological stress activates this cancer-stimulating cascade by causing the release of acetylcholine that activates α₇nAChRs in the nervous system and nAChRs containing the α₃-or α₅-subunits in the hypothalamus and adrenal medulla, resulting in the release of noradrenaline and adrenaline into the bloodstream.

AA: Arachidonic acid; AKT: Serine threonine protein kinase B;

βAR: β-adrenergic receptor; CREB: cAMP response element binding;

EGFR: EGF receptor; GABA-B-R: GABA-B receptor; nAChR: Nicotinic acetylcholine receptor; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;

PKA: Protein kinase A.