Published evidence compiled in this review supports the hypothesis that the development, progression, and responsiveness to prevention and
therapy of the most common human
cancers is strongly influenced, if not entirely orchestrated, by an imbalance in stimulatory and inhibitory neurotransmission. The
neurotransmitters acetylcholine,
adrenaline, and
noradrenaline of the autonomic nervous system act as powerful upstream regulators that orchestrate numerous cell and tissue functions, by releasing
growth factors, angiogenesis factors and
metastasis factors,
arachidonic acid, proinflammatory
cytokines, and local
neurotransmitters from
cancer cells and their microenvironment. In addition, they modulate proliferation, apoptosis, angiogenesis, and
metastasis of
cancer directly by intracellular signaling downstream of
neurotransmitter receptors.
Nicotine and the tobacco-specific
nitrosamines have the documented ability to hyperstimulate neurotransmission by both branches of the autonomic nervous system. The expression and function of these
neurotransmitter pathways are cell type specific. Lifestyle, diet, diseases, stress, and pharmacological treatments modulate the expression and responsiveness of
neurotransmitter pathways. Current preclinical testing systems fail to incorporate the modulating effects of neurotransmission on the responsiveness to
anticancer agents and should be amended accordingly. The
neurotransmitter gamma-aminobutyric acid has a strong inhibitory function on sympathicus-driven
cancers whereas stimulators of cyclic
adenosine monophosphate/
protein kinase A signaling have strong inhibitory function on parasympathicus-driven
cancers. Marker-guided restoration of the physiological balance in stimulatory and inhibitory neurotransmission represents a promising and hitherto neglected strategy for the prevention and
therapy of
neurotransmitter-responsive
cancers.