The data summarized in this review suggest that neurotransmitter receptors of the (-adrenergic, nicotinic, and GABA families are critically involved in the development and progression of some of the most common human cancers and that cross-talk between (-adrenergic, membrane estrogen, and EGF receptors can greatly amplify the resulting signals. Small airway epithelial cell-derived adenocarcinoma of the lungs, duct-derived adenocarcinoma of the pancreas as well as ER+ and ER- adenocarcinomas of the breast all appear to be under positive growth control by p-adrenoreceptors. In the case of ER-breast cancer cells, GABA has been shown to counteract the p-adrenergic stimulation of cell migration. In light of the prominent inhibitory effects of this neurotransmitter in the central nervous system, it is to be expected that GABA may also inhibit p-adrenergic receptor-mediated stimulation of cell proliferation in adenocarcinomas of the lungs, pancreas, and breast. Studies to test this hypothesis are currently underway in our laboratory. In addition, p-adrenergic signaling counteracted by GABA has been implicated in the migration and metastatic potential of adenocarcinomas of the colon . On the other hand, the a7nAChR has documented stimulatory effects on the growth of SCLC and this response appears to be counteracted by p-adrenergic receptor signaling. The susceptibility of these neurotransmitter receptors to agonists and antagonists can be greatly modulated by preexisting disposition, environmental factors, life style, preexisting non-neoplastic diseases and the chronic intake of certain medications. The receptors can be up or down-regulated by chronic exposure to lig-ands and they can be sensitized or desensitized by agents that increase or decrease their second messenger signals. In addition, exposure after cessation of smoking to agents that stimulate or inhibit such receptor-mediated pathways may promote or prevent the progression of premalignant lesions and small tumors into overt cancer. It is particularly worrisome that recent studies have identified agents widely believed to have general cancer preventive effects as stimulators of intracellular cAMP. Among such agents are P-carotene , green or black tea which contain significant levels of the phosphodiesterase inhibitors theophylline and caffeine, as well as several soy isoflavones and plant polyphenols . Investigations in human small airway epithelial cells and adenocarcinoma cells that expressed the bronchiolar Clara cell-specific CC10 protein have shown that p-carotene stimulated the proliferation of these cells by increasing intracellular cAMP, leading to activation of PKA, CREB and ERK1/2 . By contrast, increased cAMP and PKA activation in response to p-carotene caused a strong inhibition of cell proliferation and ERK1/2 activation in human large airway epithelial cells . Accordingly, the effects of cAMP and its upstream receptors are highly cell type-specific and may have promoting effects on the most prevalent human adenocarcinomas while inhibiting SCLC and other cancers derived from cells (e.g. large airway epithelial cells) under negative growth control by cAMP. In addition, long-term management of cardiovascular disease by p-blockers, or the chronic use of p2-AR agonist inhalers in asthmatics may significantly modulate the risk for the development of cancers influenced by p-adrenergic signaling. On the other hand, a host of neurological and psychiatric disorders include malfunctioning nAChR signaling and are clinically managed by nicotinic agonists or stimulators of effectors of these receptors. Tools, such as molecular imaging of receptors and signaling components need to be developed to identify which signaling pathway(s) are hyperactive in individuals prior to the manifestation of cancer, in order to selectively inhibit those pathways and thus prevent the development of cancer in a custom-tailored way.
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