Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness

Abstract

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL- ;-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL- ;LSL- ;-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Subdiaphragmatic vagotomy or knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. .

Tumor Neurobiology and the War of Nerves in Cancer

“…The case of pancreatic cancer is particularly interesting, as a recent study has highlighted that cancer stemness is suppressed by cholinergic nerves (11). In contrast to previous denervation experiments in prostate (5) and gastric (8) cancers, the authors have observed that denervation of cholinergic nerves stimulates pancreatic cancer progression (11).…”

“…It was also shown that the denervation of adrenergic nerves resulted in the inhibition of pancreatic tumor progression, and that adrenergic nerves release catecholamines that activate ADRβ2-mediated adrenergic signaling in cancer cells ( 10 ). Interestingly, cholinergic nerves and cholinergic signaling have recently been shown to inhibit pancreatic tumor progression ( 11 ), raising the possibility of a more complex neural regulation in pancreatic cancer. More than 80% of axons running in the vagus nerve are sensory ( 12 ).…”

“…More than 80% of axons running in the vagus nerve are sensory ( 12 ). Although sensory nerves have been shown to promote pancreatic cancer ( 9 ), vagal denervation accelerates pancreatic cancer ( 11 ). This observation argues for a distinct suppressive effect by the vagal cholinergic axons.…”

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

“…Moreover, we showed that sympathetic axons slow pancreatic tumor progression through local suppression of CD163 + macrophage subsets at lesion sites. Recent studies reported a similar inhibitory role of the parasympathetic nervous system in PDAC, which is exerted in part by the suppression of myeloid cells 6,7 . Tumor formation and progression have been widely regarded as dependent on autonomic nerve function, stimulating interest in clinical investigation of inhibitors of adrenergic and/or muscarinic cholinergic signaling in the treatment of certain cancers.…”

“…The role of the autonomic nervous system in PDAC development has been addressed in recent studies that have revealed a more complex and unexpected picture than that suggested by research on other cancer models. Indeed, the interruption of parasympathetic innervation or activity strongly promotes PDAC progression in Kras-mutated mouse models, revealing an unexpected anti-tumor effect of parasympathetic cholinergic signaling 6,7 . The role of the sympathetic nervous system in PDAC has been studied in terms of tumor response to stress and has shown context-dependent effects.…”