Editors' ChoiceCancer

Of nerves and stomach cancer

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Sci. Signal.  07 Mar 2017:
Vol. 10, Issue 469, eaan0914
DOI: 10.1126/scisignal.aan0914

Blocking a feed-forward cholinergic loop between gastric neurons and the mucosal epithelium may inhibit proliferation in tumor-associated stem cells.

Peripheral nerves that innervate the gastrointestinal mucosa release acetylcholine that stimulates the proliferation of stem cells, which promotes organogenesis during development and helps maintain homeostasis of the gut in adults. However, stem cell proliferation is also associated with tumor development. Hayakawa et al. found a feed-forward signaling loop between nerves and enteric tumor cells that promote tumor growth (see commentary by Monje). In various mouse models, acetylcholine released from the nerves stimulated the proliferation of LGR5+ crypt stem cells in the gastric epithelium in a manner dependent on YAP-to-WNT signaling. Nerve growth factor (NGF) secreted by those stem cells then triggered the recruitment of more cholinergic neurons to the gut, stimulating further stem cell proliferation. Blocking NGF or cholinergic signaling inhibited tumor development in mice. NGF and YAP abundance correlated with each other and with tumor stage and metastasis in tumor samples from gastric cancer patients. The findings suggest that this intercellular axis could be targeted to slow tumor growth in patients.

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