Fig. 3: A bidirectional crosstalk between nerves and cancer in pancreas and liver.

Nerve fibers as branches of neuron infiltrate the TME and control cancer cells initiation, growth and metastasis mainly through three interactions pathways: a Direct contact in a synapse pathway, neuron as presynaptic cell via secretion of neurotransmitters and neuropeptides such as acetylcholin act on neurotransmitter receptors such as acetylcholin receptors on postsynaptic cell to regulate epithelial proliferation, stem cell activity, both nerve and liver or pancreatic cancer cells can be as pre- or post-synaptic cells in this communication. b Paracrine pathway, within TME, addition to direct influence, nerves communication with cancer can be mediated by regulation of tumor-related stroma cells. And the paracrine signals (neurotrophic growth factors) derived by cancer cell promote nerve axonogenesis or neurogenesis in TME. c Systemic pathway, nervous system can influence cancer cells activities through regulation the function of immune system mediated by elevated systemic circulating catecholamines. PNI can also be a consequence of circulating signals from cancer cells [42, 59].