Emerging Roles of the Nervous System in Gastrointestinal Cancer Development

SIMPLE SUMMARY: Nerve–cancer cross-talk has increasingly become a focus of the oncology field, particularly in gastrointestinal (GI) cancers. The indispensable roles of the nervous system in GI tumorigenesis and malignancy have been dissected by epidemiological, experimental animal and mechanistic data. Herein, we review and integrate recent discoveries linking the nervous system to GI cancer initiation and progression, and focus on the molecular mechanisms by which nerves and neural receptor pathways drive GI malignancy. ABSTRACT: Our understanding of the fascinating connection between nervous system and gastrointestinal (GI) tumorigenesis has expanded greatly in recent years. Recent studies revealed that neurogenesis plays an active part in GI tumor initiation and progression. Tumor-driven neurogenesis, as well as neurite outgrowth of the pre-existing peripheral nervous system (PNS), may fuel GI tumor progression via facilitating cancer cell proliferation, chemoresistance, invasion and immune escape. Neurotransmitters and neuropeptides drive the activation of various oncogenic pathways downstream of neural receptors within cancer cells, underscoring the importance of neural signaling pathways in GI tumor malignancy. In addition, neural infiltration also plays an integral role in tumor microenvironments, and contributes to an environment in favor of tumor angiogenesis, immune evasion and invasion. Blockade of tumor innervation via denervation or pharmacological agents may serve as a promising therapeutic strategy against GI tumors. In this review, we summarize recent findings linking the nervous system to GI tumor progression, set the spotlight on the molecular mechanisms by which neural signaling fuels cancer aggressiveness, and highlight the importance of targeting neural mechanisms in GI tumor therapy.