The Nervous System Contributes to the Tumorigenesis and Progression of Human Digestive Tract Cancer

Abstract

Tumors of the gastrointestinal tract are one of the highest incidences of morbidity and mortality in humans. Recently, a growing number of researchers have indicated that nerve fibers and nerve signals participate in tumorigenesis. The current overarching view based on the responses to therapy revealed that tumors are partly promoted by the tumor microenvironment (TME), endogenous oncogenic factors, and complex systemic processes. Homeostasis of the neuroendocrine-immune axis (NEI axis) maintains a healthy in vivo environment in humans, and dysfunction of the axis contributes to various cancers, including the digestive tract. Interestingly, nerves might promote tumor development via multiple mechanisms, including perineural invasion (PNI), central level regulation, NEI axis effect, and neurotransmitter induction. This review focuses on the association between digestive tumors and nerve regulation, including PNI, the NEI axis, stress, and neurotransmitters, as well as on the potential clinical application of neurotherapy, aiming to provide a new perspective on the management of digestive cancers.

Figure 1

The functions and molecular mechanism of GABA and its receptors in cancer development. (a) The GABARs contain 5 major subunits, and stimulation of GABAR with GABA will activate the chloride ion channel. The change of electric potential further activates the calcium ion channel and increases the intracellular calcium concentration. The activation of the PKA pathway also increases calcium concentration. The higher concentration of calcium promotes tumor cell apoptosis and activates the MAPK pathway to achieve multiple biological effects. (b) The GABBRs are G protein-coupled receptors. When agonists are combined, it will suppress the cAMP pathway and promote the PKC pathway. PKA suppression inhibits the growth of tumor, while the activation of the PLC/PKC pathway regulates multiple activities via FAK which are associated with IGF1R and RTK. The activation of PKC increases intracellular calcium concentration to induce cell apoptosis. Additionally, other signaling pathways such as YAP also participate in the process of GAGBR-dependent tumor-suppressive or oncogenic roles.

Figure 2

The YAP/TAZ pathway and tumor gene proliferation. The Hippo signaling pathway, also known as the Salvador/Warts/Hippo (SWH) pathway, is named after Hippo (Hpo), a protein kinase in drosophila and a key regulatory factor in the pathway. This pathway is composed of a series of conserved kinases that control organ size by regulating cell proliferation and apoptosis. Once it senses the extracellular growth inhibition signal, it activates a cascade of kinase phosphorylation reactions, culminating in phosphorylation of downstream effector factors YAP and TAZ. Cytoskeleton proteins bind to phosphorylated YAP and TAZ, causing them to remain in the cytoplasm and reduce their nuclear activity, thus achieving regulation of organ size and volume.