Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment

Abstract

The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.

Fig. 1. Interaction between neurotransmitters, colorectal cancer, and tumor microenvironment.

Regulatory signals related to tumor growth, apoptosis, autophagy, invasion, and metastasis may be transmitted through the BGA via the parasympathetic, sympathetic and enteric nervous systems. In addition, neurotransmitters and neurotrophic factors may be secreted from non-neural cells and exert both paracrine and autocrine effects on CRC cells, as well as immune cells, endothelial, and stromal cells in the TME. The balance between stimulatory and inhibitory signals through the activation of specific receptors can affect CRC progression and metastatic spread by promoting cancer cell proliferation, migration, and invasion, tumor angiogenesis and inflammation in the TME. ACh Acetylcholine, BGA brain–gut axis, BDNF brain-derived nerve growth factor, CRC colorectal cancer, DA dopamine, E epinephrine, EMT epithelial to mesenchymal transition, GABA gamma-aminobutyric acid, 5-HT serotonin, MDSC myeloid-derived suppressor cells, NE norepinephrine, TME tumor microenvironment. [Adapted from “Gut–Brain Axis” and “Tumor Microenvironment”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.].