Neural influences in colorectal cancer progression and therapeutic strategies

Abstract

Purpose: This review aims to elucidate the neural mechanisms driving colorectal cancer (CRC) growth, metastasis, and therapeutic resistance, summarizing the roles of neurotransmitters, neurotrophic factors, and neural signaling in carcinogenesis. It further explores therapeutic strategies targeting neural dependencies in CRC.

Methods: A comprehensive PubMed search was conducted using the keywords colorectal cancer and tumor innervation, focusing on studies published between 2000 and 2024. The review synthesizes evidence across four domains: neurotransmitter-receptor interactions, gut-brain-microbiota axis dynamics, neuroimmune modulation, and neural regulation of cancer stem cells, discussing their collective impact on CRC pathophysiology.

Results: Neural innervation significantly influences CRC progression. For instance, the neurotransmitter serotonin promotes tumor growth and metastasis via paracrine and autocrine stimulation, while neurotrophic mediators like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) activate oncogenic signaling through receptor tyrosine kinases (RTKs). Downstream pathways, such as Wnt/β-catenin signaling, are modulated by neural inputs, underscoring CRC's neurodevelopmental dependency and highlighting their potential as therapeutic targets.

Conclusion: Neural mechanisms are pivotal in CRC progression, revealing novel therapeutic avenues. Strategies targeting neurotransmitter synthesis, neurotrophic signaling, or neuroimmune crosstalk may disrupt tumorigenic loops while preserving systemic nervous system integrity. Future research must prioritize translating these insights into clinical interventions to improve patient outcomes. Elucidating the intricate interplay between neural mediators and cancer pathogenesis, coupled with developing therapies specifically targeting the neurogenic basis of CRC aggressiveness, represents a critical frontier in oncology.

Keywords: Colorectal cancer; Gut-brain axis; Mechanism; Neural innervation; Targeted therapy.

Fig. 1

Specific crosstalk between cancer and neuronal cells. Adrenergic signaling in tumor cells induces the release of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), augmenting neural density within tumor regions. This heightened innervation amplifies adrenergic pathway activity, resulting in norepinephrine (NE) accumulation. NE activates β-adrenergic receptors (β-ARs) and reprograms cancer-associated fibroblasts (CAFs), which subsequently secrete NE-mimetic cytokines. These cytokines further upregulate β-AR expression on tumor cells, establishing a self-perpetuating loop that drives tumor progression

Fig. 2

The interaction between the nervous system and the immune system. Immune cells are activated via toll-like receptors (TLRs) localized on sensory neurons cells that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) released from host-damaged cells, thereby triggering a signaling cascade that culminates in the release of pro-inflammatory cytokines (PICs). These cytokines subsequently exert influence on the central nervous system (CNS) through both humoral circulation and neural circuitry. Simultaneously, neurotransmitters including substance P (SP), β-endorphin (β-EP), norepinephrine (NE), and neuropeptide Y (NPY) may participate in signal transduction processes and demonstrate modulatory roles in inflammatory responses