Role of Sympathetic and Parasympathetic Nerves in the Development of Gastric Cancer Through Antagonism
The autonomic nervous system, comprising the sympathetic and parasympathetic nerves, plays a significant role in the occurrence and development of gastric cancer (GC). These nerve fibers form a network within the gastric wall submucosa and muscularis, regulating gastric peristalsis and secretion. The sympathetic and parasympathetic systems antagonize and coordinate with each other under the central nervous system’s regulation to maintain physiological balance. However, their dysregulation can contribute to the pathogenesis of GC. This article explores the intricate roles of these nervous systems in GC development, highlighting their antagonistic interactions and the involvement of gastrointestinal hormones.
The Role of the Parasympathetic Nervous System in Gastric Cancer
The parasympathetic nervous system, primarily mediated by the vagus nerve, has been implicated in promoting GC growth. The vagus nerve exerts its effects through the high distribution of nerve fibers and the secretion of acetylcholine (ACh) neurotransmitters. Studies have shown that the incidence of tumors in the lesser curvature of the stomach is significantly higher than in the greater curvature, a region with dense vagal innervation. This observation suggests a direct correlation between vagal activity and tumorigenesis.
Experimental evidence further supports this relationship. Zhao et al. conducted vagal neurectomy in mice to observe tumor growth. They found that the incidence of tumors after bilateral vagotomy and pyloroplasty (VTPP) was 17%, compared to 86% in mice undergoing pyloroplasty (PP) alone. Additionally, unilateral anterior vagotomy (UVT) resulted in a 14% incidence of anterior gastric tumors and a 76% incidence of posterior gastric tumors. These findings underscore the vagus nerve’s role in promoting GC.
At the molecular level, exogenous ACh stimulation has been shown to promote the proliferation of GC cells. Moreover, GC cells can synthesize and secrete ACh through choline acetyltransferase (ChAT), creating an autocrine loop that fuels their growth. Both endogenous and exogenous ACh activate the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways through the M3 muscarinic receptor (M3R), driving cell proliferation. Conversely, cholinesterase (CHE) inhibits GC cell growth by breaking down ACh, highlighting the delicate balance between ACh production and degradation in GC progression.
The Role of the Sympathetic Nervous System in Gastric Cancer
In contrast to the parasympathetic system, the sympathetic nervous system appears to have a protective role against GC. Immunohistochemical staining of 82 GC surgical specimens revealed that sympathetic nerve fibers densely cover the small arteries of the normal gastric wall. However, in cancerous tissues, these fibers are significantly reduced, particularly in cases with lymph node invasion and metastasis. This reduction suggests a loss of sympathetic innervation in GC progression.
Further studies have corroborated this finding. Bae et al. observed that the density of sympathetic nerve fibers in patients with pT4 GC was significantly lower than in those with pT1–3 GC. Additionally, the expression of β1-adrenergic receptors decreased with increasing lymph node metastasis, while β2-adrenergic receptors were highly expressed in well-differentiated GC. These findings indicate that sympathetic nervous system activity and adrenergic receptor expression are inversely related to GC malignancy.
The Antagonistic Interaction Between Sympathetic and Parasympathetic Systems
The development of GC is influenced by the antagonistic interplay between the sympathetic and parasympathetic nervous systems. While the vagus nerve promotes tumor growth through ACh secretion, the sympathetic system exerts inhibitory effects. This balance is further modulated by gastrointestinal hormones, such as gastrin.
Gastrin has been identified as an inhibitory factor in GC. Studies have shown that gastrin secretion increases significantly when vagal function is inhibited or blocked. The sympathetic nervous system stimulates gastrin secretion through β2-adrenoceptors, further enhancing its inhibitory effects on GC. Thus, the simultaneous excitation of the sympathetic system and inhibition of the vagus nerve create a synergistic environment that promotes gastrin production, thereby suppressing GC.
The Role of Estrogen in Gastric Cancer and Its Interaction with the Sympathetic Nervous System
Globally, the incidence of GC is significantly lower in women than in men, suggesting a protective role for estrogen. Wang et al. demonstrated that women undergoing estrogen replacement therapy for more than three years had a 60% reduced risk of GC. Estrogen’s protective effects are mediated through its interaction with estrogen receptors. At low concentrations, estrogen stimulates tumor growth by activating estrogen receptor α36 (ERα36). However, at high concentrations, it inhibits ERα36 expression, thereby suppressing GC development.
The sympathetic nervous system plays a crucial role in mediating estrogen’s effects. Estrogen enhances sympathetic nerve excitation by regulating neurotrophic protein receptors in neurons. Prolonged elevation of estrogen levels also promotes the growth of sympathetic nerve fibers. Thus, the reduction in sympathetic nerve fiber distribution and estrogen levels correlates with an increased risk of GC. This interplay suggests that estrogen affects GC development through its modulation of the sympathetic nervous system.
Conclusion
The development of gastric cancer is a complex process influenced by the antagonistic interactions between the sympathetic and parasympathetic nervous systems. The parasympathetic system, mediated by the vagus nerve and ACh secretion, promotes tumor growth, while the sympathetic system exerts inhibitory effects through adrenergic receptors and gastrin production. Estrogen further modulates this balance by enhancing sympathetic activity and suppressing tumorigenesis.
Understanding the roles of these nervous systems and their interactions provides valuable insights into GC pathogenesis. Targeting the autonomic nervous system and its associated hormones may offer novel therapeutic strategies for GC. Traditional Chinese medicine, with its holistic approach, holds promise in modulating the autonomic nervous system to treat GC effectively.
doi.org/10.1097/CM9.0000000000001348
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