Bridge of imbalance: How does the brain-gut axis act as a catalyst for gastrointestinal tumors in aging

Table 1 The influence of the neural and endocrine pathways on gastrointestinal cancers[121,122,137,209-212]

Species	Cancer	Models	Mechanism	Marker	Consequence	Ref.
GABA	Colon cancer	Sleep deprivation mouse model	Sleep deprivation can promote the expression of miR-223-3p in colon cancer cells through GABA, leading to downregulation of the E3 ligase CBLB and inhibition of c-Myc ubiquitination	GAD1, VGAT, GAT1, c-Myc protein	Sleep deprivation promote the occurrence and development of colon cancer via GABA release	Bao et al[122]
Ach	Gastric cancer	Human gastric cancer cells	Ach promotes cell proliferation and stimulates phosphorylation of ERK and AKT in gastric cancer cells	ERK, AKT, IC50	Ach acts through M3 muscarinic receptor to activate the EGFR signaling and promote gastric cancer cell proliferation	Yu et al[209]
5-HT	Colorectal cancer	Apcmin (min: Multiple intestinal neoplasia)/+ mice	5-HT promotes the occurrence and development of colorectal cancer by binding to 5-HT receptor and activating Wnt/β-catenin signaling pathway	β-catenin, TPH1, TPH2	Neurotransmitter 5-HT drives the self-renewal of colorectal CSCs and tumorigenesis	Zhu et al[121]
Norepinephrine	Gastric cancer	Chronic stress mouse model	Sympathetic neurotransmitters promote the malignant biological behaviour of GC cells by activating ADRB2	ADRB1, ADRB2	Activation of β2-adrenergic signals can promote the growth of gastric cancer xenografts under chronic stress	Zhang et al[210]
SP/NK1R	Colorectal cancer	SW480 cells model	SP exerts its oncogenic effects through NK1R activation, functioning as a critical driver of proliferation	MMP-2, MMP-9	The SP/NKR1 signaling pathway improved the colon cancer metastatic and angiogenic properties	Golestaneh et al[211]
Hypothalamic oxytocin	Colitis-associated cancer	AOM/DSS-induced CAC mouse model	Activation of OxtPVN neurons suppressed colitis-associated colorectal cancer progression through inhibition of CG-SMG neuronal activity	PCNA	Depletion of Oxt neurons promotes colorectal cancer progression	Pan et al[137]
Neurotrophin-3	HCC	HCC cells (Huh-7 and HCCLM3)	NTF3 acts as a ligand and binds to the p75NTR receptor and promotes apoptosis through the JNK and P38 MAPK pathways	NTF3, E-cadherin, N-cadherin, Ki67, p75NTR	NTF3 overexpression suppresses the proliferation of HCC cells, reduces their migration and invasion ability, increases apoptosis, and induces cycle arrest	Yang et al[212]

GABA: Gamma-aminobutyric acid; Ach: Acetylcholine; 5-HT: 5-hydroxytryptamine; SP: Substance P; NK1R: Neurokinin-1 receptor; HCC: Hepatocellular carcinoma; AOM: Azoxymethane; DSS: Dextran sulfate sodium; CAC: Colitis-associated colorectal cancer; ERK: Extracellular signal-regulated kinase; AKT: Protein kinase B; GC: Gastric cancer; Oxt: Hypothalamic oxytocin; PVN: Paraventricular nucleus; CG-SMG: Celiac-superior mesenteric ganglia; NTF3: Neurotrophin-3; JNK: C-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; EGFR: Epidermal growth factor receptor; CSC: Cancer stem cells; GAD1: Glutamate decarboxylase 1; VGAT: Vesicular gamma-aminobutyric acid transporter; GAT1: Gamma-aminobutyric acid transporter 1; IC₅₀: Half maximal inhibitory concentration; TPH1: Tryptophan hydroxylase 1; TPH2: Tryptophan hydroxylase 2; ADRB1: Adrenergic receptor beta 1; ADRB2: Adrenergic receptor beta 2; MMP-2: Matrix metalloproteinase-2; MMP-9: Matrix metalloproteinase-9; NTF3: Neurotrophin 3; PCNA: Proliferating cell nuclear antigen; p75NTR: P75 neurotrophin receptor.