## 2 Most Significant Neurotransmitters in Cancer Development and Progression
& [19,20] \\ Acetylcholine (Ack, C\({}_{\text{3N}}\)H\({}_{\text{n}}\)O\({}_{\text{2+}}\)) & & & Ach is a well-known neurotransmitter of the neuronal system, it is also synthesized in non-neuronal cells & [21,22] \\ C\({}_{\text{3N}}\)NH\({}_{\text{4N}}\)O\({}_{\text{2+}}\) & & & & \\ \cline{1-1} \cline{3-4}  
Prior research has explored the relationship between cancer and dopamine and found that decreased dopamine expression can result in tumor development [47]. Knockdown of the expression of dopamine results in the inhibition of IGF-1 (insulin-like growth factor-1), which is responsible for the proliferation of gastric cancer cells and angiogenesis. Meanwhile, upregulating the Kruppel-like factor 4 (KLF4) gene, a well-known cell cycle regulator, can also inhibit proliferation [16]. In another study, it was demonstrated that dopamine could exert an antagonistic action in colon, breast, and stomach cancer, which means its stimulation could inhibit the growth of tumors [48]. However, the effect of dopamine is not clear yet as, in some cases, it also proved its inability to inhibit the proliferation and migration of cancer cells, indicating that its action is either dose-dependent or expression-based in different cancers [49]. Serotonin is another important neurotransmitter that exerts a mitogenic function in the development and progression of several cancers, such as lung, prostate, liver, melanoma, and pancreas [50; 51; 52]. An in vitro study showed that tryptophan hydroxylase 1 (TPH1), an enzyme catalyzing serotonin production, is highly expressed and facilitates breast cancer onset by sustaining mammary epithelial cells' growth [53]. Similarly, serotonin secretion concurrently enhances cell proliferation in the liver and pancreatic cancer. Therapeutically, inhibition of serotonin receptors, such as the hydroxryptamine receptor 2B (HTR2B) in pancreatic cancer and the 5-hydroxryptamine receptor 2B (5-HT2B) in the liver, has been shown to prevent cancer cell proliferation, angiogenesis, and metastasis [54; 55]. In recent years there has been a rise in the number of studies targeting the complex of neurotransmitters, i.e., epinephrine (E) and norepinephrine (NE), and their GPCR, which drive several biological processes in cancer onset and progression, including proliferation, survival, angiogenesis, and invasion [56]. In addition, much research has been carried out on the genes encoding GPCR receptors in the context of cancer pathogenesis through the activation of the signaling cascade via the \(\beta\)1/2-adrenooreceptor (\(\beta\)-AR)--cyclic-AMP (cAMP)--protein kinase A (PKA). The underlying mechanism of promoting cancer initiation and development by E and NE through \(\beta\)-AR has been correlated to many cancers, including lung, ovarian, colon, and breast cancer, suggesting that E, NE, and the GPCR represent a potential diagnostic and therapeutic target in these types of cancer [57; 58; 59; 60; 61]. It is now well recognized that acetylcholine (ACh) also has tumor-promoting activity, including proliferation, differentiation, migration, and angiogenesis in the colon and gastric cancer via increased expression of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) [62; 63]. This association was also investigated in another study showing that inhibition of nicotinic ACh (n-ACh) receptors (n-AChR), which are upregulated in squamous cell lung carcinomas (SCC), limited basal and nicotine-stimulated growth of SCC [64]. In a different study, it was observed that n-ACh served as a potent mediator of the nuclear factor kappa B (NFkB) inflammatory pathway by activating the sympathetic nervous system in stressful events, leading to a cancer-like condition [65; 66]. Researchers suggested novel cancer therapies based on targeting the ACh receptors [67].