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(Hyland and Cryan 2010; Barnard et al. 1998; Bormann 2000; Cryan and Kaupmann
2005). GABAA receptors are heteropentamers formed by five types of subunits,
with a central chloride ion-selective channel gated by GABA (Olsen and Sieghart
2009). GABAB receptors are heterodimers composed of two subunits, GABAB1
and GABAB2 (Calver et al. 2000; Bettler et al. 2004). GABAB1 and GABAB2
subunits are differentially expressed (Calver et al. 2000) in the human GI tract. The
GABAB1 receptor subunit and its splice variants, GABAB1a and GABAB1b, are
predominantly expressed whereas the GABAB2 has been detected in the human
lower esophageal sphincter (LES), cardia, and corpus (Torashima et al. 2009).
In cancer cells, it has mostly been observed that the expressions of GABA
receptors are significantly changed. In GC tissues, the GABA content and GAD
activity were reported to be significantly higher than normal stomach tissues and
correlate to the grade of cancer (Matuszek et al. 2001). In colon adenocarcinoma,
GABA level and GAD activity were significantly higher than normal macroscopically unchanged human colon tissues of the same patient. In subcutaneous CX-2
colon adenocarcinoma grown in athymic nu/nu mice, the GABA level and GAD
activity were higher in tumors than the unchanged colon wall (Kleinrok et al. 1998).
In CRC, GABA type A receptor subunit delta (GABRD) was significantly increased
compared to that in normal colon tissues and was associated with later TNM stages
and decreased survival times. Overexpression of GABRD in CRC cell lines promoted the proliferation and migration of CRC ce lls while silencing of GABRD
in CRC cell lines inhibited cell proliferation and migration. Gene Set Enrichment
Analysis (GSEA) with The Cancer Genome Atlas Colon Adenocarcinoma (TCGACOAD) confirmed that GABRD overexpression was positively correlated with gene
sets defining EMT which is essential for met astatic progression, the formation of
new blood vessels from preexisting vessels in the TME and hedgehog signaling
pathway, which plays an important role in the tumorigenesis of CRC (Niu et al.
2020). Migration and invasion of SW480 colon carcinoma cells in a three-
dimensional collagen matrix was inhibited by GABA via the GABAB receptor by
reducing the NE-induced migration to spontaneous migration levels by significantly
decreasing cAMP concentration (Joseph et al. 2002).
Binding of GABA to GABAA receptors that are overexpressed in the KATO III
GC cell line significantly promoted the proliferation of KATOIII cells by activating
the ERK-1/2/cyclin D1 pathway (Maemura et al. 2009). Also GABA via GABAB
receptor inhibited gastric carcinogenesis induced by N-methyl-N′-nitro-Nnitrosoguanidine (Tatsuta et al. 1990) and reduced azoxymethane-induced experimental colon carcinogenesis (Tatsuta et al. 1992) in Wistar rats.
3.6 Neuropeptides
3.6.1 Neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino acid residue peptide of the pancreatic polypeptide family, which is found in the brain and autonomic nervous system and in
different peripheral tissues including the colon (Holzer et al. 2012; Chakroborty et al.
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2022). It interacts with a family of G-protein coupled receptors (Y1, Y2, Y4, Y5, and
Y6) belonging to the rhodopsin-like super family (class1) of receptors which couple
to Gi and thus decrease forskolin mediated cAMP accumulation in a variety of cell
lines and tissues (Holzer et al. 2012; Reubi et al. 2001; Rasiah et al. 2006; Cox 2008;
Rettenbacher and Reubi 2001; Hyland and Cox 2005). NPY is another
neuromediator that is abundantly secreted by enteric neurons . NPY has been
shown to be associated with number of intestinal diseases like intestinal inflammation and inflammatory bowel diseases (Jeppsson et al. 2017; Chandrasekharan et al.
2008). However, its role growth and progression of GI tumors is still not well
explored. NPY has been primarily linked to inflammation-associated GI tumors.
There are only handful of reports regarding the role of NPY in GC and CRC. NPY
expression was reported in tumor cells of primary gastric alveolar soft-tissue sarcoma (Yagihashi et al. 1991). The average plasma level of NPY is reported to be
lower in gastric and CRC patients than normal individuals and NPY levels were
negatively associated with tumor size (> 5 cm) and loss of body weight (> 3 kg)
(Li et al. 1998). Negative correlation between NPY level and tumor stage was also
evident in GC but not in CRC (Li et al. 1998). In contrary in another study performed
with tumor and normal gastric tissues it was shown by cDNA microarray-based
comparative genomic hybridization that NPY gene was amplified in GC (Yang
2007). These contradictory findings indicate that the role of NPY in GI cancers is
still controversial. Although there are only a few reports regarding the role of NPY in
GC and CRC from human sample studies, there are recently some reports from
animal model studies that show the regulatory role of NPY in GI cancers
(Chakroborty et al. 2022). NPY was reported to regulate tumorigenesis by promoting proliferation (PI3-K/pAkt), and by downregulating microRNA-375 (miR-375)dependent apoptosis in intestinal epithelial cells in a dextran sodium sulfate (DSS)
model of inflammation-induced tumorigenesis (Jeppsson et al. 2017). In an
axozymethane/dextran sodium sulfate (AOM/DSS)-induced mouse model of inflammatory CRC, upregulation of NPY was associated with increased a ngiogenesis.
NPY and Y2 receptor upregulation was related to higher expression of TNF-α,
which promotes progression of colon carcinogenesis (Sarkar and Chakroborty
2014). Significant upregulation of NPY was seen in CT26 colon cancer tissues
where a dual regulatory role of NPY was reported. NPY via Y1 receptors, which
are predominantly expressed by tumor cells, controls the proliferation and growth of
the cancer cells (Goswami et al. 2020). NPY by acting through Y2 receptors that are
mostly expressed by the endothelial cells also controls the functions of these cells
present in the tumor microenvironment (Chakroborty et al. 2022). Recent findings
demonstrated that NPY acts through Y2R to promote angiog enesis in colon cancer
by activating the ERK/MAPK pathway in colonic endothelial cells (Chakroborty
et al. 2022 ).
3.6.2 Substance P (SP)
SP, a small undecapeptide, is a member of the large family of structurally related
peptides, the tachykinins which have a conserved carboxyl-terminal domain
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(Phe-X-Gly-Leu-Met-NH2, X hydrophobic or aromatic; Harrison and Geppetti
2001) and share common pharmacological properties. SP mediates its actions by
binding to its high-affinity neurokinin-1 receptor (NK-1R; Pernow 1983; Maggi
et al. 1997), which is a seven transmembrane domain G-protein coupled receptor. At
high concentrations, SP can also activate neurokinin-2 (NK-2R) and neurokinin-3
(NK-3R) receptors (Regoli et al. 1994). In GC and CRC, SP activates the NK-1
receptor, which is expressed on primary colon and gastric adenocarcinoma cells. SP
and NK1R expressions were upregulated in CRC compared to adjacent normal
tissues and were significantly associated with lymph node metastasis and poor
prognosis (Mou et al. 2016). Similar high overexpression of NK-1R was reported
in GC cells and tissues (Rosso et al. 2008). Presence of different isoforms of NK-1R
was reported in GC cells and tissues. Activation of the NK-1 receptor resulted in
promotion of a number of processes like mitogenesis, angiogenesis, cell survival,
migration, and metastasis, thereby proving its involvement in regulation of the TME
(Mayordomo et al. 2012). SP also promoted N-methyl-N′-nitro-N-nitrosoguanidineinduced gastric carcinogenes is (Tatsuta et al. 1995) and the number of SP-positive
nerves might be related to GC progression (Feng et al. 2011).
3.6.3 Vasoactive Intestinal Peptide
Vasoactive intestinal peptide (VIP), a 28-residue amino acid peptide, is a member of
the secretin/glucagon hormone superfamily. It was first isolated from porcine duodenum and characterized in 1970. It is widely distributed in the CNS and PNS as
well as in the respiratory, reproductive, cardiovascular, and GI systems (Iwasaki
et al. 2019). In the GI tract it is mainly localized in the myenteric and submucosal
neurons and nerve terminals and as its name implies, is a potent vasodilator (Larsson
et al. 1976; Costa and Furness 1983). VIP mediates its actions through VPAC1 and
VPAC2, which are class B of G-protein coupled receptors, also known as the
secretin receptor family. VIP regulates a number of GI functions such as gastric
acid secretion, intestinal anion secretion, cellular motility, vasodilation, smooth
muscle relaxation, and intestinal contractility (Iwasaki et al. 2019).
In addition to regulating several physiological function in the GI tract, VIP has
also been implicated in the pathogenesis of both GC and CRC. Both VPAC1 and
VPAC2 are overexpressed in GC and CRC. While VPAC1 primarily expresses on
the epithelial cells, VPAC2 expression is mainly on smooth muscle cells of the GI
tract (Iwasaki et al. 2019). VPAC1 is overexpressed colon (96%) and gastric
adenocarcinomas (54%) (Reubi et al. 2000). It was reported that 35% of welldifferentiated colon cancers, 65% of moderately differentiated tumors and 87% of
poorly differentiated colon cancers expressed VPAC1. VPAC1 overexpression was
reported in blood vessels and tumor-associated macrophages (Liu et al. 2014).
Another study however reported that VIP inhibited the progression of GC by
depressing the activation of TAM, which resulted in reduced expressions of
TNFα, IL-6, IL-12, and iNOS. VI-treated TAM could significantly reduce the
growth of MKN45 GC (Chen et al. 2015a, b). VIP could also inhibit proliferation
of colonic cancer-cells (Lelièvre et al. 1998). In the APC(Min/+) model of
168 D. Chakroborty and C. Sarkar
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spontaneous colon cancer, defects in the expressions of the anti-inflammatory
neuropeptides, VIP, and pituitary adenylate cyclase-activating peptide (PACA P),
increased colonic inflammation, which resulted in increased initiation and progression of colonic cancers (Vinuesa et al. 2012). VIP stimulated proliferation of HT29
colon cancer cells by activation of Ras/Rap1-B-Raf-ERK pathway (Alleaume et al.
2003) and VIP antagonists, neurotensin(6–11)VIP(7–28) inhibited HCT-15 cancer
cell growth (Levy et al. 2002). Furthermore, antagonist treatment of SpragueDawley rats bearing colon tumors after injection with azoxymethane (AOM)
(15 mg/kg/week) for 2 weeks showed reduced tumor volume, lymphocyte infiltration, and the number of dysplastic crypts (Levy et al. 2002 ). However, in Colon
26-L5 adenocarcinoma cells, VIP was reported to reduce the invasive potential of
tumor cells (Og asawara et al. 1997). VIP and its receptor, VPAC1, can serve as
potential prognostic markers and therapeutic targets for GC as higher VIP/VPAC1
expressions were observed in GC compared to normal tissues which showed positive
correlations with tumor stage, metastases, and poor survival. Activation of VPAC1
by VIP significantly increased transient receptor potential vanilloid 4 (TRPV4)mediated Ca2+ entry, which led to GC progression in a Ca2+ signaling-dependent
manner. In addition, as a positive feedback mechanism, VPAC1/TRPV4/Ca2+
signaling increased the expression and secretion of VIP in GC cells (Tang et al.
2019).
4 Conclusion
In recent years, our knowledge has significantly improved in understanding the role
played by nerves and neurotransmitters/neuromodulators in development and progression of non-CNS solid tumors. GI cancers are of significant interest in this area
as the organs in the GI tract are not only richly innervated by nerves from the CNS
but also by the GI tract’s own nervous system, the ENS (Costa 2000; Lomax et al.
2009; Bharucha 2003; Phillips and Powley 2007; Uesaka et al. 2016; Burns and
Thapar 2006). The ENS plays a critical role in regulating GI tract functions and
maintaining homeostasis which is largely dependent upon the proper functioning of
the ENS/CNS, failure of which leads to several GI diseases including GC and CRC
(Costa 2000; Lomax et al. 2009; Di et al. 2019; Kulkarni et al. 2018; Duraker et al.
2003; Schledwitz et al. 2021). Neurotransmitters or neurohormones as messenger
molecules have thus emerged as important players in the growth and progression of
GC and CRC (Chakroborty et al. 2004, 2008; Basu and Dasgupta 1997; Basu and
Dasgupta 1999). Initially, the role of the CNS in regulating the growth of GC and
CRC was extensively studied as it was considered as the primary source of the
neuromodulators in the GI tract. However, with the evidence of synthesis and
secretion of different neurotransmitters by nonneuronal sources in the GI tract like
gastric and colonic epithelial cells, entero endocrine cells, endothelial cells, immune
cells, cancer cells and the presence of neurotransmitter receptors in tumor cells and
Role of Neuromodulators in Regulation of the Tumor Microenvironment.. . 169
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other cells in the TME, this area of research has taken a dramatic turn in last two
decades. Understanding the interactions between the neuromodulators and the
cancer cells and other cells within the TME that regulate the growth of GC and
CRC will therefore contribute to unraveling new therapeutic targets (Basu and
Dasgupta 1997 , 1999; Chakroborty et al. 2004, 2008, 2022 ; Cheng et al. 2008;
Cianchi et al. 2003; Dowling et al. 2015; Mezey et al. 1998, 1999; Gershon and Tack
2007; Sarkar et al. 2022; Shah et al. 2021).
Despite a growing interest in recent years in studying these neuromodulators and
their connection to tumor development and progression, our knowledge is limited
due to the lack of sufficient number of studies that involve human subjects over long
durations and also due to the lack of suitable number of appropriate animal models
that faithfully mimic the complex and diverse TME observed in GC and CRC which
have often resulted in contradictory reports. A more comprehensive approach toward
understanding the funct ions of these neuromodulators in individual component of
the TME is therefore needed. Currently available advanced techniques such as
single-cell RNA-Seq data and spatial transcriptomics can be used to develop a
complete inventory of TME cells and assess the expression levels of different
neurotransmitter receptors in individual TME component in GC and CRC patients
(Ahmed et al. 2022; Mangiola et al. 2021; Hernandez et al. 2021; Zhu et al. 2017). In
vivo gene editing strategies of candidate genes identified from high- resolution
transcriptomic mapping and creation of relevant human organoids together with
live-cell imaging can be used to study the progression of GC and CRC (Ahmed et al.
2022; Mangiola et al. 2021; Hernandez et al. 2021; Zhu et al. 2017). Also, in order to
develop novel ENS-based therapeutic strategies for GC and CRC, it is needed that
more human studies be conducted to confirm the clinical relevance of experimental
findings. In addition, continued research and identification of novel targets that
contribute to the modulation of the TME to promote metastatic progression will
further help to improve therapeutic approaches.
In this chapter, we have summarized some of the important findings regarding the
role of neuromodulators in the TME of GC and CRC that were reported to date
including the findings from our own laboratory. The summary of the functions of the
neuromodulators in the TME of GC and CRC is provided in Table 1. With more
studies in the field, the key gaps in knowledge regarding the mechanisms of GC and
CRC carcinogenesi s can be filled which will lead to the identification of sensitive
biomarkers for diagnosis and designing of effective therapeutic interventions to
improve patient outcomes. Therefore, a better understanding of neurotransmitters
and neuropeptides, their receptors, and the therapeutic efficacy of their agonists and
antagonists is warranted. A number of agents targeting the neurotransmitters such as
the DA receptor agonists and antagonists, the beta-blockers, ACh receptor
antagonists, and 5-HT receptor blockers are being widely used in the clinics for
the treatment of various diseases. With their known safety pro files, these agents can
easily be repurposed for any new use in therapy.
170 D. Chakroborty and C. Sarkar
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Table 1 Summary of the functions of the neuromodulators in the tumor microenvironments of
gastric and colorectal cancers
Neuromodulator Role in gastric and colon cancers References
Acetylcholine 1. Promotes gastric cancer cell
Catecholamines
Dopamine 1. Inhibits VEGF-mediated
Epinephrine and
norepinephrine
Serotonin 1. Paradoxical in nature
migration and invasion via promotion
of epithelial to mesenchymal
transition
2. Promotes colon cancer cell
migration by enhancing the secretion
of MMPs
3. Regulates drug resistance in gastric
cancers
angiogenesis in gastric and colon
cancers
2. Promotes vessel normalization and
endothelial cell quiescence in colon
cancer
3. Promotes pericyte migration and
maturation in tumor
microenvironment
4. Improves perfusion, reduces
hypoxia and enhances drug
availability in tumor
microenvironment in colon cancer
5. Inhibits gastric cancer cell
proliferation
1. Promote proliferation, invasion,
and survival of gastric cancer cells
2. Enhance glycolysis in gastric
cancer cells
3. Promote epithelial to mesenchymal
transition in gastric cancer cells
4. Promote resistance against
therapeutic and targeted agents in
gastric and colon cancers
5. Promote secretion of VEGF,
MMPs, and AP1 in gastric cancers
6. Promote proliferation and
migration of tumor endothelial cells
and tumor angiogenesis both in
gastric and colon cancers
2. Plays protective role in the early
stages of tumor development by
promoting DNA repair activity in
cancer cells in colon cancer
3. Promotes colon cancer cell
proliferation by activating serotonin
re-uptake transporters and receptors
in colon cancer
Yu et al. (2017)
Yang et al. (2016)
Cheng et al. (2008)
Hering et al. (2021)
Felton et al. (2018)
Xian et al. (2013)
Chakroborty et al. (2011),
Chakroborty et al. (2004), and
Sarkar et al. (2022)
Sarkar et al. (2008) and
Ganguly et al. (2010)
Zhang et al. (2019)
Yao et al. (2009)
Wang et al. (2021)
Shi et al. (2010)
Shi et al. (2013)
Pu et al. (2012)
Liu et al. (2015)
Kannen et al. (2020)
Ye et al. (2021)
Gershon and Tack (2007
Xu et al. (2006)
Sakita et al. (2019)
Tutton and Barkla (1978),
Chan et al. (2020), Balakrishna
et al. (2021), Zamani and Qu
(2012), Peters et al. (2014)
) and
(continued)
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Table 1 (continued)
Neuromodulator Role in gastric and colon cancers References
4. Creates pro-inflammatory
microenvironment promoting
colorectal cancer progression
5. Promotes angiogenesis in colon
cancer
Nitric oxide 1. Promotes VEGF-mediated
γ-Aminobutyric
acid
Neuropeptide Y 1. Promotes cell proliferation of
Substance P 1. Promotes lymph node metastasis in
angiogenesis in colorectal cancer
2. Lack of inducible nitric oxide
synthase in Apc(min/+)mice
promotes tumorigenesis
3. In gastric cancer inducible nitric
oxide synthase expression is related
to increased VEGF expression,
microvessel density, lymph node
metastasis, and decreased immune
responses
4. Endothelial nitric oxide promotes
angiogenesis in gastric cancer
1. GABARD overexpression
promotes proliferation and migration
of colorectal cancer cells
2. GABARD overexpression
correlates with gene set defining
epithelial to mesenchymal transition,
angiogenesis in colorectal cancer
3. GABA via GABAA receptors
promotes proliferation of gastric
cancer cells activating the ERK-1/2/
cyclin D1 pathway
4. GABA via GABAB inhibits gastric
carcinogenesis and experimental
colorectal carcinogénesis
colorectal cancer cells
2. Inhibition of NPY promotes
apoptosis on colon cancer cells
3. Promotes cell proliferation,
migration and tubule formation
capabilities of endothélial cells
4. Promotes angiogenesis in colon
cancer
colon cancer
2. Promotes mitogenesis,
angiogenesis, cell survival, and
migration metastasis of colon cancer
cells
3. Promotes gastric carcinogenesis
Nocito et al. (2008) and
Schneider et al. (2021)
Song et al. (2002)
Karadayı et al. (2013)
Yamaguchi et al. (2005) and
Zhang et al. (2011)
Wang et al. (2005)
Niu et al. (2020)
Maemura et al. (2009) and
Tatsuta et al. (1990)
Sarkar and Chakroborty (2014)
Jeppsson et al. (2017)
Goswami et al.(2020)
Chakroborty et al. (2022)
Mou et al. (2016) and
Mayordomo et al. (2012)
Tatsuta et al. (1995)
Feng et al. (2011)
(continued)
172 D. Chakroborty and C. Sarkar
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Table 1 (continued)
Neuromodulator Role in gastric and colon cancers References
Vasoactive
intestinal
polypeptide
1. Inhibits gastric cancer by
depressing activation of tumorassociated macrophages
2. Inhibits proliferation of colonic
cancer cells
3. Stimulate proliferation of colonic
cancer cells by activation of
Ras/Rap1/B/Raf/ERK pathway
4. Ras antagonist treatment reduces
tumor volume, lymphocyte
infiltration, and number dysplastic
crypts formation in colon cancer
5. Reduces invasive potential of
colon 26-L5 adenocarcinoma cells
6. Promotes gastric cancer
progression in Ca2+ signalingdependent manner
Chen et al. (2015a, b)
Lelièvre et al. (1998)
Alleaume et al. (2003)
Levy et al. (2002)
Ogasawara et al. (1997)
Tang et al. (2019)
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