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Role of Neuromodulators in Regulation of the Tumor Microenvironment.. . 155
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as well as in the chief cells of the stomach (Xie et al. 20 05). GC cells secrete
ACh. Exogenous ACh promotes GC cell proliferation in a dose-dependent manner
(Yu et al. 2017). ACh was reported to support GC cell invasion and migration via M
receptors by promoting epithelial-to-mesenchymal (EMT) transition. EMT is a
biological process that confers metastatic properties to cancer cells whereby epithelial cells, which normally interact with basement membrane, undergo multiple
biochemical changes and assume a mesenchymal cell phenotype, which is
characterized by enhanced mobility, invasion, and resistance to apoptotic stimuli
(Kalluri and Weinberg 2009). In MKN45 and MGC803 human GC cells, it was seen
that ACh stimulation increased the expression of mesenchymal markers, vimentin,
fibronectin, matrix metalloproteinases (MMP2 and MMP9) and decreased the
expression of E-cadherin. Addition of M3R antagonist inhibited the migratory
properties of GC cells both in the presence and absence of exogenous ACh. This
finding suggested that ACh secreted by the GC cells acts in an autocrine manner to
promote GC cell migration and invasion, and thereby supports cellular metastasis in
GC (Yang et al. 2016). ACh has also been shown to promote the growth and
progression of CRC. In addition to neurons and enteric neuroepithelial cells, ACh
is also expressed and secreted by CRC cells, resulting in an autocrine activation loop
(Cheng et al. 2008; Hering et al. 2021). Higher levels of M
AChR compared to
3
normal epithelium were reported in colon adenocarcinomas (Cheng et al. 2008).
Stimulation of these receptors increased colon cancer cell migration and invasion by
increasing the cellular release of a key collagenase, matrix metalloproteinase-1
(MMP-1) (Felton et al. 2018). Degradation of collagens of the ECM by MMP-1
facilitates metastasis and its overexpression is associated with poor prognosis in
CRC (Murray et al. 1996 ; Langenskiöld et al. 2013; Kim et al. 2021).
Unlike mAChR, nAChRs are ligand-gated ion channels composed of five individual subunits that assemble in pentameric fashion to form a central ion-conducting
channel (Millar 2003; Wu et al. 2015). There are 17 individual subunits (α1–α10,
β1–β4, δ, ε, and γ). nAChRs are broadly divided into two categories: 1. heteromeric
subtypes composed of α and β subunits and 2. homomeric subtypes composed of α
subunits only (Wu et al. 2015). In the ENS, binding sites for heteromeric nAChRs
and expression of several subunit mRNAs were detected. α3, α5, and β4 are most
common subunits in the GI tract that form functional heteromeric nAChRs in
neurons of the myenteric and submucosal plexus throughout the GI tract
(Wu et al. 2015; Rueda Ruzafa et al. 2021).
nAChRs have been shown to play important roles in the progression of both GC
and CRC (Hajiasgharzadeh et al. 2020). It was reported that the proliferation
of human GC cells was promoted by nicotine via activation of alpha7-nAChR
(Shin et al. 2008; Dang et al. 2016; Chen et al. 2015a, b). The functions of nicotine
or nicotine-derived nitrosamine ketone (NNK), the two important components in
cigarette, that enhance GC cell migration, are mediated by activation of α7-nAChR.
This activation either leads to EMT with downregulation of E-cadherin and
upregulation of ZEB-1 and snail and promotion of the migration of GC cells via
the MEK/ERK pathway (Lien et al. 2011) or upregulation of fibronectin, an extracellular matrix glycoprotein shown to play a key role in migration and invasion of
3
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tumor cells (Wang et al. 2012; Wang and Hielscher 2017). Moreover, α7-nAChR
activation by nicotine results in increased angiogenesis, tumor invasion, and metastatic progression of GC by stimulating the COX-2/VEGF/VEGFR signaling pathway (Shin et al. 2005). In addition, α7-nAChR has been shown to be involved in
drug resistance in GC cells both in a positive and negative manner. Studies indicate
that the effectiveness of 5-FU, one of the chemotherapeutic drugs used to treat GC,
is limited due to the emergence of drug resistance in GC cells (Xian et al. 2013).
GC cells were less responsive to 5FU treatment as cellular apoptosis induced by
5-FU treatment was significantly less upon inhibition of nAChR. This indicates
the involvement of α7-nAChR in the regulation of chemo sensitivity in GC cells
(Chen et al. 2015a, b). However, contradictory reports show that the inhibition of
α7-nAChR actually sensitizes GC cells to chemotherapeutic agents such as paclitaxel and ixabepilone (Tu et al. 2016a, b). Therefore, more studies are needed to
delineate the role of α7nAChR in chemosensitivity/chemoresistance observed in
GC. Studies have also reported the expression of nAChRs in colon cancer cells
(Dinicola et al. 2013). Stimulation of α7-nAChR in HT29 human CRC cells
promoted proliferation of these cells in vitro (Wong et al. 2007). Furthermore,
colon cancer cells showed increased migration and invasion in vitro upon stimulation of nAChRs via the activation of p38 MAPK pathway (Dinicola et al. 2013;
Xiang et al. 2016). NNK can also promote colon cancer metastasis through
α7-nAChR by inducing Snail and ZEB1, 2 major transcription repressors of
E-cadherin and thereby downregulating E-cadherin (Wei et al. 2009).
3.2 Catecholamines
Catecholamines are monoamines with a single amide side chain attached to the
catechol group. They are the major neurotransmitters that are known to function in
the CNS as well in the periphery of the body (Basu and Dasgupta 2000). There are
three major catecholamines, i.e., dopamine (DA), epinephrine (E), and norepinephrine (NE) which control a wide number of functions in the body. Catecholamines in
the body are derived from the aromatic amino acid tyros ine (L-tyrosine) by a series
of synthetic reactions controlled by the rate-limiting enzyme tyrosine hydroxylase
(TH) (Chakroborty et al. 2009; Sarkar et al. 2013). TH in presence of the cofact or
tetrahydrobiopterin converts L-tyrosine to levodopa or dihydroxyphenylalanine
(L-DOPA) which is then converted to DA by the enzyme L-dopa decarboxylase.
In subsequent synthetic reactions catalyzed by dopamine beta hydroxylase and
phenylethanolamine N-methyl transferase (Hadjiconstantinou and Neff 2008), DA
is further converted to E and then to NE. Of the three major catecholamines, DA is
known for its role in controlling the motor and cognitive functions of the body. The
dopaminergic pathways are associated with control of locomotion, synthesis and
secretion of number of hormones in the CNS (Mercuri et al. 1997). The other two
catecholamines, E and NE, are primarily known for their ability to control the “flight
or fight” response in the body (Mittal et al. 2017; Tank and Lee Wong 2015).
However, all these major catecholamines, in addition to their primary functions in
Role of Neuromodulators in Regulation of the Tumor Microenvironment.. . 157
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the CNS, perform a number of other functions in the periphery (Basu and Dasgupta
2000; Chakroborty et al. 2009; Sarkar et al. 2013; Mittal et al. 2017; Tank and Wong
2015). The catecholamines regulate basic physiological responses in the GI tract
such as GI motility, gastric emptying, proliferation, and renewal of gastric and
colonic epithelial cells (Chakroborty et al. 2004; Szabo 1979; Eisenhofer et al.
1997; Mezey et al. 1999;Gáti et al. 1975; Bojö et al. 1991). In addition to their
role in GI physiology, the catecholamines are also associated with a numbe r of GI
disorders such as ulcers, inflammatory bowel diseases (IBD), and with the development and progression of GC and CRC (Szabo 1979; Mezey et al. 1999; Ugalde et al.
2021; Kurnik-Łucka et al. 2021). In the GI tract, both post-ganglionic nerve fibers
and the cells in the GI system especially the chromaffin cells from adrenal medulla
and the gastric epithelial cells have been identified as major sources of
catecholamines (Szabo 1979; Eisenhofer et al. 1997; Mezey et al. 1999). These
catecholamines mediate their actions on different cell populations by acting through
specific receptors that are expressed on the surface of these cells (Mittal et al. 2017;
Mezey et al. 1999;Gáti et al. 1975; Bojö et al. 1991; Kurnik-Łucka et al. 2021).
While NE and E work via α and β adrenoreceptors (ADR), the diverse actions of DA
on effector cells are mediated through five major types of DA receptors (D1 through
D5) (Missale et al. 1998; Basu and Dasgupta, 2000; Mezey et al. 1999;Gáti et al.
1975; Bojö et al. 1991; Kurnik-Łucka et al. 2021) expressed on the surface of these
cells. The fi
structural properties, are further categorized into two major classes, the D1 class and
the D2 class (Basu and Dasgupta 2000; Chakroborty et al. 2004 ; Mezey et al. 1999).
All of them characterize as GPCR. While D1 class of DA receptors, which includes
D1 and D5 receptors, are known to couple with Gs protein and stimulate adenylate
cyclase resulting in intracellular accumulation of cAMP, the D2 Class of DA
receptors, i.e., D2, D3, and D4 are known to couple with Gi protein that inhibits
adenylate cyclase and formation of intracellular cAMP and activates the K+
channels in the effector cells (Missale et al. 1998; Basu and Dasgupta 2000;
Chakroborty et al. 2004; Mezey et al. 1999). All types of catecholam ine receptors
are expressed in the GI system and these receptors together with their ligands are
extensively involved in a number of physiological processes. It is therefore not very
surprising that any change in expressions, activity, or receptor distribution has
profound impact on GI physiology. Perturbation of catecholamines from their
normal expressions and activities has been shown to be associated with number of
diseases in the GI tract including GI malignancies (Chakroborty et al. 2004; Mezey
et al. 1999 ; Eisenhofer et al. 1997).
ve major types of DA receptors, based on their pharmacological and
3.2.1 Epinephrine and Norepinephrine
In GC and CRC, E and NE promote tumor growth (Mehedințeanu et al. 2021; Pan
et al. 2021; Yao et al. 2009; Coelho et al. 2015). Most of the information regarding
their involvement in tum or progression come from studies where stress has been
shown to play a major role in cancer progression (Zhang et al. 2019; Pan et al. 2021;
Coelho et al. 2015) as E and NE are the two major stress hormones in the body
(Zhang et al. 2019; Chakroborty et al. 2009; Sarkar et al. 2013; Kurnik-Łucka et al.
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2021; Coelho et al. 2015). The activation of sympathetic adrenal medullary axis
influences tumor growth by promoting proliferation of tumor cells and by regulating
the cells in the TME (Zhang et al. 2019; Chakroborty et al. 2009; Sarkar et al. 2013;
Kurnik-Łucka et al. 2021; Coelho et al. 2015). E and NE are principal
catecholamines secreted by sympatho-adrenal system. NE is primarily produced
by sympathetic nerves while the major source for E is adrenal medulla (Mravec
et al. 2020; Cole and Sood 2012). Human sample studies as well as information from
animal studies have confirmed that chronic behavioral stress impacts multiple
aspects of tumor growth from initiation to metastatic progression. Elevated levels
of free E and NE have been detected in the plasma samples collected from GC
patients which are associated with worse prognosis and poorer survival rate in these
patients (Zhang et al. 2019; Mehedințeanu et al. 2021; Pan et al. 2021; Zhi et al.
2019; Wang et al. 2021). Studies indicate that both E and NE can alter the functions
of cancer cells and stromal cells such as fibroblasts , immune cells, and endothelial
cells both in GC and CRC. In GC upon stimulation of E and NE, cell proliferation,
invasion, and survival were increased (Zhang et al. 2019; Shi et al. 2013). In
addition, both E and NE control cancer cell metabolism in GI cancers. A higher
expression of NE was reported in human GC tissues collected from patients compared to normal gastric tissues (Zhang et al. 2019; Wang et al. 2021). The expression
level of E and NE was associated with the enhanced glycolysis observed in GC cells
(Wang et al. 2021). In CRC, activation of protein kinase A (PKA) pathway via
epinephrine-β-adrenergic receptor (β-AR) –cyclic AMP (cAMP) – was shown to
directly promote tumor cell proliferation (Mravec et al. 2020). In addition, NE was
shown to promote EMT and facilitate cell metastasis in GC cells (Shan et al. 2014).
Both in GC and in CRC, E and NE-induced stimulation of β adrenergic receptor was
reported to increase therapeutic resistance against chemotherapeutic agents like
Cisplatin and 5-FU. In addition, E and NE-induced stimulation of β adrenergic
receptor also increased therapeutic resistance to targeted agents like trastuzumab in
GC. Using in vitro studies and in vivo xenograft model, it was reported that
stimulation of β2-adrenergic receptor in GC cells enhances the production of
MUC4 by these cells. The increase in MUC4 in the cells leads to resistance against
targeted therapy like trastuzumab (Shi et al. 2013). In another study, it was shown
that long-time exposure to catecholamine adrenaline/epinephrine enhanced the
expression of P-glycoprotein in cells, which led to multidrug resistance in colon
cancer cells. Adrenaline promoted the proliferation of HT29 colon cancer cells and
increased chemoresistance in the cells by decreasing cisplatin-induced apoptosis. It
increased the expression of miR155 in colon cancer cells in a NFĸB-dependent
manner (Yao et al. 2009; Shi et al. 2013; Pu et al. 2012).
In addition to their direct effect on tumor cells, NE and E also control the
functions of different stromal cells both in GC and CRC (Chakroborty et al. 2009;
Sarkar et al. 2013; Mehedințeanu et al. 2021; Shi et al. 2013). NE was reported
to promote several cytokines and growth factors such as VEGF and matrix
metalloproteinases (MMPs) (Chakroborty et al. 2009; Sarkar et al. 2013;
Mehedințeanu et al. 2021; Shi et al. 2010). E promotes the secretion of MMP 7 by
GC cells via activation of signal transducer and activator of transcription 3 and
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activator protein 1 (AP1) and thereby facilitates the process of cellular metastasis
(Shi et al. 2010). In addition, E and NE are known as potent stimulators of the
process of neo-vessel formation/angiogenesis in cancer tissues (Chakroborty et al.
2009; Sarkar et al. 2013). They can directly (acting on endothelial cells via adrener-
gic receptors present on endothelial cell surface) and indirectly (inducing the release
of angiogenic factors from other types of cells) stimulate the process of tumor
angiogenesis and thus help in tumor progression (Chakroborty et al. 2009; Sarkar
et al. 2013). Chronic stress has been reported to be associated with increased
angiogenic response and decreased efficacies of anti-angiogenic agents in vivo
(Chakroborty et al. 2009; Sarkar et al. 2013). Studies suggest that enhanced NE,
observed in stressed subjects, reduces the effect of anti-angiogenic therapies in colon
tumors due to enhanced production of angiogenic factors like VEGF and IL-8
(Zhang et al. 2019; Chakroborty et al. 2009; Sarkar et al. 2013; Yang et al. 2009).
Activation of the adrenergic receptors in chronic stress was associated with increased
angiogenesis and tumor growth in a mouse model of CRC (Liu et al. 2015).
Furthermore, several studies have confirmed the involvement of β-AR-cAMPPKA signaling pathway in the TME in promoting the process of angiogenesis and
hence helping in tumor growth and progression (Wong et al. 2011).
3.2.2 Dopamine
In addition to the two other catecholamines, the third catecholamine, DA is also
known to control a number of functions of the GI system. DA in the GI system is
primarily known for its protective action on gastric mucosal epithelial cells. In the GI
tract, in addition to the neuronal source, studies have also reported non-neuronal
synthesis and release of DA. DA receptors are expressed throu ghout the GI tract
(Feng et al. 2020). Both the stomach and colon synthesize and contribute significant
amounts of DA to the circulation. TH, the rate-limiting enzyme for DA synthesis,
DA transporters, and vesicular monoamine transporters were also reported to be
present in the acid-producing parie tal cells of the stomach (Chakroborty et al. 2009;
Sarkar et al. 2013; Eisenhofer et al. 1997; Mezey et al. 1999; Kurnik-Łucka et al.
2021). DA D1b receptor is the most abundant DA receptor subtype in gastric and
duodenal epithelium. The gastric epithelia possess the hallmarks of functional DA
neuroendocrine cells, suggesting that DA has an important role in self-protective
mechanisms of the GI tract (Eisenhofer et al. 1997; Mezey et al. 1999; Mezey et al.
1998). Studies have shown its protective role in gastric ulceration where hypo and
hyper DA contents have been linked to increased and reduced incidence of peptic
ulcers (Altschuler, 1996; Ozdemir et al. 2007; Feng et al. 2020). However, in
contrast to the two other major catecholamines , E and NE, that promote tumor
progression in GC and CRC, the role of DA in tumor progression is mainly
inhibitory (Chakroborty et al. 2009; Sarkar et al. 2013 ). While E and NE mediate
their functions via α and β adrenergic receptors present on tumor and stromal cells,
DA primarily exerts its effect via its own specific D1 and D2 classes of receptors that
when activated inhibit tumor progression (Chakroborty et al. 2009; Sarkar et al.
2013; Chakroborty et al. 2011, 2004). Studies have reported the presence of DA
receptors on cancer cells and also on stromal cells such as immune cells,
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macrophages, and smooth muscle cells (Chakroborty et al. 2004, 2009, 2011; Sarkar
et al. 2013). However, the effect of DA in GC and CRC depends upon the expression
and involvement of the particular DA receptor sub type. The effect is also cell typespecific. The growth inhibitory effect of DA on GC and CRC is primarily mediated
via D2 receptors present on the surface of endothelial cells forming the tumor blood
vessels (Chakroborty et al. 2011, 2004). Alteration in expression of DA D2 receptors
was noted both in both human GC and CRC tissues (Chakroborty et al. 2011, 2004;
Basu and Das gupta 1997; Basu and Dasgupta 1999). A significant loss of tissue DA
and TH has been noted in both GC and CRC (Chakroborty et al. 2011; Chakroborty
et al. 2004). The stomach has been identified as a major DA-producing organ in the
GI tract and a total loss of DA and TH was reported in GC tissues. Loss of DA, both
in GC and CRC, was shown to promote tumor growth in these organs (Chakroborty
et al. 2004, 2011). It was reported that DA acting through its D2 receptors can
regulate VEGF-A-induced angiogenic processes in vivo (Basu et al. 2001). Loss of
DA in GC and CRC therefore promoted tumor growth and progression by
augmenting the proces s of formation of neovessels in these tissues (Chakroborty
et al. 2004, 2011). However, DA-mediated action on VEGF-A-induced angiogenesis
differs from that of angiogenic processes mediated by E and NE. Unlike regulating
the expression of VEGF secretion by cancer cells and other cells in the TME, DA has
been reported to interfere with the binding of VEGF to its receptor VEGF receptor
2 (VEGFR-2) resulting in inhibition of the process of angiogenesis (Basu and
Dasgupta 1997; Chakroborty et al. 2004, 2008, 2009; Sarkar et al. 2013; Zhang
et al. 2019). In GC and CRC, stimulation of DA D2 receptors in tumor endothelial
cells, either by DA or its specific receptor agonists, could inhibit VEGF-induced
activation/phosphorylation of VEGFR2 expressed on the endothelial cells. In addition to its role in neovessel formation, DA was also reported to regulate the structure
and functions of blood vessels in CRC (Chakroborty et al. 2011 36). Tumor blood
vessels differ from normal blood vessels in structure and as well as in function. They
are tortuous, have chaotic arrangements and extremely permeable or leaky in nature
(Nagy et al. 2009, 2010). Studies have indicated that loss of endogenous DA is
associated with abnormal blood vessel structures in CRC and exogenous administration of DA can successfully normalize the morphology of tumor blood vessels by
acting on the two important cellular components of the vessels: the pericytes that
surround the blood vessels and the endothelial cells that form the blood vessels
(Chakroborty et al. 2011). DA via D2 receptors present in these cells directly
upregulated angiopoietin 1 (Ang1) expression in pericytes (Chakroborty et al.
2011). Ang1 produced by the pericytes helps in stabilizing the endothelium and
normalizing the structure and functions of the blood vessels (Armulik et al. 2005;
Morikawa et al. 2002; Jain 2003; Fiedler and Augustin 2006). DA also upregulated
zinc finger transcriptional factor, Krüppel-like factor-2 (KLF2) expression in tumor
endothelial cells in CRC (Chakroborty et al. 2011). KLF2 is an important regulator
of not only endothelial cell functions like differentiation and proliferation, but it also
regulates vessel stabilization by inducing endothelial cells quiescence (Dekker et al.
2006; Boon et al. 2007; Lin et al. 2010). Importantly, vessel stabilization by DA
increased the concentration of anticancer agent 5-FU in the CRC tissues
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(Chakroborty et al. 2011; Sarkar et al. 2008). 5-FU concentrations in CRC tissues
were significantly (2.2 times) increased in CRC mice treated with DA and 5-FU
compared to control mice treated only with 5-FU (Chakroborty et al. 2011). In GC,
DA via D2 receptors inhibited the proliferation of tumor cells via upregulation of
Krüppel-like factor 4 and down-regulation of insulin-like growth factor receptor-I
(IGF-IR) and AKT phosphorylation in these cells (Ganguly et al. 2010). Reports also
indicate that unlike the tumor endothelial cells, the expression of D2 receptors in
GC cells is low (Basu and Dasgupta 1997) and upon their activation epidermal
growth factor (EGF)-mediated GC cell invasion and migration is inhibited via the
EGFR/AKT/MMP-13 pathway (Huang et al. 2016).
3.3 Serotonin
Serotonin or 5-hydroxytryptamine (5-HT) is another important neurotransmitter in
the GI tract. It is a monoamine neurotransmitter which is derived from the amino
acid L-tryptophan by a two-step process. In the first step tryptophan is converted by
the enzyme, tryptophan hydroxylase (TPH), to 5 hydroxy-L-try ptophan. In the
second step that is catalyzed by the enzyme 5hydroxy tryptophan decarboxylase/
aromatic L amino acid decarboxylase, 5 hydroxy-L-tryptophan is converted to 5-HT
(Di et al. 2019; Höglund et al. 2019). TPH, which is the rate-limiting enzyme for
5-HT biosynthesis, is encoded by two genes, i.e., TPH1 and TPH2, which have
different tissue distributions. TPH2 is mainly responsible for serotonin biosynthesis
in the CNS and TPH1 is primarily expressed in enterochromaffin cells in intestinal
mucosa and responsible for serotonin biosynthesis in the periphery (Schneider et al.
2021; Lesurtel et al. 2008). The functions of 5-HT in the human body are similar to
that of DA. Like DA, in the CNS, 5-HT controls functions like mood, cognition and
sleep cycle, learning, and memory. 5-HT is mostly known for its involvement in
mood correction in humans. It has also been associated with psychological disorders
(Di et al. 2019; Höglund et al. 2019; Strasser et al. 2016; Jenkins et al. 2016). It
mediates its action through a specific receptor system called the serotonergic receptor system (Di et al. 2019; Höglund et al. 2019; Strasser et al. 2016; Jenkins et al.
2016; Mawe and Hoffman 2013). This receptor system consists of 7 families of
GPCR and ligand-gated ion channels, 5-HT1-5HT7 (Mawe and Hoffman 2013;
Shah et al. 2021). Of these, only the 5-HT3 receptor is a ligand-gated ion channel
(Lummis 2012). Though 5-HT controls several functions of the CNS, in the human
body only 2–3% of the total 5-HT produced comes from the CNS. The GI system,
particularly the enterochromaffin cells and the intestinal epithelial cells of the GI
tract are regarded as the major sources of 5-HT. These cells roughly contribute about
85–90% of body’s total 5-HT content (Shah et al. 2021). In addition to these two
types of cells, the blood cells, particularly the platelets, are regarded as major
contributors of 5-HT in the body (Shah et al. 2021). These cells play important
roles in synthesis, uptake, and storage of 5-HT in the body. The functions of 5-HT in
GI tract include but are not limited to regulation of GI tract motility, gastric
emptying, and inhibition of secretion of gastric acids (Mawe and Hoffman 2013;
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Shah et al. 2021). The 5-HT system was reported to be associated with several GI
functional disorders such as GI motility dysfunction, diarrheal diseases, and constipation. Modulation of serotonergic system has been explored and validated in the
treatment of GI disorders (Mawe and Hoffman 2013 ; Shah et al. 2021). In addition to
its regulatory role in GI functions, 5-HT also acts as a mitogen in the GI system
where it enhances the intestinal epithelial cell proliferation. In addition, 5-HT also
plays a protective role against inflammation-associated injury or insult in the GI
tract. Due to its ubiquitous presence in the GI tract as an ENS neurotransmitter and as
a regulator of intestinal motility and inflammation, the role of 5-HT in the GI cancers
where cells divide uncontrollably is complicated (Shah et al. 2021).
Both from animal studies as well as from studies involving human patient-derived
samples, it was reported that 5-HT is associated with the development and progression of both GC and CRC. Its role however is paradoxical in nature as studies have
associated 5-HT with both progression as well as inhibition of these cancers (Agaev
and Guliev 1977; El-Salhy 2005; Kannen et al. 2020; Ye et al. 2021; Gershon and
Tack 2007). Increase of 5-HT levels was reported to be associated with severe
symptoms in colitis as well as in CRC (Kannen et al. 2020). While overexpression
of 5-HT in CRC has been identi fied as a predictor for poor prognosis and disease
recurrence in CRC patients, a protective role of 5-HT was also reported particularly
in the early stages of CRC development. This is not unusual since 5-HT plays an
important role in protecting the intestinal epithelium from inflammation-associated
injury which justifies its protective role in the early stages of CRC (Kannen et al.
2020). This also explains why patients taking blockers of 5-HT reuptake have a
reduced risk of CRC development (Xu et al. 2006). Using tryptophan hydroxylase
1 knockout (Tph1KO) and transgenic (Tph1fl/flVillinCre) CRC mouse models with
a defective 5-HT synthesis system, it was reported that serotonin deficiency
facilitated carcinogen-induced DNA damage in colonic epithelial cells and thereby
promoted tumor progression. This study reported a novel protective role of 5-HT
which promoted DNA repair activity during early CRC stages (Sakita et al. 2019). In
contrast, studies have also reported that 5-HT promoted CRC cell proliferation by
activating reuptake transporters and receptors (Tutton and Barkla 1978). Increased
plasma 5-HT levels in CRC patients (Kannen et al. 2020; Dowling et al. 2015) are
associated with metastasis, poor recurrence-free survival, and overall survival (Xia
et al. 2018). Increased 5-HT expression was reported to promote the development of
colorectal tumors in animals as well. Studies conducted on mouse models have
reported that 5-HT by creating a pro-in flammatory microenvironment can promote
CRC progression (Chan et al. 2020; Balakrishna et al. 2021). 5-HT at a smaller dose
(10 μg/kg of the body weight) enhanced cell proliferation or increased the mitotic
rates of colonic epithelial cells in a dimethyl hydrazine-induced rat model of colon
adenocarcinoma. Reduction in colonic epithelial cell proliferation was achieved
upon inhibition of 5-HT receptors expressed in these cells (Tutton and Barkla
1978). In addition to regulating the proliferation of CRC cells, 5-HT plays a major
role in the regulation of angiogenesis in the TME (Zamani and Qu 2012). The
proangiogenic effect of 5-HT is mediated through the activation of HTr1, HTr2, and
HTr3 (Peters et al. 2014). Reduced angiogenic respon se and reduced tumor growth
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were reported in an allograft model of CRC developed in 5-HT deficient mice which
supported the proangiogenic role of 5-HT in CRC. In the TME, 5-HT was shown to
regulate the expression of MMP12 in tumor-infiltrating macrophages. Deficiency in
peripheral 5-HT resulted in reduction of MMP12 expression in these macrophages
leading to an increase in circulatory angiostatin, which is an endogenous angiogenesis inhibitor. The increase in angiostatin resulted in inhibition of angiogenesis
and thereby tumor growth in these animals (Nocito et al. 2008). Peripheral
5-HT–deficient (Tph1-/-) mice showed reduced CRC growth with enhanced
accumulation of functional CD8+ T cells which improved overall survival of the
mice. The 5-HT-deficient (Tph1-/-) mice also expressed less programmed cell
death 1 ligand 1 (PD-L1) (Schneider et al. 2021).
3.4 Nitric Oxide
Nitric oxide (NO) plays a major role in immunological defense and GI carcinogenesis (Wang et al. 2005; Ambs et al. 1999) and is primarily synthesized in cells through
the conversion of l-arginine to l-citrulline by the enzyme nitric oxide synthases
(NOS) (Förstermann and Sessa 2012; Campos et al. 1995). The three wellcharacterized NOS isoforms are encoded by different genes-inducible NOS
(iNOS) is encoded by NOS2, endothelial NOS (eNOS) is encoded by NOS3, and
neuronal NOS (nNOS) is encoded by NOS1. nNOS and eNOS are the constitutive
and Ca++-dependent isoforms of NOS and iNOS is the Ca++-independent isoform.
eNOS and nNOS isoforms are expressed in different cells and are activated due to a
rise in intracellular calcium resulting in calmodulin-binding (Förstermann and Sessa
2012; Campos et al. 1995; Costa et al. 2016). iNOS on the other hand has a higher
affinity for calmodulin and therefore is not dependent on calcium for activation and
can be induced by inflammatory cytokines, stimulation of endotoxins, and hypoxic
conditions (Förstermann and Sessa 2012). NOS isoforms generate NO at different
levels. iNOS also produces higher amounts of NO in a shorter time (Förstermann and
Sessa 2012; Eroglu et al. 2017).
Chronic inflammation is important for the initiation and progression of GI
cancers. Tumor tissues express different levels of NOS at different stages of progression. nNOS, eNOS, and iNOS have been characterized in the GI tract (Calatayud
et al. 2001). A report on GI cancers suggested that most of these cancers had
adherent iNOS expression; however, whether this expression was high or low
depends upon the cancer type (de Oliveira et al. 2017). High iNOS activity was
reported in colonic adenomas before they transitioned to carcinomas (Ambs et al.
1999). Furthermore, higher expressions of iNOS and eNOS were also reported
(Yagihashi et al. 2000; Ambs et al. 1998) in CRC. Even though increased iNOS
levels in CRC patients were reported when compared with the surrounding normal
tissue, the expression was reported to decline as a function of tumor progression
toward a more metastatic state (Ambs et al. 1999; Goodman et al. 2004). Contrary to
this, a study also reported that iNOS expression and activity decreased or was absent
in colonic tumor tissues whereas normal colonic epithelium showed the presence and
164 D. Chakroborty and C. Sarkar
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activity of iNOS (Moochhala et al. 1996). In another study, a strong correlation
between iNOS expression, microvessel density/angiogenesis, and VEGF expression
was reported in CRC. This study suggested that iNOS promoted VEGF-mediated
tumor angiogenesis in CRC (Cianchi et al. 2003). When a human colonic adenocarcinoma cell line was engineered to generate nitric oxide (NO), increased tumor
growth was seen and the tumors were more vascularized (Jenkins et al. 1995).
Interestingly, opposite results were seen in Apc (Min/+) colon cancer where lack
of iNOS promoted tumorigenesis (Scott et al. 2001). APC/Wnt/β-catenin pathway, a
major player in EMT transition is often dysregulated in CRC. APC downregulates
B-catenin, which prevents polyp formation in healthy individuals (Bienz and Clevers
2000).
GC development is a multistage process and a study indicated that during the
progression from normal to pre-cancerous lesions to GC, iNOS, along with VEGF
were significantly increased and the expression of iNOS correlated with lymph node
metastasis (Song et al. 2002). NO overproduction by iNOS is an important pathogenic factor in H. pylori-induced gastritis (Nam et al. 2004; Goto et al. 1999). Gastric
epithelial cells exposed to bacterium generate reactive oxygen species (ROS) and
iNOS causing genetic alterations that result in GC (Nardone 2003; Choudhari et al.
2013). iNOS expression in GC is related to VEGF expression, increased microvessel
density, lymphangiogenesis, and lymph node metastasis (Song et al. 2002; Karadayı
et al. 2013; Yamaguchi et al. 2005; Zhang et al. 2011). An inverse correlation was
however noted with dendritic cell infiltration indicating that while iNOS promoted
angiogenesis and lymphangiogenesis, it suppressed immune responses in gastric
carcinoma (Yamaguchi et al. 2005). Thus iNOS expression can be a biomarker for
poor prognosis in GC.
eNOS was also reported to be an independent prognostic factor in GC patients. Its
expression is significantly upregulated in GC and correlates with poor prognosis and
shorter OS (Zou et al. 2021). eNOS also promotes angiogenesis in GC (Wang et al.
2005).
3.5 g-Aminobutyric Acid
γ-aminobutyric acid (GABA) is primarily known as an inhibitory neurotransmitter
that plays a major role in CNS in reducing the neuronal excitability. GABA is widely
distributed both in the CNS as well as in the peripheral tissues like pancreas,
stomach, colon, and uterus. In the GI tract, particularly in the large intestine,
GABAergic neuronal cells, mainly interneurons, are found in submucosal and
myenteric plexus (Hyland and Cryan 2010; Krantis 2000). They account for 5–8%
of the tota l myenteric neurons (Krantis 2000). In the colon, GABA predominantly
co-localizes with somatostatin, and to a lesser extent with enkephal ins and NO
(Krantis 2000). Enteric GABA is primarily synthesized from glutamate by the
enzyme l-glutamate decarboxylase (GAD) in the myenteric plexus and mucosal
endocrine-like cells. There are two major classes of GABA receptors: ionotropic
receptors GABAA and GABAC receptors and metabotropic receptor GABAB
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