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Deregulation of Immune System in Gastric Cancer Development, How.. . 113
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Helicobacter pylori Virulence Factors,
https://t.me/med1917
Pathogenicity, and Gastric Cancer
Alaa M. Elgohary
, Nourhan M. Gomaa, Mohamed A. Ibrahim,
Hagar S. Ahmed, Shimaa M. Ibraheem, and Mustafa H. Frag
Abstract
Gastric cancer is a common cancer with a high incidence and mortality rate
worldwide. Unfortunately, early-stage gastric cancer is asymptomatic. Consider-
ing that, it is one of the reasons for late detection. Gastric cancer which is strongly
related to the Helicobacter pylori infection is more common in East Asian
countries and developing countries with low sanity levels. The prolonged infec-
tion with H. pylori increases the risk of developing gastric ulcers, thereby
activating the route of chronic inflammation and subsequently the onset and
development of gastric cancer. Although H. pylori is not the only cause of all
duodenal and gastric ulcers and the infection by H. pylori alone cannot explain
the development of gastric cancer, understanding the mechanisms governing the
H. pylori persistence will empower our research tools starting from early detec-
tion to bacterial eradication. This chapter includes but is not limited to the
H. pylori virul ence facto rs correlated to its invasiveness and the pathways that
increase the risk of developing gastric cancer. The potential of escaping the acidic
conditions through the secretion of cytoplasmic and surface urease, the bacterial
compass (the sheathed flagella and chemotaxis system) that directs the bacteria to
the epithelial cells, its adherence, and the release of pathogenic proteins (mainly,
VacA and CagA) that interact with and alter the normal behavior of host cells.
The topics discussed in this chapter outline the H. pylori adaptation and persis-
tence and how the host cell/bacterial factors interactions can strengthen the
cellular oncogenic properties and increase its vulnerability to gastric cancer.
Keywords
CagA · Gastric cancer · H. pylori · VacA · Virulence factors
A. M. Elgohary (✉) · N. M. Gomaa · M. A. Ibrahim · H. S. Ahmed · S. M. Ibraheem · M. H. Frag
Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
e-mail: aelgohary@cu.edu.eg
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2023_183
Published online: 28 September 2023
117
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1 Introduction
Helicobacter pylori are one of the most common bacteria, which infects half of the
people worldwide, mainly in developing countries. The refore, H. pylori infection is
considered a criterion for a low-sanity environment (Hooi et al. 2017).
H. pylori is an ancient, most prevalent human pathogen. H. pylori is a spiralshaped, gram-negative, microaerophilic, flagellated bacterium that can convert its
spiral shape to coccoid. Both shapes enhance its survival and invasiveness in the
host gastric microenvironment. The spiral form enables bacterial mobility while the
coccoid form provides the ability to colonize the mucous membrane of the gastric
epithelium (Maixner et al. 2016). In 1982, Robin Warren and Barry Marshall first
discovered and identified the correlation between H. pylori and peptic ulcers
(Marshall and Warren 1984).
H. pylori infection significantly contributes to several gastrointestinal diseases,
such as chronic gastritis, duodenal, peptic ulcers, and gastric adenocarcinoma. The
transmission of the pathogen is through oral–oral or oral–fecal routes. The World
Health Organization (WHO) declared H. pylori a class I carcinogen, as they increase
the risk of developing gastric cancer by about sixfold (Humans 1994). The
prolonged infection could contribute to the precancerous cascade, starting from the
chronic inflammation of gastric mucosa that could lead to subsequent mucosal
atrophy and intestinal metaplasia, the precursor for carcinoma (Fig. 1). The chronic
bacterial infection increases the risk of developing a non-cardia gastric adenocarcinoma; this cancer type hits the main part of the stomach excluding the parts near the
esophagus.
Gastric cancer is a multifactorial disease, whereas the complex interplay between
bacterial virulence factors, host susceptibility, genetic variations, and environmental
factors, such as salty preservative food, nutritional deficiency, alcohol, and tobacco
consumption, all contribute to different clinical outcomes (McGuire 2016; Di Ciaula
et al. 2020 ).
Gastric adenocarcinoma is the fifth diagnosed cancer worldwide based on
GLOBOCAN 2018 and the third leading cause of cancer death (Bray et al. 2018).
Gastric carcinoma is a malignant epithelial tumor of the stomach mucosa with poor
survival statistics throughout the world. It remains a significant clinical problem,
with over one million new cases worldwide. The incidence rates in men are twice
that in women, while East Asian countries report strikingly increasing rates, especially the Republic of Korea, with the highest rates in both sexes. Most new
diagnoses of gastric cancer per year mainly occur in South American countries
and Asia. The incidence rate of gastric cancer that corresponds to H. pylori infection
in East Asian countries is eightfold higher than in North America (Rawla et al.
2019).
The journey to the host stomach epithelial cell s entails precise steps on the
infection scope. H. pylori prefer to grow at neutral pH. The intriguing questions
are how these bacteria seek refuge from the harsh acidic stomach environment
(pH 1–2) and avoid gastric mucosa turnover, then how its persistence can develop
into gastric cancer. Here, we highlight the factors and pathways of H. pylori during
Helicobacter pylori Virulence Factors, Pathogenicity, and Gastric Cancer 119
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Fig. 1 The schematic diagram highlights the progression of disease outcomes after infection and
the bacterial pathogenicity and virulence factors. H. pylori possess cytoplasmic and surface urease
enzyme to neutralize gastric acidity. Flagella and chemotaxis mediate H. pylori motility and
colonization of the mucus layer. Adhesins mediate its binding to receptors on gastric epithelium.
The main virulence factors VacA and CagA interact with a multitude of signaling cascades,
inducing the transduction of proinflammatory genes
their journey to the host stomach, highlighting the potential role of their toxins in
sophisticated clinical outcomes that can be developed within certain circumstances
to gastric carcinogenesis.
1.1 Adaptation in the Acidic Environment
1.1.1 Urease Activity
H. pylori initiates its journey by combating the hostile acidic conditions by producing ammonia through its urease enzyme activity. Additionally, more proteins such as
the periplasmic α-carbonic anhydrase activity are required for stomach colonization
(Elizabeth et al. 2005).
The cytoplasmic urease enzyme, which exists within the bacterial cytoplasm,
represents 10% of the total bacterial protein at a pH of 6 or 7. Urease depends on the
nickel cofactor and neutralizes the acid by producing ammonia and carbon dioxide
from urea. Thus, H. pylori urease activity keeps its cytoplasm ic and periplasmic
pH near neutrality when exposed to the acidic lumen (pH 1–2) (Xia 2022).
The urease gene cluster consists of seven genes, two of which are coded for
nickel-dependent urease (ureA/B), one for proton-gated plasma membrane urea
channel (UreI), and four for accessory assembly proteins (ureE-H) included in nickel
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processing. The Cryo-EM structure of the urease active site during the delivery of the
nickel ion is determined by Nim et al. ( 2023).
UreI works with the cytoplasmic urease; when UreI senses the periplasmic pH, it
opens at acidic pH and closes at neutral pH. Once the channel opens, urea from the
gastric lumen is diffused to the cytoplasm and hydrolyzed by the cytoplasmic urease
into carbon dioxide and ammonia, while the latter immediately protonates to form
ammonium. Accordingly, UreI neutralizes the protons enter ing the periplasm by
releasing the ammonia across the inner membrane, while the formed urea-derived
ammonium is assimilated into the bacterial ami no acid pool (Miller and Maier 2014).
Moreover, H. pylori have a urease enzyme on its surface. Therefore, the surface or
free urease activity has a role in neutralizing the acidic environment surrounding the
bacteria (Kao et al. 2016 ; Miller and Maier 2014).
Further to its role in colonization, urease can escape phagocytosis in the innat e
immune response by modifying the phagosome pH and megasome formation. Thus,
H. pylori can survive in macrophages (Schwartz and Allen 2006).
Cunha et al. solved the crystal structure of the 1.1 MDa urease with an inhibitor in
its active site by Cryo-EM. This detailed structure considers a way to develop a
targeted and highly specific drug (Cunha et al. 2021).
1.1.2 Flagella and Chemotaxis System
Four to seven polar-sheathed flagella facilitate the movement of H. pylori through
the mucosal layer to reach the neutral pH basal layer (Kao et al. 2016). The flagellum
comprises three main structures (the basal body, the hook, and the flagellar filament).
The basal body, which is located in the cytoplasm and inner membrane, contains
several protein structures and plays an essential role as a source of energy for
bacterial motility. The second part is the hook, which is described as a short and
curved structure composed of multiple copies of a single protein (FlgE) (Loconte
et al. 2017). Its function connects the basal body with the flagellar filament. The last
structure is the flagellar filament, composed of two flagellins (FlaA and FlaB)
encoded by flaA and flaB, which are necessary for bacterial motility (Lertsethtakarn
et al. 2011 ).
A flagellum is composed of ~25–30 relatively conserved proteins. The essential
structural proteins of the H. pylori flagellum include HpaA, FlaA, FlaB, FliD, and
FlgK (Tang et al. 2008;Gu2017). These proteins are primary targets of the immune
system. They cause neutrophil filtration, secret anti-flagellin-antibodies, and IL-8
(acts as inflammation factor), but they cannot be recognized by toll-like receptor
5 (TLR-5) (Mori et al. 2012; Aihara et al. 2014;Gu2017) because of a shield made
by the flagellar sheath, HpaA. It is also discovered that the enhanced glycosylation
level of the FlaA leads to intense infection. Furthermore, the loss of a gene encoding
a cardiolipin synthase in H. pylori strain G27 prohibits flagellum assembly (Chu
et al. 2021 ).
The bacterial ability to infect the host stomach may be abolished if there are any
mutations in just one gene of flagella and the chemotaxis system (Howitt et al. 2011).
Flagella, deemed the main factor for colonization, causes more infection than
nonmotile bacteria and enables H. pylori to stay longer (Gu 2017).
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The chemotactic system is another crucial system in promoting motility, hence,
H. pylori colonization. The chemotactic signaling system, considered as the bacterial
nose, is a process that senses and influences flagellar rotation toward favorable
environmental signals and directs it away from harmful ones, promoting chronic
stomach infection. In addition, it fosters colonization and plays a role in modulating
immune responses to the host. The core chemotaxis proteins that are found in all the
chemotaxis systems are the chemoreceptors TLPA, TlpB, TlpC (the transmembrane
chemoreceptors with sensing domains at periplasm), TlpD (a cytoplasmic receptor),
CheW coupling protein, CheA kinase, and CheY response regulators. Moreover, the
auxiliary chemotaxis proteins found only in some systems include CheV1, CheV2,
and CheV3 coupling proteins, CheZ phosphatase, and ChePep chemotaxis proteins
(Lertsethtakarn et al. 2015; Johnson and Ottemann 2018). The chemotactic signals
could be repellents, such as the acidic pH, the bile and reactive oxygen species,
or attractants such as urea and arginine, sensed by TlpB and TlpA, respectively
(Sweeney et al. 2018).
The sensed chemorepellents activate autophosphorylation of CheA; then, the
phosphoryl group is passed to CheY via hist idine-to-aspartate phosphorelay. The
phosphorylated CheY interacts with the flagellar motor, leading to its rotation in a
clockwise direction; thus the bacteria change direction. Furthermore, attractants
suppress the autophosphorylation of CheA since the non-phosphorylated CheY
cannot interact with the flagellar motor, so the bacteria swim straight without
changing direction. Readers are referred to more articles for mol ecular details
beyond the role of chemoreceptors in colonization (Keilberg and Ottemann 2016;
Johnson and Ottemann 2018; Liu and Ottemann 2022).
1.2 Attachment to Host Cells (Adhesins)
Once H. pylori colonize the host stomach’s mucosal layer, they interact with the
receptors expressed on the gastric epithelium surface by their adhesins. This interaction is vital in bacterial protection from displacement due to peristalsis and gastric
emptying. Moreover, it enables the bacter ia to get nutrients and metabolic substances
to improve their growth and enhance the delivery of their toxic materials.
Many adhesins exist; it is believed that the H. pylori outer membrane proteins
(OMPs) have a pivotal role in adhesion and gastric cell colonization. Among the
OMPs, sialic acid–binding adhesin (SabA/HopP), blood antigen–binding adhesin
(BabA/HopS), adherence-associated lipoproteins (AlpA/HopC and AlpB/HopB),
outer inflammatory protein A (OipA/HopH), and helicobacter outer membrane
protein Q (HopQ) (Huang et al. 2016; Matsuo et al. 2017; Xu et al. 2020).
It is suggested that BabA and HopQ have a vital role in the translocation of
Cytotoxin-Associated Gene A (CagA), the virulence factor enhancing the incidence
of gastric cancer.
BabA is the first adhesin described in H. pylori, which is expressed by most
disease-causing H. pylori strains. H. pylori employ BabA to bind to fucosylated
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Lewis b blood–group antigen, which is expressed on the epithelium cells of the host
when H. pylori initially infect the human stomach (Ilver et al. 1998).
It is demonstrated that cases wi th triple positive H. pylori (BabA, vacAs1 type,
and CagA) exhibit severe inflammation and have a higher incidence of adenocarcinoma than that with double positive H. pylori (vacAs1 type and CagA) strains
(Doohan et al. 2021).
HopQ is identified to bind to the host cell receptor carcinoembryonic antigen–
related cell adhesion molecules (CEACAMs). CEACAMs are related explicitly to
the development of gastritis and gastric cancer (Behrens et al. 2020). Furthermore, it
is reported that HopQ is an essential factor for CagA translocation. Its deletion
reduces the CagA activation–dependent (NF-κB, mitogen-activated protein kinase
(MAPK) pathway and interleukin 8 secretions) signaling pathways (Belogolova
et al. 2013 ).
OipA is reported to induce the remodeling of the actin stress fibers by the
phosphorylation of focal adhesion kinase (FAK) (Tabassam et al. 2007). Additionally, both OipA and CagA are essential for fully activating interleukin 8 (IL8)
promotor, but with activation of diff erent upstream signaling. OipA is involved in
the phosphorylation of signal transducers and activators of transcription 1 (STAT-1)
and the upstream pathway for interferon-stimulated responsive element (ISRE)
activation. ISRE is the required factor for IL8 gene transcription (Yamaoka et al.
2004). Furthermore, Braga et al. revealed that oipA “on” status is associated with
gastric cancer (Libanez et al. 2019).
1.3 Pathogenicity of H. pylori
In addition to the previously mentioned virulence factors, the pathogenicity of
H. pylori is severe in the presence of two main factors: vacuolating toxin (VacA)
and cytotoxin-associated gene pathogenicity island (cagPAI) (Fig. 1).
1.3.1 Vacuolating Cytotoxin A
VacA is a crucial pore-forming toxin secreted by H. pylori that forms vacuole-like
membrane vesicles in the cytoplasm of gastric epithelial cells, hence its name. Once
ejected by H. pylori, monomeric VacA assembles into water-soluble hexameric
oligomers, binds and inserts into the lipid membrane to form anion-selective membrane channels, and then internalizes to host cells (Caso et al. 2021). The temporal
order of oligomerization, membrane insertion, and pore formation is still under
investigation. A previous report proves that VacA binds to the lipid rafts although
neither the oligomerization state nor the membrane channel formation is required for
raft binding (Raghunathan et al. 2018).
VacA causes far-reaching effects and contributes to H. pylori persistence and
colonization. The toxin exerts multiple effects on immune cells, especially T cells,
B cells and macrophages, and epithelial cells including the disruption of mitochondrial functions, stimulation of autophagy/apoptosis, and blockade of T cell proliferation. For more details on the VacA modulation to multiple pathogenic pathways,
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