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Zaika, A. Bacterial&Viral Pathogens in Gastric Carcinogenesis. Encyclopedia. Available online: https://encyclopedia.pub/entry/9471 (accessed on 22 December 2025).
Zaika A. Bacterial&Viral Pathogens in Gastric Carcinogenesis. Encyclopedia. Available at: https://encyclopedia.pub/entry/9471. Accessed December 22, 2025.
Zaika, Alexander. "Bacterial&Viral Pathogens in Gastric Carcinogenesis" Encyclopedia, https://encyclopedia.pub/entry/9471 (accessed December 22, 2025).
Zaika, A. (2021, May 10). Bacterial&Viral Pathogens in Gastric Carcinogenesis. In Encyclopedia. https://encyclopedia.pub/entry/9471
Zaika, Alexander. "Bacterial&Viral Pathogens in Gastric Carcinogenesis." Encyclopedia. Web. 10 May, 2021.
Bacterial&Viral Pathogens in Gastric Carcinogenesis
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13081878

Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tumor types, gastric carcinogenesis is tightly linked to infectious events. Infections with Helicobacter pylori (H. pylori) bacterium and Epstein–Barr virus (EBV) are the two most investigated risk factors for GC. These pathogens infect more than half of the world’s population. Fortunately, only a small fraction of infected individuals develops GC, suggesting high complexity of tumorigenic processes in the human stomach. Recent studies suggest that the multifaceted interplay between microbial, environmental, and host genetic factors underlies gastric tumorigenesis. Many aspects of these interactions still remain unclear.

gastric tumor gastric pathogens H. pylori EBV p53 p14ARF

1. Introduction

Approximately 13–15% of human cancers worldwide can be attributed to infectious agents [1]. One demonstrative example is gastric cancer (GC), which is strongly associated with infections caused by Helicobacter pylori (H. pylori) bacteria and other pathogens. Despite all efforts, gastric cancer remains a serious clinical problem. Over seven hundred thousands of deaths related to GC have been reported in 2020, ranking the fourth most-deadliest tumor in the World [2]. The incidence of GC is characterized by complex dynamics and geographical variation. Its occurrence slowly declines in North America and most Western European countries, but its burden remains very high in Asia, Latin America, and Eastern Europe [3]. Multiple histological and anatomical classifications of GC have been proposed over time. For more than half a century, the characterization of GC was largely based on Lauren’s criteria, in which GC was divided into intestinal, diffuse and, undetermined types [4][5]. In 2010, the World Health Organization (WHO) expanded this classification by identifying papillary, tubular, mucinous and poorly cohesive (including signet ring cell carcinoma and other variants), and unusual histological variants [6].

Another approach to GC classification is based on the molecular profiling using gene expression and DNA sequencing analyses. A comprehensive study by the Cancer Genome Atlas consortium (TCGA) proposed four molecular subtypes of GC: (1) tumors positive for Epstein–Barr virus (EBV), (2) microsatellite unstable tumors (MSI), (3) genomically stable tumors (GS), and (4) tumors with chromosomal instability (CIN) [7]. More clinically relevant molecular classification has been presented by the Asian Cancer Research Group (ACRG). This study used gene expression data to describe molecular subtypes linked to distinct patterns of molecular alterations and disease progression and prognosis. Based on these criteria, GC was separated into four groups: MSI-high, microsatellite-stable/p53 inactive (MSS/TP53−), microsatellite-stable/p53 active (MSS/TP53+), and microsatellite-stable/epithelial-to-mesenchymal transition (MSS/EMT) subtypes [8]. Additional classifications have also been proposed [9].

2. H. pylori and Gastric Cancer

H. pylori is a spiral-shaped gram-negative microaerophilic bacterium that, in the process of evolution, adapted to survive and thrive in the human stomach. Since the seminal discovery of H. pylori and its role in gastritis and peptic ulcer disease by Robin Warren and Barry Marshall [10], studies of this pathogen have been continuing for more than three decades. Among many important findings during this period of time, discovery of the relationship between H. pylori and noncardia gastric cancer, and the characterization of gastric tumorigenesis as a stepwise inflammatory process, initiated by H. pylori, played key roles [11]. The stepwise model that emphasizes the role of chronic inflammation and consecutive pathological changes has been proposed by Dr. Pelayo Correa, and has stood the test of time [12]. According to this model, intestinal-type GC is the end result of lengthy progressive changes in the gastric mucosa that start with chronic gastritis, followed by atrophic gastritis, intestinal metaplasia (IM), dysplasia and invasive tumor. In 1994, H. pylori was recognized as a type I carcinogen by the International Agency for Research on Cancer [13]. The clinicopathological role of H. pylori was further highlighted by studies showing that H. pylori eradication reduces gastric inflammation and decreases the risk of premalignant and malignant lesions in the stomach [14]. Several effective anti–H. pylori treatment regiments have been developed and successfully used in clinic [15][16][17].

Besides IM, another type of metaplasia, called spasmolytic polypeptide-expressing metaplasia (SPEM), is also associated with chronic H. pylori infection and gastric adenocarcinoma [18]. It develops as a results of transdifferentiation of chief cells following persistent stomach injury and loss of parietal cells in the gastric oxyntic mucosa [18][19].

H. pylori typically infects humans at an early age, leading to decades-long chronic infection and mucosal injury that may progress to GC at older age. H. pylori is responsible for almost 90% of all noncardia gastric cancers [11][20]. Although infection with H. pylori is very common worldwide, only a small fraction of infected individuals develops GC, indicating complexity of tumorigenic interactions between bacteria and host cells. Among H. pylori virulence factors cytotoxin-associated gene A (CagA) protein and vacuolating cytotoxin A (VacA) are the most studied determinants associated with gastric carcinogenesis (Figure 1) [21][22][23][24].

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Figure 1. H. pylori alters cellular homeostasis during infection. H. pylori colonization of the human stomach is responsible for aberrant activation of multiple oncogenic pathways, induction of DNA damage, disruption of the epithelial barrier, and modulation of the host immune response. CagA, VacA, and other virulence factors play a key role in these processes [22][25][26].

2.1. The cag Pathogenicity Island (cag PAI) and CagA Protein

The cagA gene, which encodes CagA protein, is located at the 3′ end of the cag pathogenicity island, a 40-kilobase bacterial genomic DNA fragment that is thought to be acquired by horizontal transfer of genetic material. The products of the cag PAI form highly organized type IV secretion system (T4SS) pili that functions as a sophisticated molecular machine delivering CagA inside gastric epithelial cells. There are also evidences that bacterial lipopolysaccharides, peptidoglycans, and DNA can be delivered by the T4SS [22][26][27][28][29]. After translocation, CagA is phosphorylated by host tyrosine kinases belonging to the SRC and ABL families at the EPIYA (Glu-Pro-Ile-Tyr-Ala) repeatable motifs located at the carboxy-terminal end of the CagA molecule. The EPIYA motifs are responsible for binding of CagA to multiple host proteins and dysregulation of their functions. Currently, four distinct EPIYA types (-A, -B, -C, and -D) have been identified based on surrounding amino acid sequences. The EPIYA motifs are commonly assembled in the A-B-C(D) arrangements, where the EPIYA-C and rarely EPIYA-D fragments can be present in multiple copies. H. pylori strains carrying the EPIYA-C and EPIYA-D motifs have different geographical distribution. The EPIYA-C motif is typically found outside East Asia, whereas the East Asian strains predominantly carry the EPIYA-D motif [30].

This phenomenon has clinicopathological significance. Systematic review and meta-analysis of published research have shown that the presence of EPIYA-D and multiple EPIYA-C motifs are significantly associated with an increased risk of gastric cancer in the United States/Europe and Asia [31][32].

In addition to the EPIYA motif, the C-terminus of the CagA protein contains another repeatable sequence named the CagA-multimerization motif (CM) [33]. The CM motif comprises 16 amino acid residues and is responsible for homodimerization of CagA and interaction with PAR1b/MARK kinase, playing a critical role in the epithelial cell polarity. [33]. East Asian CagA usually has a single copy of East Asian type of the CM motif, while Western CagA retains multiple copies of Western type of the CM motifs. The polymorphism of the CM and EPIYA motifs explains differences in molecular weight of CagA protein that can vary from 120 to 145 kDa between H. pylori variants [33].

Based on current understanding, CagA is the most significant single factor defining gastric tumorigenesis. Multiple human studies have found considerable associations between infections with CagA-positive H. pylori bacteria and an increased risk of gastric cancer [21][34][35][36]. There are also multiple experimental evidences showing that CagA functions as an oncoprotein. CagA transgenic mice, in which effects of other virulence factors were excluded, developed gastric epithelial hyperplasia and hematopoietic and gastrointestinal malignancies, including gastric adenocarcinoma [37]. Similarly, transgenic expression of CagA in zebrafish causes intestinal epithelial hyperplasia and, in combination with loss of p53, produces intestinal small cell carcinomas and adenocarcinomas [38]. CagA also enhances growth and invasion of tumors generated by expression of oncogenic Ras in Drosophila [39].

Oncogenic pursuit of CagA is mediated by aberrant activation of multiple signaling cascades that are known to be altered in gastric cancer (RAS/ERK, WNT/β-catenin, JAK/STAT, PI3K/AKT, and others) and inhibition of tumor suppressors. CagA is the first bacterial protein that has been shown to induce degradation of p53 tumor suppressor, activating the PI3K/AKT/MDM2/ARF-BP1 and ERK/MDM2-pathways [40][41] (Figure 2). Previously, only viral proteins, such as HPV E6, were known to degrade p53 [30]. CagA is responsible for altering expression of N-terminally truncated p53 isoforms: ∆133p53 and ∆160p53 [42]. Interestingly, the dysregulation of p53 occurs in a strain-specific manner, with tumorigenic H. pylori strains having a stronger ability to affect p53 [40][43]. Tumorigenic H. pylori strains also decrease activity of other tumor suppressors: p14ARF, SIVA1, and p27(KIP1) [43][44][45][46].

Cancers 13 01878 g002 550

Figure 2. Regulation of tumor suppressor proteins by gastric pathogens. Gastric pathogens: H. pylori and oncogenic viruses inhibit key tumor suppressors proteins p53, p14ARF, and others. These events result in inhibition of the DNA damage and oncogenic stress responses, two key mechanisms important for prevention of gastric carcinogenesis.

Interaction of H. pylori with gastric cells increases the levels of reactive oxygen and nitrogen species and induces oxidative stress and DNA damage in a CagA-dependent and -independent manner [47][48][49][50]. Although the entire spectrum of H. pylori–induced DNA damage is currently unknown, the formation of oxidized nitrated DNA lesions and single- and double-strand DNA breaks has been shown. Double-strand breaks in DNA are particularly detrimental, as these lesions are extremely difficult to repair resulting in highly cytotoxic and mutagenic effects [47][49][51][52][53][54][55][56]. H. pylori can also induce damage of mitochondrial DNA likely contributing to cellular senescence and gastric cancer initiation [57].

Induction of DNA damage by H. pylori is exacerbated by inhibition of p53 and multiple DNA repair pathways that are important for proper activation of the DNA damage response [40][42][49][52][58][59][60][61].

CagA is known to function as an anti-apoptotic protein. Multiple prosurvival factors and pathways have been shown to be induced by CagA, and among them are kinases AKT and ERK; antiapoptotic members of the B-cell lymphoma 2 (BCL-2) protein family MCL-1, BCL-2, and BCL-Xl; and others [62][63][64][65]. CagA is responsible for the suppression of proapoptotic factors such as SIVA1, BIM, and BAD; downregulation of autophagy; and induction of inflammation [46][62]. Human infections with CagA-positive H. pylori strains are characterized by strong inflammation and severe damage of gastric tissues [66][67][68][69][70].

It has been reported that CagA protein has a profound impact on various cellular functions, including epithelial cell barrier, cell polarity, proliferation, apoptosis, EMT, autophagy, miRNA biogenesis, inflammatory and DNA damage responses, and others. It affects activities of multiple kinases and cell signaling pathways. A partial list includes the following: EGFR, c-MET, SRC, cABL, CSC, aPKC, PAR1, PI3K, AKT, FAK, GSK-3, JAK, PAK, MAP, MDM2, p53, p14ARF, p27, RAS, β-catenin, NFκB, and multiple NFκB-related pathways [43][44][46][71][72][73][74][75][76][77][78]. It is not completely clear how one bacterial protein produces so pleiotropic effect. One plausible explanation is that CagA acts as a scaffolding protein that interacts with a large number of the host regulatory proteins, tethering them into aberrant enzymatic complexes and altering their normal functions [79].

2.2. VacA and Other Virulence Factors

VacA toxin is another virulence factor that plays a major role in tumorigenesis, associated with H. pylori infection. Its name originates from the ability to cause cell vacuolation in cultured eukaryotic cells. VacA has been classified as a pore-forming toxin. Although many toxins can form pores, the amino acid sequence of VacA is not closely resembled sequences of other known bacterial toxins [22][80][81]. The biosynthesis of VacA includes several sequential steps. Following protein translation, the VacA precursor undergoes complex proteolytic cleavage that produces 88 kDa active toxin that either secreted into the extracellular space or retained on the bacterial surface. The secreted VacA protein binds to target cellular membranes, forming an anion-selective membrane channel [82][83].

Multiple functions have been found to be associated with VacA activity, including disruption of the gastric epithelial barrier, interference with antigen presentation, suppression of autophagy and phagocytosis, inhibition of T cells and B cells that are thought to help bacteria to establish persistent infection [84][85][86][87][88]. The ability of VacA to inhibit autophagy and lysosomal degradation facilitates the accumulation of oncogenic protein CagA in gastric epithelial cells [89].

There are considerable variations in VacA sequences. Three main regions of diversity have been recognized in VacA: the signal sequence region (or “s”), the intermediate region (or “i”), and the middle region (or “m”). Based on sequence heterogeneity, the s region was subdivided into s1 (further subdivided into s1a, s1b, and s1c) and s2 types, the i region was subdivided into i1 and i2 types, and the m region was subdivided into m1 and m2 (further subdivided into m2a and m2b) types [85][90]. The incidence of GC has been found to be higher in populations infected with H. pylori variants containing type s1/i1/m1 of vacA, compared to populations infected with H. pylori type s2/i2/m2 of vacA [36][84][85]. Bacterial strains carrying type s1 and m1 vacA alleles have been associated with epithelial damage, increased gastric inflammation, and duodenal ulceration [91][92][93].

Besides CagA and VacA, H. pylori expresses a number of other cancer-associated virulence determinants. Outer-membrane proteins (OMPs) are among them. These proteins are important for bacterial adherence, colonization, survival, and persistence [94]. These factors also promote gastric diseases by affecting the signaling pathways in the host cells, enhancing activity of the T4SS, and altering immune responses [94]. H. pylori expresses a large repertoire of OMPs divided into five major families based on their sequence similarities [95]. The largest and the most studied family is the Family 1, which comprises the Hop (for H. pylori OMP) and Hor (for Hop related) proteins. The two most studied H. pylori adhesins in the Hop subgroup are BabA(HopS) and SabA(HopP), which have been originally identified to interact with the fucosylated-Lewis B (LeB) and the sialylated-Lewis X (sLeX) blood group antigens, respectively, mediating binding of H. pylori to extracellular matrix and gastric epithelial cells [96][97]. BabA potentiates activity of the T4SS [98] and is involved in induction of double-strand breaks in host cells [49]. SabA increases the colonization density and inflammation in human stomach [97][99]. Several studies analyzed associations of BabA and SabA expression with clinical outcome. The BabA status of infecting bacteria has been found to be associated with the presence of intestinal metaplasia, gastric adenocarcinoma, and MALT (Mucosa-Associated Lymphoid Tissue) lymphoma [96][100][101][102][103][104]. Similarly, the SabA status was correlated with an increased risk of premalignant lesions and gastric cancer [105][106]; however, some studies produced contradictory results [99][107].

Other OMPs, such as OipA(HopH), HopQ, and HomB, have also been implicated in gastric tumorigenesis [102][108][109][110][111][112][113][114][115]. Further studies are needed to better characterize properties of OMPs and their roles in gastric tumorigenesis.

3. Gastric Microbiota

The stomach is not a sterile organ, despite its high acidity. It is populated by complex gastric microbial communities that affect tumorigenic processes and are important for the maintenance of human health.

The composition of normal gastric microbiota is diverse and highly dynamic with the most abundant phyla: Proteobacteria, Firmicutes, Bacteroidetes, Fusobacteria, Actinobacteria, and others [116][117]. On the other hand, H. pylori has been found to be the most prevalent bacteria in the stomach of H. pylori-infected individuals [116][118]. H. pylori can induce profound changes in the composition of gastric microbiota [117][119][120][121][122][123][124][125]. Analyses of gastric microbiota in specific pathogen-free (SPF) mice revealed that H. pylori infection decreases abundance of normal gastric flora, such as Lactobacilli, and increases the presence of Clostridia, Ruminococcus spp., Eubacterium spp., Bacteroides/Prevotella spp., and others [122]. Similar phenomenon was observed in Mongolian gerbils [124][125][126]. These alterations can be explained, at least in part, by physiological changes caused by persistent H. pylori infection [127]. Induction of chronic inflammation and suppression of acid production can facilitate growth of various non–H. pylori bacterial species [127][128][129]. Many aspects of these interactions still remain controversial. Some studies did not find significant differences in the microbial composition between H. pylori–positive and –negative individuals [116][130][131]. It is likely that multiple confounding factors, such as level and type of inflammation, drug treatment (such as treatment with proton pump inhibitors), and the presence of precancerous and cancerous lesions, have to be taken into consideration during analyses of gastric microbiota.

Phylogenetic diversity of the stomach microbiome is changed during progression from gastritis to intestinal metaplasia and GC in human patients [120][132][133][134]. H. pylori colonization of the human stomach is frequently decreased in patients with advanced premalignant and malignant lesions, while abundance of Streptococcus, Lactobacillus, Veillonella, Clostridia, and others is increased [132][133][134][135][136]. Decline in Porphyromonas, Neisseria, and S. sinensis species and concomitant increase in Lactobacillus coleohominis and Lachnospiraceae were found to correlate with progression from gastritis to GC [133]. Changes in the gastric microbiota were also observed after surgical treatment of GC patients [137].

Synergetic interactions of bacteria with H. pylori to promote gastric neoplasia have been convincingly demonstrated by using transgenic insulin–gastrin (INS–GAS) mice [138][139]. It was found that H. pylori infection causes less severe gastric lesions and delayed onset of gastric intraepithelial neoplasms (GINs) in germ-free INS–GAS mice compared to mice with complex gastric microbiota [140]. In another study, infection of INS–GAS mice with restricted Altered Schaedler flora (rASF), containing Clostridium, Lactobacillus, and Bacteroides species, was sufficient to develop gastric dysplasia [141]. Infection with H. pylori further accelerated the onset of gastric lesions in rASF-infected mice [142]. Notably, antimicrobial therapies delayed onset of GIN not only in INS–GAS mice infected with H. pylori, but also in animals without H. pylori infection, thus indicating that non–H. pylori bacteria, including those considered as commensals, may represent an additional GC risk, particularly in H. pylori–infected susceptible individuals. [140][142][143][144].

It is not completely clear how non–H. pylori microbiota synergizes with H. pylori to induce GC. One plausible explanation includes overgrowth of bacteria, converting nitrogen compounds into potentially carcinogenic N-nitroso compounds [129]. It was shown that reduction of gastric acidity causes growth of nitrate-reducing bacteria, which produce carcinogenic N-nitrosamine [128][145][146]. It is also possible that various non–H. pylori bacteria promote sustained inflammation that contributes to development of GC.

Interactions within the gastric microbiome are complex and may result in various outcomes. Colonization of C57BL/6 mice with the enterohepatic Helicobacter species, H. bilis or H. muridarum, before challenge with H. pylori, was found to reduce H. pylori–induced gastric injury [147][148]. Similarly, oral Lactobacillus strains were shown to suppress H. pylori– and H. felis–induced inflammation in both mice and gerbils [125][149][150][151][152]. Consistent with rodent models, certain Lactobacilli were also found to suppress H. pylori growth and gastric mucosal inflammation in human individuals [153][154].

One interesting aspect of complex biological interactions in the stomach is the influence of helminthiasis. Parasitic worms are known to be involved in the development of various human malignancies [155]. However, certain types of helminths can decrease the risk of GC [156][157]. Infection of mice with enteric helminth (Heligmosomoides polygyrus) has been found to attenuate progression of premalignant gastric lesions induced by H. pylori and H. felis [156][158]. It was also suggested that helminths may decrease the incidence of H. pylori-associated GC in certain world populations due to their immunomodulating effects [157][159].

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