Gastric cancer is one of the types of cancer that is associated with Helicobacter pylori infection. The infection starts in childhood, and 50–90% of the population in the world is infected. The clinical symptoms can be stomach pain, gastritis, atrophy gastric, and only 2–3% of the infected population developed gastric cancer. The majority of gastric cancers are adenocarcinomas. From Lauren’s histological classification, gastric cancer is divided into two large groups: intestinal and diffuse. The cells that gives rise to them are different and the epidemiologic features and diagnosis are different according to gender and age; however; the survival rate is approximately of 5-years. Surgery is the only radical treatment, but the adjuvant treatment is chemotherapy and radiotherapy which unfortunately lead to only a modest survival benefit. On this review, we describe the major risk factors associated with the bacteria: cagPAI, CagA, VacA, HOPs, as well as host immune and inflammatory responses: immune cells, Toll-like receptors, cytokines, immune signal pathway, genetic predisposition, such as single nucleotide polymorphisms (SNP’s) and environmental factors: age, high salt intake, diets low in fruit and vegetables, alcohol intake, and tobacco use. Finally, we included the interaction of all factors for the development of gastric cancer. Knowing and understanding the role of all factors in the development of gastric cancer will allow the implementation of better therapies and improve patient prognosis.
- Helicobacter pylori
- inflammatory response
- gastric cancer
2. Virulent factors from
H. pyloriand its interaction with the host
2.1 Virulence factors and their association with gastric cancer
CagPathogenicity Island and Cag A
The major protein that was identified as a product of the multigene
CagA is a protein considered an oncoprotein; it is translocated into gastric epithelial cells by the type IV secretory system of the pathogen, inducing multiple signaling cascades . There are two distinct types of
The CagA is injected into the host cell through the type IV secretion system (T4SS). In the cytoplasm, CagA is phosphorylated at its EPIYA motifs; CagA alters the host cell signaling in both manners, phosphorylation- dependent and phosphorylation-independent. After its translocation into the host epithelial cells, the EPIYA-motifs of CagA undergo tyrosine (Y)-phosphorylation via cellular kinases, such as Csk, c-Src, and c-Abl. The phosphorylated tyrosine interacts with the Src homology 2 phosphatase (SHP2) or with the adapter protein Grb2 and hinders cell–cell adhesion, cellular proliferation, IL-8 expression, and cellular elongation via the activation of cell signaling pathways, such as Ras–ERK MAP kinases (Rap1 → B-Raf → Erk) and Wnt-β-signaling .
Li et al., 2018 demonstrated that CagA stimulates YAP signaling pathway activation leading to gastric tumorigenesis in AGS cells. This in vitro result was also supported by the finding that
The interaction of
A high-salt diet modifies the expression of the CagA protein and transcriptome level in
Using an animal model, Noto
VacA is a pore-forming cytotoxin that plays a role interacting with gastric cells, induces vacuole formation, and apoptosis in mammalian cells; it is a pro-toxin of 140 kDa that is secreted through the auto-transporter pathway. The mature protein 88 kDa secreted toxin undergoes proteolysis in two fragments: p33 and p55 . The
The studies have revealed that the combination of different sequences in the three regions can determine the capability of vacuolation.
VacA is a risk factor for gastric mucosal atrophy. All s1/i1/d1 strains are called East Asia
The secretion inside the VacA cell induces the production of antibodies against VacA; however, there is a meta-analysis in which an association of VacA antibody with peptic ulcer disease and gastric cancer risk is observed; furthermore, the higher level of antibody response to VacA is associated with a risk of extra-gastric disease, such as colorectal cancer in African Americans .
Another target of VacA inside the cells is the endoplasmic reticulum; it produces stress and activates autophagy and increased cellular death. VacA is very important to survival efficacy through a transient receptor potential membrane channel mucolopin 1 (TRPML1) activity that inhibits the lysosomal and autophagy killing of bacterial cells to promote the establishment of an intracellular niche that allows bacterial survival, in addition to an altered host immune response, mainly through the inhibition of T cell activation and proliferation (Figure 1) .
2.1.3 Outer membrane proteins and gastric cancer
The outer membrane is the outer barrier of Gram-negative bacteria that contains outer membrane proteins (OMPs) resistant to the external environment. The OMPs have a variety of biological functions, such as maintaining the outer membrane structure and guaranteeing the material transportation especially, the OMPs participate in the adherence of
188.8.131.52 BabA (HopS)
Blood group antigen-binding adhesin (babA) is a 78-kDa outer membrane protein encoded by the babA2 gene, which binds the fucosylated Lewis b antigen (Leb) on the surfaces of gastric epithelial cells. The specific manner by hydrogen bonds network structure formed between four residues of Lewis b and eight amino acids of BabA.
184.108.40.206 Sialic acid-binding adhesin (SabA)
SabA binds to gangliosides with fucose substitutions of the N-acetyllactosamine like the dimeric sialyl-Lex antigen . SabA is the second most commonly reported adhesin in
The outer inflammatory protein A (OipA), also called HopH,
In an animal model, mice were inoculated with immunogenic OipA and
Another OMP that plays an important role in the initial colonization is the
So far, we already know which virulence factor helps Helicobacter to colonize and persistent in the stomach, but what happens with the immune response of the host and their genetic susceptibility?
2.2 Host characteristics
2.2.1 Genetic susceptibility
Host genetic susceptibility depends on polymorphisms of genes involved in
The receptor which recognizes multiples virulence factor of
It has been shown that
Metanalysis of TLR2–196 to −174 showed in a Japanese population that this deletion decreased the induction of IL-8 and is associated with a risk of gastric cancer compared with controls group , but this correlation failed in a Chinese population; this may indicate an ethnic consideration in the incidence of stomach cancer.
Single nucleotide polymorphisms (SNPs) of the TLR4 receptor were associated with an increased cell death against
The second part of the activation of the pattern recognition receptors on the leukocyte and epithelial/endothelial cells induce the production of cytokines. All these elements are part of the inflammatory environment, they could regulate tumor growth and metastasis, cause discomfort symptoms, and potentially influence the tumor prognosis .
Another pathogenic factor of
After the activation of immune and epithelial cells, there is a production and secretion of pro-inflammatory and anti-inflammatory cytokines such as tumor necrosis factor (TNF-α), IL-1β, IL-8, and IL-10 , which leads to the recruitment of macrophages, neutrophils, and lymphocytes to the gastric tissue .
Once the infection starts, dendritic cells are the first cells to arrive to the gastric mucosa and produce IL-6, IL-1β, IL-12, and TNF-α, which causes inflammation and Th1 response. During atrophic gastritis, the macrophages are polarized to M1 subtype and induce proliferation of T cells; however,
In dendritic cells (DC), VacA causes a decreased expression of CD40, CD80, CD86, MHC class II, and decreases the secretion of IL-1β, IL12p70 and TNF-α; the major effect of the down expression is the inhibition of the T cell response .
Patients infected with
There is some evidence that virulence factors such as VacA and CagA cause damage in gastric cells and result in peptic ulcer, even gastric cancer. Now we know that the severity of gastric diseases depends on the virulence factor together with the host factor.
2.2.2 Immune factors
Immune dysregulation plays a pathogenic role in the development of cancer.
Chronic inflammation of the gastric mucosa evolves in three forms: (1) antral-predominant, (2) corpus-predominant, and (3) diffuse . Antral-predominant gastritis promotes duodenal ulcers whereas corpus-predominant gastritis promotes gastric ulcers .
In atrophic gastritis, the principal and parietal cells are replaced by globlet cells as the lesion progresses giving way to intestinal cancer; this transformation is called metaplasia. In general, there are two different types of metaplasia, intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM); both types of metaplasia are associated with the progression of intestinal-type gastric cancer.
In intestinal metaplasia, globet cells express intestinal markers such as Muc2 and Trefoil factor 3 (TFF3) .
In spasmolytic polypeptide-expressing metaplasia (SPEM), the cells have a morphological characteristic more typical of deep antral gland cells or Brunner’s glands, expressing Muc6 and Trefoil factor 2 (TFF2).
The type II cytokines, including IL-4, IL-5, and IL-9, can activate type II innate lymphoid cells (ILC2). These lymphocytes respond to IL-33 producing IL-13 .
The development of metaplasia involves alarming cytokines, such as IL-33 and IL-13. IL-13 induces chief cell trans differentiation into SPEM, following the loss of parietal cells from the corpus of the stomach, and activated macrophages, which promotes the resolution of inflammation and wound repair . Subsequently, it drives the progression of metaplasia to become more proliferative with increased intestinal characteristics; furthermore, SPEM is a phenotype in the atrophic gastritis and correlates with intestinal-type gastric cancer .
In general, gastric cancer shows an immunosuppressive character. There are tumor-infiltrating leukocytes, such as CD8+ T cells, CD68+ macrophages, and CD4+ T cells, that represent 15%, 13%, and 11% of all intratumorally cells, respectively. The role of the immune response has a strong selective pressure on the tumor and allows its growth; finally, it helps the cancer-immunoediting process, one of the mechanisms to demonstrate it is the down expression of PD1/PDL1. This response induces pro-tumoral effects such as angiogenesis and metastasis . In our experience, the immune response can be a diagnostic marker to gastric cancer independently of the histological subtype (Figure 3) .
2.3 Environmental factors
2.3.1 Dietary factors
The dietary factors that have an important impact on gastric cancer are low intake of fresh fruits and vegetables, high-sodium diet, salt-preserved food, red and cured meat; all these are associated with gastric cancer risk.
High alcohol intake, tobacco smoking, and high weight were associated with gastric cancer risk in a prospective study in a studied cohort, demonstrating that 62% of cardia gastric cancer could have been prevented if the population had followed a healthy lifestyle . The primary prevention of gastric cancer includes healthy diet, anti-
2.4 Development of gastric cancer
Gastric cancer is a carcinoma that occurs sporadically most of the times. It is associated to
Most gastric cancers are diagnosed at an advanced stage; 25–50% of the cases will develop metastasis. The main treatment with curative-intent in gastric cancer patients is surgery, being associated with approximately a 5-years survival rate of 20–25%; therefore, additional treatments are chemotherapy and radiotherapy but unfortunately they lead only to a modest survival benefit .
In 1965, Lauren described two histologically different stomach adenocarcinomas, diffuse and intestinal. The diffuse type is considered an endemic cancer type.
Diffuse adenocarcinoma affects mostly women and younger populations. The intestinal type is related to preneoplastic changes, such as chronic atrophic gastritis and intestinal metaplasia of mucous membranes. This type causes tumors in the peripheral part of the stomach. Intestinal adenocarcinoma is an epidemic type of cancer for it occurs in regions with a high risk of gastric cancer morbidity. It affects mostly men and older populations [36, 45].
The ratio of intestinal and diffuse types varies among countries. For example, intestinal type is more common and occurs more often in the distal stomach, in high-risk area and it is often preceded by long-standing precancerous lesion in European countries.
Another classification was proposed by the Word Health Organization (WHO). There are four histological subtypes: papillary, tubular, mucinous and poorly cohesive. Both classifications are inadequate, for they stratify patients regarding tumor behavior, prognosis, and response to specific treatment.
There is also the molecular classification in which gastric cancer is divided into four genomic subtypes: Chromosomal instability, Microsatellite instability, Genomic stability, and Epstein Barr virus-associated .
Chromosomal instability is associated with loss or gain of tumor suppressor genes, such as TP53, and receptor tyrosine kinase mutation that affects the cell cycle gene and MET, RAS, BRAF, HER2, and EGFR; the tumors are located at the gastro-esophageal junction .
Microsatellite instability is associated with abnormal absences of the protein expression and it is diagnosed by immunohistochemistry or polymerase chain reaction (PCR); the sensitivity of the test is between 83 and 89% and the specificity is 89–90% .
Genomic stability: in diffuse gastric cancer the main somatic genomic alterations are CDH1, ARIDIA and RHOA, and they are involved in cellular motility .
Epstein Barr virus-associated: 10% of gastric cancer patients have been detected with Epstein bar virus, especially in far East Asian patients and it is more frequent in younger persons .
Development of gastric cancer associated to
Cancer gastric is a multifactorial cancer and many factors can play a role in its incidence. In the present review, several
Different histological types of gastric cancer and anatomic location might suggest different etiologies of gastric cancer; however, genetic predisposition and inflammatory response have a consequence in a process regulating proliferation, evasion of apoptotic development of synergistic complex for the development gastric cancer, and, eventually, metastasis.
It is necessary to know the different risk factors involved in the development of gastric cancer in order to implement better therapies and a better prognosis for patients.
We acknowledgment to the Hospital Infantil de México Federico Gómez, SSA for the economic support.
Conflict of interest
“The authors declare no conflict of interest.”
|ARID1A||AT-richnteractive domain-containig protein 1 A|
|BabA||Blood group antigen-binding adhesin|
|CDH1||gene coding E-cadherine|
|C1ND||C in the N-terminal domain|
|cag PAI||cag Pathogenicity Island|
|CEACAMs||Carcinoembryonic antigen-related cell adhesion molecules|
|EGRF||Epidermal growth factor receptor|
|FAK||Focal adhesion kinase|
|FoxO||transcription factors of class O|
|HER2||Human epidermal growth factor receptor|
|ILC||Innate lymphoid cells|
|iNOS||inducible nitric oxide synthase|
|Leb||Lewis b antigen|
|MET||Receptor tyrosine kinase|
|NF-κB||Nuclear factor kappa B|
|OipA||Outer inflammatory protein A|
|OMPs||Outer membrane proteins|
|PCR||Polymerase chain reaction|
|PD1/PD-L1||Programmed death 1/ligands PD-L1|
|RHOA||Ras homolog family member A|
|SHP2||Src homology 2 phosphatases|
|SNPs||Single nucleotide polymorphisms|
|SPEM||Spasmolytic polypeptide-expressing metaplasia|
|T4SS||Type IV secretion system|
|TFF2||Trefoil factor 2|
|TFF3||Trefoil factor 3|
|TRPML1||Transient receptor potential membrane channel mucolopin|