Helicobacter pylori induced gastric carcinogenesis - The best molecular model we have?
Introduction
Gastric cancer (GC) remains one of the leading cancer types around the world. Although the epidemiological trend over the past 50 years shows a global decline of GC incidence in the general [1], incidence rates in subjects below 50 years of age show the opposite trend [2,3]. Research of the past decades had a clear affinity to Helicobacter pylori (H. pylori) infection as the most distinct, easily assessable and most clinically relevant risk factor. With overwhelming scientific evidence supporting this link [4], it became obvious that additional factors are likely to be involved in gastric carcinogenesis. In this review, we provide an updated overview on various models of gastric carcinogenesis. In addition to the established models, such as H. pylori, diet etc., we provide an overview on carcinogenesis models with focus on molecular classification of GC.
Section snippets
GC from a clinical perspective
The majority of GC are adenocarcinoma, which develop from the epithelial cells of the stomach in a step-wise manner. It is well accepted that substantial part of GC are linked to chronic inflammation that leads to mucosal alterations and subsequently cancer and has been know as Correa’s cascade [5]. One of the crucial initial events in this cascade is chronic active mucosal inflammation triggered by H. pylori and which may then further progress to preneoplastic conditions such as chronic
GC from a molecular perspective
Several attempts have been made to characterise GC on molecular level. Probably the first in-depth success was achieved by the application of a multi-omics approach by The Cancer Genome Atlas (TCGA) Research Network. Based on the analysis of single nucleotide polymorphisms (SNP), somatic copy-number data, whole-exome sequencing, mRNA and miRNA sequencing, DNA methylation profiling and reverse-phase protein arrays, the group could identify distinct GC clustering and proposed four molecular GC
H. pylori-driven models of gastric carcinogenesis
The knowledge on H. pylori-induced gastric carcinogenesis is based on evidence from human but also animal studies. In their pivotal study, Uemura et al. showed that GC develops in H. pylori infected, but not in uninfected subjects [8]. The authors have prospectively studied 1526 subjects with and without H. pylori infection to evaluate the gastric cancer risk related to infection. Specifically, they identified severe AG, corpus-predominant gastritis and intestinal metaplasia as a risk factors
Diet and environmental factors as trigger of gastric carcinogenesis
Epidemiological studies have revealed that besides H. pylori also diet and other factors contribute to gastric carcinogenesis. High salt and meat consumption are probably the most relevant factors for gastric carcinogenesis in humans [29]. Subjects with highest in comparison to the lowest salt exposure have up to 2-fold increase in GC risk [30]. The working group of the International Agency for Research on Cancer (IARC) classified processed meat as carcinogenic to humans (Group 1 carcinogen) on
Beyond H. pylori triggered models
H. pylori is probably the best studied factor in gastric carcinogenesis so far, which is also mirrored in basically all guidelines and recommendations on management of H. pylori infection [[39], [40], [41]]. Nevertheless, a subgroup of the GC patients is not linked to an active or past H. pylori infection, and furthermore a subgroup of patients shows no mucosal alterations that are linked to Correa’s cascade. With a global decline of H. pylori infection rates, an increasing rate of GC in young
Pathway-driven models of gastric carcinogenesis
With an increasing understanding of the molecular alterations in the gastric carcinogenesis, there is also a trend to break down the molecular pathways into subsequent steps and identify potential key players in this heterogenic and multifactorial disease. In this chapter, we provide an update on novel gastric carcinogenesis models with focus on data derived from the TCGA classification. Some of the most relevant and representative models of the past years are provided in Table 1.
The microbiome and gastric carcinogenesis models
With implementation of the novel sequencing tools, there has been a shift from the H. pylori-centric toward a more global assessment of the stomach microbiota. Different regions of the GI tract show distinct bacterial communities [80]. The comparison of intraluminal and mucosal bacterial communities revealed differences that may be involved in disease progression [81]. The microbiome of GC patients is associated with significant differences in microbial diversity, decreased abundance of
Future direction and concluding remarks
Over the past decade, a substantial amount of data has been gathered and every piece of knowledge contributes to our present understanding of gastric carcinogenesis. While the initial steps were strongly influenced by the discovery of H. pylori, subsequent steps highlight the complexity of the interaction of multiple factors. Among various factors, H. pylori remains undoubtedly the main and probably most easily manageable risk factor from an epidemiological perspective. However, there are novel
Practice points
- •
Gastric carcinogenesis is a multifactorial disease that develops through a cascade of events influenced by H. pylori, diet, environmental factors, microbiota alterations etc.
- •
Assessment of the predisposing factors and mucosal preneoplastic features (atrophic gastritis and intestinal metaplasia) are crucial for risk stratification, screening, primary and secondary prevention and treatment
- •
Even though the traditional histological classification maintains its value for GC management, the molecular
Research agenda
- •
With the increasing generation of multi-omics data on molecular alterations, there is an increasing need for translational research to understand the impact of those alterations for clinical management of GC patients
- •
H. pylori infection is one of the key factors in gastric carcinogenesis, however, it is crucial to identify and evaluate additional predisposing factors in clinical settings and daily practice
- •
H. pylori-independent gastric carcinogenesis increasingly gain attention and further
Declaration of competing interest
The authors declare no potential conflicts.
Acknowledgements
Alexander Link is principle investigator of the Microbiota-related “LiLife”-Project supported by the funds of European Commission through the “European funds for regional development” (EFRE) as well as by the regional Ministry of Economy, Science and Digitalization as part of the “Autonomie im Alter” research group.
References (89)
- et al.
Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial
Lancet
(2008 Aug 2) - et al.
A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer
Gastroenterology
(2007 Sep) - et al.
Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection
Gastroenterology
(1998) - et al.
Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies
Gastroenterology
(2007) - et al.
Carcinogenesis of Helicobacter pylori
Gastroenterology
(2007) - et al.
Helicobacter felis eradication restores normal architecture and inhibits gastric cancer progression in C57BL/6 mice
Gastroenterology
(2005) - et al.
Carcinogenicity of consumption of red and processed meat [Internet]
- et al.
Recurrent fusion genes in gastric cancer: CLDN18-ARHGAP26 induces loss of epithelial integrity
Cell Rep
(2015 Jul 14) - et al.
Loss of tight junction protein Claudin 18 promotes progressive neoplasia development in mouse stomach
Gastroenterology
(2018 Dec 1) - et al.
Deficiency of stomach-type Claudin-18 in mice induces gastric tumor formation independent of H pylori infection
CMGH
(2019 Jan 1)
Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial
Lancet
An Msh2 conditional knockout mouse for studying intestinal cancer and testing anticancer agents
Gastroenterology
PPARD and interferon gamma promote transformation of gastric progenitor cells and tumorigenesis in mice
Gastroenterology
Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer
Gastroenterology
Analysis of transcriptionally active bacteria throughout the gastrointestinal tract of healthy individuals
Gastroenterology
Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
CA A Cancer J Clin
Emerging cancer incidence trends in Canada: the growing burden of young adult cancers
Cancer
Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035
Gut
Helicobacter pylori: perspectives and time trends
Nat Rev Gastroenterol Hepatol
The gastric precancerous cascade
J Dig Dis
The two histological main types OF gastric carcinoma: diffuse and SO-called intestinal-type carcinoma. AN attempt at a histo-clinical classification
Acta Pathol Microbiol Scand
Comprehensive molecular characterization of gastric adenocarcinoma
Nature
Helicobacter pylori infection and the development of gastric cancer
N Engl J Med
Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands
Gut
Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis
Gut
Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial
J Am Med Assoc
Interleukin-1 polymorphisms associated with increased risk of gastric cancer
Nature
TLR1 and PRKAA1 gene polymorphisms in the development of atrophic gastritis and gastric cancer
J Gastrointest Liver Dis
Cigarette smoking and gastric cancer in the stomach cancer pooling (StoP) project
Eur J Canc Prev
Dietary salt intake and risk of gastric cancer
Canc Treat Res
Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma [Internet]
Helicobacter pylori vacA genotype is a predominant determinant of immune response to Helicobacter pylori CagA
World J Gastroenterol
Atrophic gastric changes in both Helicobacter felis and Helicobacter pylori infected mice are host dependent and separate from antral gastritis
Gut
Inflammation and Cancer: I. Rodent models of infectious gastrointestinal and liver cancer [Internet]
Am J Physiol - Gastrointest Liver Physiol Am Physiol Soc
Fusobacterium nucleatum as a prognostic marker of colorectal cancer in a Japanese population
J Gastroenterol
Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse
Proc Natl Acad Sci U S A
Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis
Gastroenterology
Diet and the risk of gastric cancer: review of epidemiological evidence
Salt intake and gastric cancer risk according to Helicobacter pylori infection, smoking, tumour site and histological type
Br J Canc
Diet and upper gastrointestinal malignancies
Gastroenterology
Helicobacter pylori infection promotes gastric carcinogenesis in a mice model
J Gastroenterol Hepatol
High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice
Canc Res
Effects in rats of sodium chloride on experimental gastric cancers induced by N methyl N’ nitro N nitrosoguanidine or 4 nitroquinoline 1 oxide
J Natl Cancer Inst
Cited by (7)
Dysprosium particles decorated Ambroxol imprinted polymer sensor to detect carbide-treated mango
2023, Sensors and Actuators A: PhysicalDifferential Expression of Long Noncoding RNA HOTAIR in Intestinal Metaplasia and Gastric Cancer
2022, Clinical and Translational Gastroenterology