Helicobacter pylori induced gastric carcinogenesis - The best molecular model we have?

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Abstract

Gastric carcinogenesis can be described as a consequence of multilevel molecular alterations that is triggered by a cascade of events. Historically, diet and environmental factors have been identified to substantially contribute to carcinogenesis before the discovery of Helicobacter pylori (H. pylori). But H. pylori infection has revolutionized the understanding of gastric carcinogenesis. Although the model of H. pylori-driven carcinogenesis remains valid, there is a continuous effort to precisely delineate the molecular pathways involved and to understand the interplay with additional risk factors including recent relevant knowledge on the stomach microbiota. In this review, we provide an updated view on the models of gastric carcinogenesis. This includes historically appreciated H. pylori-induced models and expands these taking recent molecular data into consideration. Based on the data provided, we conclude that indeed H. pylori-carcinogenesis remains one of the best-established models at least for a subset of gastric cancers. Implementation of the recently identified molecular subtypes in novel genetic animal models is required to expand our knowledge on H. pylori-independent carcinogenesis.

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.

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