Helicobacters and cancer, not only gastric cancer?

doi:10.1016/j.semcancer.2021.08.007

Seminars in Cancer Biology

Volume 86, Part 2, November 2022, Pages 1138-1154

https://doi.org/10.1016/j.semcancer.2021.08.007 Get rights and content

Abstract

The Helicobacter genus actually comprises 46 validly published species divided into two main clades: gastric and enterohepatic Helicobacters. These bacteria colonize alternative sites of the digestive system in animals and humans, and contribute to inflammation and cancers. In humans, Helicobacter infection is mainly related to H. pylori, a gastric pathogen infecting more than half of the world's population, leading to chronic inflammation of the gastric mucosa that can evolve into two types of gastric cancers: gastric adenocarcinomas and gastric MALT lymphoma. In addition, H. pylori but also non-H. pylori Helicobacter infection has been associated with many extra-gastric malignancies. This review focuses on H. pylori and its role in gastric cancers and extra-gastric diseases, as well as malignancies induced by non-H. pylori Helicobacters. Their different virulence factors and their involvement in carcinogenesis is discussed. This review highlights the importance of both gastric and enterohepatic Helicobacters in gastrointestinal and liver cancers.

Graphical abstract

Introduction

Microorganisms present in our microbiota interact with our mucous membranes, influencing health and disease throughout our life. While this diverse microbial community is essential for physiological development and immunological homeostasis, alterations in this ecosystem are linked to chronic and inflammatory diseases, and cancers. In order to identify therapeutic targets and/or potential prognostic biomarkers, it is important to understand the cross-talk between our microbiota and gastrointestinal cancers [1]. More than 13% of human cancers are linked to infectious agents [2]. Though the involvement of viruses in human cancers is well recognized (herpesviruses, adenovirus, papillomaviruses, hepatitis viruses, retroviruses …), that of bacteria, on the other hand, is less studied. Nevertheless, the involvement of chronic bacterial infections in carcinogenesis has been established since 1994 with Helicobacter (H.) pylori, a bacterium classified as a type I carcinogen by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) [3]. Since then, numerous Helicobacter species have been shown to drive carcinogenesis in humans and animals (Table 1).

The Helicobacter genus belongs to the Helicobacteraceae family together with Sulfuricurvum, Sulfurimonas, Sulfurovum, Thiovulum, and Wolinella genera. The Helicobacteraceae family is dominated by the Helicobacter genus, which is currently composed of 55 species, among which 46 species have been validly published [4]. However, most Helicobacter species do not only colonize the gastric mucosa but can also colonize alternative sites of the digestive tract (saliva, cecum, colon, pancreas, liver) in various hosts (mammals, birds, reptiles) and have also been identified in aqueous environments. Genotypic and phylogenetic analyses usually separate Helicobacter taxa into 2 main clades: gastric and enterohepatic species, each comprising of 18 and 30 validly published species, respectively.

In the past decades, reports on bacterial chronic infection, inflammation and carcinogenesis in mammals have emerged at an increasing pace. This review focuses on Helicobacter infection and carcinogenesis in the digestive tract of animals and humans.

Section snippets

Gastric Helicobacters and cancer

Despite some descriptions of spiral bacteria colonizing the stomach of animals reported since the end of the 19^th century, and the human stomach as from the beginning of the 20^th century, interest in these Campylobacter-resembling organisms emerged only in 1982 when Marshall and Warren successfully cultured Helicobacter pylori from the stomach of nearly all patients with active chronic gastritis, duodenal ulcer, or gastric ulcer [5,6].

Enterohepatic Helicobacters and cancer

In 1978, Lee et Phillips reported the isolation and culture of spiral organisms from cecal crypts of mice and rats [141]. In 1988, stool cultures from patients with mild chronic gastroenteritis grew up an unusual microaerophilic gram-negative bacterium resembling Campylobacter species. For one patient, the same bacillus was also recovered from the stool of her asymptomatic daughter and asymptomatic young dog [142], suggesting transmission from animals to humans or conversely. A similar

Conclusions

Helicobacters have been shown to trigger various digestive tract malignancies in animals and humans. H. pylori is the best-known member of this genus causing gastric cancer but also associated with various extra-gastric malignancies. However, the mechanisms behind extra-gastric carcinogenic processes are not clear due to the difficulties in detecting and in cultivating H. pylori from those sites. Further studies are needed to verify the direct role of H. pylori in extra-gastric digestive

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

We would like to acknowledge the contribution of Maya Sarieddine for the proofreading of the article. The PhD fellowship of Lornella Seeneevassen was funded by the French Ministry of Tertiary Education, Research and Innovation and that of Sadia Khalid was supported by DoRa Plus programme for doctoral Students (European Regional Development Fund). Pirjo Spuul was funded by VNF20013 from Biocodex Microbiota Foundation and PUT1130 from Estonian Research Council.

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Citation Excerpt :
A recent review from our group place H. pylori carcinogenesis in the context of its microenvironment, the role of stem cells and of the microbiota which is the topic of the next paragraph [12]. It must also be noted that H. pylori could possibly be involved in other malignancies of the digestive tract [13]. Several studies aimed to characterize differences between the gastric microbiota of patients suffering from chronic gastritis or gastric pre-neoplastic lesions (atrophy, intestinal metaplasia) and those with gastric cancer.
The discovery of Helicobacter pylori in 1982 drew to an end the stomach being considered as a sterile organ. Later, the progress in molecular methods, especially Next Generation Sequencing and metagenomics, has highlighted the fact that a diverse microbiota including five major phyla could also be present in the stomach. However, when present, H. pylori is the essential species and it influences the other bacterial communities in terms of richness and evenness. It is now well accepted that H. pylori is the main risk factor for gastric cancer, especially the strains harboring the cag pathogenicity island and the CagA oncoprotein, but the need for other factors from the host and the environment can explain the important difference between those infected and those developing gastric cancer. Several studies showed a difference between the gastric microbiota of patients at various stages of development of gastric premalignant and malignant lesions, showing globally a reduced microbial diversity and an increase in the presence of intestinal commensals, especially with nitrosative functions. Other studies showed an increase in oral microbiota. These data suggest that the gastric microbiota other than H. pylori may play a role in the last steps of gastric carcinogenesis. It must also be noted that in a limited number of cases, a virus: the Epstein Barr Virus is responsible for the evolution toward gastric cancer, while in others the mycobiota also needs to be explored. Finally, the use of mice models allowed an exploration of the role of different gastric microbiota in addition to H. pylori.
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¹: These two authors contributed equally to this work.

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Helicobacters and cancer, not only gastric cancer?

Abstract

Graphical abstract

Introduction

Section snippets

Gastric Helicobacters and cancer

Enterohepatic Helicobacters and cancer

Conclusions

Declaration of Competing Interest

Acknowledgements

Lancet Glob. Health

Lancet

Ann. Oncol.

Lancet

FEMS Microbiol. Lett.

Clin. Microbiol. Infect.

J. Biol. Chem.

J. Biol. Chem.

Gastroenterology

Cell. Mol. Gastroenterol. Hepatol.

Cell Rep.

Gastroenterology

Cell. Mol. Gastroenterol. Hepatol.

Gastroenterology

Gastroenterology

Vet. Immunol. Immunopathol.

Gastroenterology

Gastroenterology

Vet. Clin. North Am. Exot. Anim. Pract.

Lancet Infect. Dis.

Understanding the cross-talk between human microbiota and gastrointestinal cancer for developing potential diagnostic and prognostic biomarkers

Semin. Cancer Biol.

Schistosomes, liver flukes and Helicobacter pylori. IARC working group on the evaluation of carcinogenic risks to humans. Lyon, 7-14 June 1994

IARC Monogr. Eval. Carcinog. Risks Hum.

LPSN - List of Prokaryotic names with Standing in Nomenclature (bacterio.net), 20 years on

Int. J. Syst. Evol. Microbiol.

Unidentified curved bacilli on gastric epithelium in active chronic gastritis

Lancet

Chapter 5.4: Stomach cancer, still one of the main cancer types worldwide

Biological agents. Volume 100 B. A review of human carcinogens

IARC Monogr. Eval. Carcinog. Risks Hum.

Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report

Gut

Helicobacter pylori infection

N. Engl. J. Med.

Effect on Helicobacter pylori eradication therapy against gastric cancer in Japan

Helicobacter

World Cancer Report - Cancer research for Cancer prevention

Pathogenesis of gastric cancer: genetics and molecular classification

Curr. Top. Microbiol. Immunol.

Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment

Gut

EGILS (European Gastro-Intestinal Lymphoma Study) Group, Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: experience from a large international series

Gut

Gastric epithelial cell kinetics in the progression from normal mucosa to gastric carcinoma

Gut

The gastric precancerous cascade

J. Dig. Dis.

Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy

Nat. Med.

Rapid development of severe hyperplastic gastritis with gastric epithelial dedifferentiation in Helicobacter felis-infected IL-10(-/-) mice

Am. J. Pathol.

Outbred mice with long-term Helicobacter felis infection develop both gastric lymphoid tissue and glandular hyperplastic lesions

J. Pathol.

APRIL-producing eosinophils are involved in gastric MALT lymphomagenesis induced by Helicobacter sp infection

Sci. Rep.

Recombinant antigens prepared from the urease subunits of Helicobacter spp.: evidence of protection in a mouse model of gastric infection

Infect. Immun.

Review: Helicobacter: inflammation, immunology, and vaccines

Helicobacter

Helicobacter pylori virulence factors exploiting gastric colonization and its pathogenicity

Toxins (Basel)

Helicobacter pylori vacuolating toxin and gastric cancer

Toxins (Basel)

The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases

Annu. Rev. Pathol.

Helicobacter pylori activate epidermal growth factor receptor- and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3beta phosphorylation

Cell. Microbiol.

Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors

Cancer Res.