Pathobiology of Helicobacter pylori-Induced Gastric Cancer

Abstract

Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori's activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.

Keywords: Gastric Cancer; H pylori; Microbiota; Stem Cells.

Figure 1

Interactions between host and H pylori genetic ancestries and risk for developing intestinal-type gastric adenocarcinoma in Colombia. Persons with high (95^th percentile) Amerindian ancestry who are infected with H pylori strains containing high (95^th percentile) African genetic content, are predicted to have severe and extensive intestinal metaplasia. If the same individuals are instead infected with H pylori strains harboring the lowest levels (5th percentile) of African ancestry (genetic match), the histologic prediction is mild gastric atrophy, a lesion with much less risk of progression to cancer. Similarly, persons harboring the lowest levels (5th percentile) of Amerindian ancestry but high African ancestry who are infected with H pylori strains of high African genetic content are predicted to have gastritis only.

Figure 2

Translational applications for using mouse or human gastroids to study H pylori-induced gastric carcinogenesis.

Figure 3

H pylori colonizes the gland base and interacts with gastric progenitor cells. H pylori are labeled green, actin red, and nuclei blue. Cells undergoing mitosis (labeled with ph-Histone) are marked by arrows.

Figure 4

H pylori micro-colony interacting with LGR5 stem cells at the base of an antral gland. H pylori are labeled red, Lgr5⁺ cells green, and nuclei blue.

Figure 5

Gastric epithelial cellular responses with carcinogenic potential that are induced by iron deficiency within the context of H pylori infection. The H pylori cag T4SS injects CagA into epithelial cells and this results in signaling that induces loss of cell polarity and effects on the epithelial junctions, pro-inflammatory phenotypes, and growth factor-like signaling that results in cellular proliferation. This also induces increased iron uptake and transcytosis. In the right panel, low levels of iron in the host induce increased adhesion and colonization of the glandular epithelium, increased number of T4SS pili, and an augmentation in levels of CagA injection and pathogenic signaling.