Abstract
More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.
Highlights
About 13% of the global cancer burden in 2018 was attributable to carcinogenic infections (de Martel et al, 2020), and Helicobacter pylori (Hp)–associated gastric cancer accounted for the largest proportion of these cancers (Plummer et al, 2015)
Counter to the belief that Hp is only important for initiating inflammation, sustained Hp infection coupled with active KRAS expression led to severe inflammation, altered metaplasia marker expression, and increased cell proliferation and dysplasia compared with Hp−/KRAS+ mice
In this study we examined the effect of Hp infection in stomachs expressing active KRAS (Table 1)
Summary
About 13% of the global cancer burden in 2018 was attributable to carcinogenic infections (de Martel et al, 2020), and Helicobacter pylori (Hp)–associated gastric cancer accounted for the largest proportion of these cancers (Plummer et al, 2015). More than 77% of new gastric cancer cases, and more than 89% of new non-cardiac gastric cancer cases, were attributable to infection with Hp (de Martel et al, 2020), a bacterium that colonizes the stomach of half the world’s population (Suerbaum et al, 2002). Studies using tissue histology rarely detected Hp in tumors, leading to a belief that Hp triggers the initial inflammatory insult in the stomach, but that Hp is essentially irrelevant by the time gastric cancer is detected; in other words, once chronic gastric inflammation develops and oncogenic pathways are activated, the presence of Hp is no longer necessary to promote metaplastic changes that lead to cancer. More sensitive molecular methods detect Hp in about half of tumors (Tang et al, 2005; Cristescu et al, 2015; Talarico et al, 2018), and eradication of Hp combined with tumor resection helps prevent tumor recurrence (Choi et al, 2018), suggesting that Hp may promote the later stages of metaplasia and cancer development in at least some individuals
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