Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer

Abstract

Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

“…We have termed this the "cyclical hit" model of tumorigenesis (Mills & Sansom, 2015;Saenz & Mills, 2018). Chronic injury of the type that repetitively induces paligenotic/metaplastic events has long been known to increase risk for acquisition of mutations and progression to neoplasm.…”

“…Eventually, a critical mutation may be unmasked during paligenosis, and a clone of cells that is unable to redifferentiate arises. We have termed this the "cyclical hit" model of tumorigenesis (Mills & Sansom, 2015;Saenz & Mills, 2018).…”

Interferon‐γ directly induces gastric epithelial cell death and is required for progression to metaplasia

“…The atrophy and metaplasia stage is the first in the gastric cancer progression sequence that carries heightened cancer risk. Moreover, other mouse models, like the TxA23 autoimmune gastritis model used here, phenocopy the progression seen in humans . Thus, if IFN‐γ is the key factor mediating the transition to atrophy/metaplasia, it may be critically important for determining which patients with chronic gastritis are at risk for progression to gastric cancer.…”

Impact factors that modulate gastric cancer risk in Helicobacter pylori‐infected rodent models

“…Local acid output is crucial for distributing Helicobacter species in the stomach. Moreover, elevated gastric pH can increase susceptibility to certain enteric infection and alter gastric and gut flora . Huang et al showed that long‐term PPI treatment augmented the GC risk in Kunming mice inoculated with MNNG despite their lacking H pylori infection .…”

“…Moreover, elevated gastric pH can increase susceptibility to certain enteric infection and alter gastric and gut flora. 87 Huang et al showed that long-term PPI treatment augmented the GC risk in Kunming mice inoculated with MNNG despite their lacking H pylori infection. 88 However, further research is needed to interpret the association between PPI use and GC risk.…”