Homeostatic Mass Control in Gastric Non-Neoplastic Epithelia under Infection of Helicobacter pylori: An Immunohistochemical Analysis of Cell Growth, Stem Cells and Programmed Cell Death

Abstract

We evaluated homeostatic mass control in non-neoplastic gastric epithelia under Helicobacter pylori (HP) infection in the macroscopically normal-appearing mucosa resected from the stomach with gastric cancer, immunohistochemically analyzing the proliferation, kinetics of stem cells and programmed cell death occurring in them. Ki67 antigen-positive proliferating cells were found dominantly in the elongated neck portion, sparsely in the fundic areas and sporadically in the stroma with chronic infiltrates. CD117 could monitor the kinetics of gastric stem cells and showed its expression in two stages of gastric epithelial differentiation, namely, in transient cells from the gastric epithelial stem cells to the foveolar and glandular cells in the neck portion and in what are apparently progenitor cells from the gastric stem cells in the stroma among the infiltrates. Most of the nuclei were positive for ssDNA in the almost normal mucosa, suggesting DNA damage. Cleaved caspase-3-positive foveolar cells were noted under the surface, suggesting the suppression of apoptosis in the surface foveolar cells. Besides such apoptosis of the foveolar cells, in the severely inflamed mucosa apoptotic cells were found in the neck portion where most of the cells were Ki67 antigenpositive proliferating cells. Beclin-1 was recognized in the cytoplasm and in a few nuclei of the fundic glandular cells, suggesting their autophagic cell death and mutated beclin-1 in the nuclei. Taken together, the direct and indirect effects of HP infection on the gastric epithelial proliferation, differentiation and programmed cell death suggested the in-situ occurrence of gastric cancer under HP infection.

Helicobacter pylori–Induced Loss of the Inhibitor‐of‐Apoptosis Protein Survivin Is Linked to Gastritis and Death of Human Gastric Cells

“…Consistent with this notion, the presence of survivin has been associated with the maintenance of stomach mucosa integrity in rats after treatment with nonsteroidal anti-inflammatory drugs [30]. However, survivin expression was observed in the proliferative neck cell population of gastric mucosa glands ( Figure 1A), which are important for regeneration of mucosal glands and surface epithelia [9,39], suggesting that survivin function appears to not necessarily be linked to cell proliferation in the gastric mucosa of humans.…”

“…Two major events have been associated with apoptosis of gastric epithelial cells-particularly in the proliferative neck zone of the glands-after H. pylori infection of the mucosa [8,9]. On the one hand, an inflammatory response is mounted against the bacteria that results in the production of reactive oxygen species and reactive nitrogen species as well as the release of proapoptotic molecules, such as tumor necrosis factor a, interferon g, and FasL [4,5,10,11].…”

Upper Gastrointestinal Carcinogenesis: H. pylori and Stem Cell Cross-Talk

“…Gastric epithelial stem cells may be the product of an altered extracellular microenvironment in the neck portion of the gastric mucosa under Hp infection, thereby possibly suggesting the in situ occurrence of gastric malignancy under Hp infection [61]. Relative human studies show that gastric cancer contains gastric tumor-initiating stem-like cells with heterogeneity and distinct hierarchy in malignancy [62].…”

Immunohistochemistry of Programmed Cell Death in Archival Human Pathology Specimens

“…Well known antibodies against beclin-1, which forms a complex with Atg14, Vps34, and Vps15 for autophagic vesicle nucleation, and against LC3 (LC3-II), which localizes in the membrane of autophagosomes, are supplied commercially (Table 1). Using these antibodies, we performed AR-IHC on archival human pathology specimens for detecting autophagy [14,15,16]. …”