Unveiling gastric stem cell dynamics in gastric atrophy and carcinogenesis: revisiting mechanisms and advancing experimental models - a narrative review.

Abstract

Gastric atrophy serves as a critical precursor in the multistep cascade of gastric carcinogenesis, yet the underlying cellular and molecular mechanisms remain incompletely understood. Emerging evidence increasingly implicates gastric stem cells (GSCs) as key mediators of epithelial regeneration and potential originators of neoplastic transformation. This narrative review comprehensively evaluates the dynamic roles of GSCs in the context of atrophic gastritis and preneoplastic progression, synthesizing findings from murine models and human studies. In doing so, we critically examine competing paradigms of GSC depletion versus expansion during carcinogenesis, contextualizing these findings within model-dependent frameworks - particularly contrasting chemical carcinogen-based protocols with Helicobacter -induced and genetically engineered mouse models. Building on these insights, accumulating data suggest that, rather than undergoing depletion, both antral and corporal GSCs often persist and may undergo clonal expansion in response to chronic inflammation and carcinogenic stimuli, thereby establishing a field cancerization effect that predisposes the mucosa to malignant transformation. Through a rigorous appraisal of experimental design, lineage tracing methodologies, and translational relevance, we identify key methodological variables contributing to discordant interpretations of GSC behavior, such as reliance on multi-chemical carcinogen models with limited translational relevance and tamoxifen-dependent lineage tracing systems prone to confounding effects. In particular, we explore the mechanistic divergence between infection-driven and chemically induced gastric injury, underscoring how these fundamentally distinct microenvironments shape stem cell fate and carcinogenic potential. To resolve these discrepancies and bridge ongoing gaps, we advocate for refined experimental approaches integrating Helicobacter felis -induced chronic atrophic gastritis models with tamoxifen-independent lineage-tracing platforms. We also highlight the promise of spatial transcriptomics and advanced organoid systems to elucidate region-specific stem cell behavior. Together, these insights contribute to a revised conceptual framework for GSC-driven gastric carcinogenesis, offering a foundation for targeted early detection and prevention strategies.