The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models

In this perspective, we briefly summarize recent advances in our understanding of gastric stem cells and their link to gastric cancer. Although the discussion is focused largely on mouse experimental models and the gastric mucosa, we correlate experimental observations with human studies as well as findings from other cancer fields, most of which have pointed to stem cells as the origin of cancer. We also comment on the role of alterations in the stem cell niche as fundamental to the development of gastric cancer. Although other gastric cell types may possess some degree of cellular plasticity and could contribute to cancer development, accumulating evidence indicates that stem cells are the major cellular origin of most cancers, including gastric cancer. The cellular origin of digestive cancers has been a long-standing question in the cancer field. Mouse models have identified long-lived stem cells in most organ systems, including the luminal gastrointestinal tract, and numerous studies have pointed to tissue resident stem cells as the main cellular origin of cancer. During gastric carcinogenesis, chronic inflammation induces genetic and epigenetic alterations in long-lived stem cells, along with expansion of stem cell niches, eventually leading to invasive cancer. The gastric corpus and antrum have distinct stem cells and stem cell niches, suggesting differential regulation of cancer initiation at the 2 sites. In this short review, we discuss recent experimental models and human studies, which provide important insights into the pathogenesis of gastric cancer.