The origin of gastric gland stem cells in gastric malignancy

Leuschacke M, Tan SH, Wong A, et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol 2017 Jun. doi: 10.1038/ncb3541. (Epub ahead of print).

Stem cell architecture of the mammalian corpus gland has been hotly debated. Current dogma states that the corpus gland stem cell resides in the gland neck (isthmus) and their progeny migrate in a bidirectional fashion to the top and bottom. In addition, recent evidence suggests a reserve population of stem cells reside at the gland base that are relatively quiescent until damage occurs where they are then capable of rapid expansion. Leushacke and colleagues have shown that Lgr5, expressed on intestinal crypt and pyloric gland stem cells, is also expressed on corpus gland stem cells. In a model that expresses the transgene in all targeted cells, Lgr5 is expressed on a subpopulation of basal chief cells. A previous study showed that chief cells express a stem cell marker called Mist1 that can act as a stem cell from the isthmus but not the base. Understanding the relationship between these two markers will be an important advance for gastric stem cell biology. Here, Lgr5-expressing chief cells did not appear to play a role in normal gland homeostasis. However, ablation of all Lgr5+ cells in the gland resulted in gland base atrophy. On high-dose tamoxifen-induced damage, Lgr5+ chief cells were able to display lineage tracing resulting in monoclonal conversion in a Wnt-dependent mechanism. The authors questioned whether Lgr5+ chief cells could act as a cell of origin for gastric cancer. Kras-dependent metaplasia originated from Lgr5+ chief cells. However, this model does not progress and is histologically metaplastic. The authors do describe the relationship of Lgr5 and other stem cell markers in human cancer and while this is convincing, nearly all cancer cells …