Current Status on Stem Cells and Cancers of the Gastric Epithelium

Abstract

Gastric cancer is still a leading cause of cancer-related mortality worldwide in spite of declining incidence. Gastric cancers are, essentially, adenocarcinomas and one of the strongest risk factors is still infection with Helicobacter pylori. Within the last years, it became clear that gastric self-renewal and carcinogenesis are intimately linked, particularly during chronic inflammatory conditions. Generally, gastric cancer is now regarded as a disease resulting from dysregulated differentiation of stem and progenitor cells, mainly due to an inflammatory environment. However, the situation in the stomach is rather complex, consisting of two types of gastric units which show bidirectional self-renewal from an unexpectedly large variety of progenitor/stem cell populations. As in many other tumors, cancer stem cells have also been characterized for gastric cancer. This review focuses on the various gastric epithelial stem cells, how they contribute to self-renewal and which routes are known to gastric adenocarcinomas, including their stem cells.

Keywords: Helicobacter pylori; SPEM; cancer stem cell; cell differentiation; gastric cancer; gastric mucosa; gastric self-renewal; gastric stem cell; metaplasia.

Figure 1

Schematic representation of the two gross types of human gastric units and their continual, bidirectional self-renewal from gastric progenitor cells (GPCs)/stem cells. Shown are the major epithelial cell types and some of their characteristic secretory products such as MUC, mucins; TFF peptides, FCGBP, IgG Fc binding protein; GKN, gastrokines; LYZ, lysozyme; LIPF, gastric lipase, PGA and PGC, pepsinogens; GIF, intrinsic factor; and HCl, hydrochloric acid; as observed in the classical fundic and antral units, respectively. The various gastric precursor cell (GPCs)/stem cell populations are marked in red: C, CCK2 receptor⁺; L, Lgr5⁺; S, Sox2⁺; T, Troy⁺; V, villin⁺; EC(L), enterochromaffin(-like); G, gastrin; SMF, subepithelial myofibroblast; (modified and updated from [15,17]).

Figure 2

Schematic representation of the trans-differentiation of mucous neck cells (MNC, blue) towards zymogenic cells (ZC, green) under the control of parietal cells (yellow); the dysregulated trans-differentiation results in formation of the “spasmolytic polypeptide-expressing metaplasia” (SPEM; orange), which characteristically secretes TFF2. Immature progenitors for MNCs (pre-MNC) in the proliferative region of fundic units mature stepwise (pre-ZC1, pre-ZC2) towards ZCs, which is accompanied by a re-organization of the secretory apparatus (mucous to serous). Shown, also, is the distribution of characteristic transcripts and proteins, which is not congruent in these cells. AR, amphiregulin; BMP, bone morphogenetic protein, HB-EGF, heparin-binding EGF-like growth factor; PTCH, Patched; TGF-α, transforming growth factor α; (modified and updated from [17,27]).