Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer

Abstract

This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, "humanized" versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model.

Keywords: GEMMs; Gastrin; Hedgehog; INS-GAS; MNU; Notch; SPEM; gp130.

Fig. 22.1

Histological structures of the gastric body of the mouse in normal and inflamed mucosal epithelia. Cell types resemble those of the human stomach. Left panel, normal uninflamed gastric mucosa. Right panel, chronically inflamed mucosa after 6-month Helicobacter felis (H. felis) infection. Annotated are the gastric pits and glands, and constituent cell types, including: (1) pit cells (foveolar cells), (2) parietal cells (large eosinophilic cells which are “fried egg”-shaped), (3) chief/zymogenic cells (basophilic cells at base of the gland), (4) mucous neck cells, and (5) smooth muscle cells of the muscularis mucosa

Fig. 22.2

Loss of parietal cells (pink) following chronic (>6 months) H. felis infection. Immunofluorescent photomicrographs of gastric corpus mucosa showing parietal cells. Parietal cells stained in pink in normal uninfected gastric mucosa (left panel) and chronically (>6 months) infected mucosa with H. felis (right panel)

Fig. 22.3

Timeline of chronic gastritis to dysplasia in experimental mouse models. Schematic depiction of Helicobacter infection leading to chronic gastritis and ultimately gastric dysplasia. Shown is the two-phase development observable in mice. The first phase indicates chronic-active inflammation after Helicobacter infection. The second phase is labeled metaplasia/dysplasia and involves a change in the microenvironment. Dysplasia/cancer in situ is observed in the antrum for Gastrin^−/− and GP130^F/F. Tumors are present in the corpus for the other models. The L-635 model is also shown as a rapid (chemical) model for the induction of SPEM. Note that human subjects develop chronic gastritis over months to years and cancer (CA) over decades

Fig. 22.4

Modifying factors for mouse models of gastric carcinogenesis. Drinking water containing chemical carcinogens MNU (a) or H. felis inoculation (b) strongly enhances stomach carcinogenesis in combination (c). Long-term administration of a COX-2 inhibitor (nimesulide) shows strong chemopreventive action against H. pylori-associated gastric transformation (d). Early, middle, or late eradication of H. felis reduces risk of gastric carcinogenesis in mice (e, f, g). Similar increased risk is observed in INS-GAS or p27^−/− mice (h–k). A high-salt diet further increases the incidence of gastric cancer (l)