Current understanding of SPEM and its standing in the preneoplastic process

Abstract

Gastric cancer is the second leading cause of cancer-related death worldwide, but the details of gastric carcinogenesis remain unclear. In humans, two preneoplastic metaplasias are associated with the precancerous stomach: intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM). While mouse models of Helicobacter sp. infection have not shown intestinal metaplasia, a number of mouse models lead to the evolution of SPEM. In this review, we summarize increasing data that indicates that SPEM arises in the setting of parietal cell loss, either following acute druginduced oxyntic atrophy or in chronic oxyntic atrophy associated with H. felis infection. Importantly, recent investigations support the origin of SPEM through transdifferentiation from mature chief cells following parietal cell loss. Novel biomarkers of SPEM, such as HE4, hold promise as specific markers of the metaplastic process distinct from normal gastric lineages. Staining with HE4 in humans and other studies in gerbils suggest that SPEM arises initially in the human stomach following parietal cell loss and then further evolves into intestinal metaplasia, likely in association with chronic inflammation. Further studies are needed to broaden our knowledge of metaplasia and early cancer-specific biomarkers that could give insights into both lineage derivation and preneoplasia detection.

Figure 1

Comparison of normal fundic gastric glands and metaplastic SPEM glands in mice. The diagram at the top depicts alterations in gland lineages between normal and SPEM glands with emergence of SPEM and foveolar hyperplasia following loss of parietal cells. Panels below show immunostaining patterns for normal and SPEM-containing glands. TFF2 (red) expressing mucous neck cells redifferentiate into intrinsic factor (green) expressing chief cell at the base of normal glands. However, TFF2 expression is expanded to the base of SPEM glands and appears within cells that show dual staining for intrinsic factor. Mist1 (green) is a differentiated chief cell marker in normal gastric glands. However, Mist1 is also expressed in some TFF2-expressing SPEM cells, suggesting transdifferentiation of chief cells. Although proliferation as detected by BrdU (red) is normally only in the progenitor zone of the upper normal gland, TFF2-expressing SPEM cells show clear proliferating cells also expressing intrinsic factor (IF). Previous studies have led to the identification of promising biomarkers of SPEM such as HE4. HE4 is not detected in normal chief cells or any normal fundic cells, but HE4 staining is strongly observed in SPEM.

Figure 2

Current model for the origin and progression of gastric metaplasias in humans. Studies have demonstrated that loss of parietal cells results in chief cell transdifferentiation and the SPEM emergence. In the presence of chronic inflammation from H. pylori infection, SPEM evolves into intestinal metaplasia then progresses on to gastric cancer. Establishment of biomarkers of these metaplastic lineages is a priority. Recent studies in mice identified HE4 as a SPEM biomarker. In humans, HE4 is not expressed in the cells of the normal fundus. However, HE4 is detected in both SPEM and intestinal metaplasia, supporting the hypothesis of SPEM progression to intestinal metaplasia.