Expression of Activated Ras in Gastric Chief Cells of Mice Leads to the Full Spectrum of Metaplastic Lineage Transitions

Abstract

Background & Aims Gastric cancer develops in the context of parietal cell loss, spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM). We investigated whether expression of the activated form of Ras in gastric chief cells of mice leads to development of SPEM, as well as progression of metaplasia. Methods We studied Mist1-CreERT2Tg/+;LSL-K-Ras(G12D)Tg/+ (Mist1-Kras) mice, which express the active form of Kras in chief cells upon tamoxifen exposure. We studied Mist1-CreERT2Tg/+;LSL-KRas (G12D)Tg/+;R26RmTmG/+ (Mist1-Kras-mTmG) mice to examine whether chief cells that express active Kras give rise to SPEM and IM. Some mice received intraperitoneal injections of the MEK inhibitor, selumetinib, for 14 consecutive days. Gastric tissues were collected and analyzed by immunohistochemistry, immunofluorescence, and quantitative PCR. Results Mist1-Kras mice developed metaplastic glands, which completely replaced normal fundic lineages and progressed to IM within 3–4 months after tamoxifen injection. The metaplastic glands expressed markers of SPEM and IM, and were infiltrated by macrophages. Lineage tracing studies confirmed that the metaplasia developed directly from Kras (G12D)-induced chief cells. Selumetinib induced persistent regression of SPEM and IM and reestablished normal mucosal cells, which were derived from normal gastric progenitor cells. Conclusions Expression of activated Ras in chief cells of Mist1-Kras mice led to the full range of metaplastic lineage transitions, including SPEM and IM. Inhibition of Ras signaling by inhibition of MEK might reverse pre-neoplastic metaplasia in the stomach.

Mitogen-activated Protein Kinase Kinase Activity Maintains Acinar-to-Ductal Metaplasia and Is Required for Organ Regeneration in Pancreatitis

“…Here we show that MEK signaling is required not only for the initiation of the metaplastic process and the associated fibroinflammatory response but also for maintaining the transdifferentiated, metaplastic state. These observations closely mirror data implicating MAPK signaling in both the initiation and maintenance of metaplasia in the chief cells of the stomach epithelium, 27 illustrating a commonality in the role of MAPK signaling on the plasticity of Mist1 expressing serous exocrine cells in different organs. 28 Genetic or pharmacologic inhibition of MEK activity consistently led to a larger population of amylase-positive acinar cells, decreased fibrosis, and an attenuated inflammatory response after the onset of pancreatitis.…”

Murine Models of Gastric Corpus Preneoplasia

“…MUC2-positive goblet cells have been identified in older amphiregulin knockout mice 42 . More recently, CDX1-positive cells and MUC2-positive goblet cells have been observed in Mist1-Kras ( G12D ) mice, but CDX2 expression was not observed 43 . The expression of CDX1 rather than CDX2 may reflect the more prominent expression of CDX1 in the duodenum, consistent with the concept that intestinal metaplasia in the stomach may represent more specifically a “duodenal metaplasia.” 44 Indeed, previous studies have suggested that intestinal metaplasia in the human corpus may reflect a duodenal lineage paradigm based on PDX1 expression 44 .…”

“…Up-regulation of phospho-ERK in metaplasia has been noted in both human beings and mice 43, 91. However, Ras mutations have been observed in only approximately 9% of gastric cancers.…”

Pyloric metaplasia, pseudopyloric metaplasia, ulcer‐associated cell lineage and spasmolytic polypeptide‐expressing metaplasia: reparative lineages in the gastrointestinal mucosa

“…Nevertheless, recent studies have shown that SPEM acquires more intestinalized phenotypes in the context of inflammatory influences, specifically alternatively activated macrophages [33,45,46]. Furthermore, increasing evidence indicates that SPEM likely represents an initial metaplastic response to gastric injury, while chronic injury and inflammation may lead to the further evolution of goblet-cell intestinal metaplasia from SPEM [30,47]. Thus, while pyloric type metaplasias in the stomach are initially reparative, their maintenance in the setting of chronic inflammation can lead to deleterious neoplastic scenarios.…”

“…While one group has suggested that SPEM arises from isthmal progenitor cells in the corpus [57], the vast majority of evidence from multiple groups indicates that chief cells are indeed the predominant origin of SPEM lineages in the stomach corpus. [42,47,56,58–60] Importantly, expression of pepsinogen I has been used as a marker of pseudopyloric metaplasia [61], consistent with the equivalence of pseudopyloric metaplasia with SPEM. Similarly, ductal metaplasia/PanIN lesions in the pancreas appear to evolve from reprogramming of zymogen-secreting pancreatic acinar cells [62].…”