Development of Mouse Models for Ménétrier's Disease.

Abstract

Ménétrier's disease (MD) is a rare acquired premalignant gastric disorder characterized by giant rugal folds, decreased acid secretion, and protein loss. MD patients show increased expression of an EGF receptor (EGFR) ligand, transforming growth factor-α (TGFα) in the stomach. The EGFR-neutralizing antibody, cetuximab, results in rapid clinical improvement and histological remission. Beyond these findings, the etiology and underlying molecular mechanisms are not well understood. The Metallothionein (MT)-TGFα transgenic mouse line is the first MD mouse model that recapitulates histopathological features of MD, including foveolar hyperplasia and loss of parietal cells. In this mouse model, TGFα is driven by the heavy metal-inducible MT enhancer/promoter. Prior studies have used zinc sulfate (ZnSO4) in drinking water or intraperitoneal injections of cadmium sulfate (CdSO4) to induce TGFα. However, we found that MT-TGFα mice develop phenotypes without heavy metal treatment, indicating leakiness of the promoter. We also found that overexpression of TGFα suppresses Mist1 expression, a transcription factor important for chief cell differentiation, thus hindering genetic manipulation in chief cells using the Mist1-CreERT2 mouse line. To overcome this, we developed an inducible mouse model (Doxi-TGFα) in which TGFα is induced by doxycycline treatment (CMV-rtTA; TetO-TGFα). Although the Doxi-TGFα mouse model develops milder phenotypes than the MT-TGFα model, it recapitulated features of MD, including foveolar hyperplasia and loss of parietal cells. Using the Doxi-TGFα mouse model, we found that spasmolytic polypeptide-expressing metaplasia (SPEM) is induced in MD, and SPEM is derived from chief cells by lineage tracing using the Mist1-CreERT2 mouse line. Both MT-TGFα and Doxi-TGFα mouse models offer in vivo models of MD and are useful for investigating the molecular mechanisms underlying MD pathogenesis and treatment options for the disease. The Doxi-TGFα mice will also be a useful model to study the effects of overexpression of TGFα in other tissues.