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.

Both Ménétrier’s disease (MD) and juvenile polyposis syndrome (JPS) are rare premalignant conditions that can lead to gastric cancer development. MD is an acquired disease without known causative mutations. MD patients are characterized by an increased expression of EGF receptor (EGFR) ligand and transforming growth factor alpha (TGF-α) in the stomach. JPS is inherited in an autosomal dominant pattern and is caused by BMPR1A or SMAD4 mutations. It is characterized by multiple polyps throughout the gastrointestinal tract along with certain SMAD4 mutations that can result in gastric polyposis. Although there are many distinct clinico- endoscopic and histopathologic features that differ between the two diseases, they also share similar features that often lead to misdiagnosis. This study aimed to identify markers that can help distinguish MD from JPS and to better understand the pathogenesis of MD by comparing differential gene expression patterns. Upon examination of MD and JPS microscopically, we found almost all cases have patchy areas mimicking each other, making it difficult to make a correct diagnosis with histopathologic examination alone. Comparative analysis between MD and JPS using ingenuity pathway analysis (IPA) revealed both common and differential gene signatures. Common gene signatures included estrogen receptor signaling, integrin signaling, mTOR signaling, and others, which may be responsible for histopathologic similarities. Among differential gene signatures, we found that claudin 18 ( CLDN18 ) is upregulated in MD and confirmed that CLDN18.2 (isoform of CLDN18) protein expression is higher in MD than JPS by immunohistochemistry. Comparative analysis between MD and normal control revealed the hedgehog (Hh) signaling pathway is upregulated in MD. Treatment with a hedgehog pathway inhibitor partially rescued the histopathologic phenotypes in a MD mouse model. The current study provides valuable insight into the potential underlying mechanism of why MD and JPS show similar clinico-pathologic features. We also identified a diagnostic marker CLDN18.2 that can help distinguish MD from JPS, genetically. Furthermore, it also shows that Hh signaling plays an important role in the pathogenesis of MD and can function as a potential therapeutic target.

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.