The role of type 2 inflammation in the initiation and progression of metaplastic differentiation and neoplastic transformation of gastric epithelia

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Chronic inflammatory damage in the stomach can lead to metaplastic differentiation of epithelial lineages and eventual development of gastric (stomach) cancer (GC). Gastric adenocarcinoma (GA) accounts for most GC cases. The etiology of GA has been described as a histopathological progression from atrophic gastritis, metaplasia, dysplasia to adenocarcinoma. Gastric metaplasia includes Spasmolytic Polypeptide-Expressing Metaplasia (SPEM), which is associated with human GA as a pre-neoplasia. Extensive studies have established H. pylori as a major environmental risk factor for GC and ~1% of infected cases are linked to GC. The role of host factors for GC are also indicated by accumulating evidence. As in other diseases, rare cases of genetic mutations can offer novel insights that may be broadly relevant. Indeed, gastritis and GC development in recently-identified rare cases of human CTLA4 haplo-insufficiency highlight the potential of chronic inflammation in GC. A recent survey of 133 patients with CTLA4 haplo-insufficiency from ~2-50 years of age found atrophic gastritis in 9% of the patients and GC in 3% of the patients. The finding from these rare cases also consists with evidence for an association of human GA with a genetic predisposed CTLA4 insufficiency due to gene polymorphisms. We recently reported a transgenic CTLA4 RNAi “knockdown” (CTLA4KD) model for GC initiated by CTLA4 insufficiency. On susceptible genetic backgrounds, CTLA4KD mice exhibited spontaneous development of SPEM with 100% penetrance, even in germ-free conditions. Corroborating the genetic evidence, CTLA4 blockade with monoclonal antibodies (mAb) also induced SPEM in mice. With age, SPEM progressed to GA in all CTLA4KD mice. Thus, CTLA4KD mice not only model human GC initiated by CTLA4 insufficiency, but also capture a shared feature of SPEM and GA progression with an entire cascade from gastritis, metaplasia to invasive adenocarcinoma. Furthermore, the CTLA4KD model illustrated a critical role of autoimmunity in GC. Autoimmunity has been suggested to be the cause of the recently identified rise of noncardia GC in Americans who are less than 50 year old, especially non-Hispanic white women. Overall, our preliminary data suggest that the causality of CTLA4 insufficiency in GC was due to a type of inflammatory “crosstalk” between immune and epithelial cells. We hypothesize that type 2 inflammation initiates metaplastic differentiation of gastric epithelia and drives malignant transformation of the pre-neoplastic lineage into invasive adenocarcinoma. Specifically, we will: 1) determine the subtypes of immune cells that cause aberrant epithelial-immune interaction in mucosae leading to metaplastic differentiation and malignant transformation; 2) examine the origin and fate of pre- neoplastic cell differentiation mediated by epithelial-intrinsic signaling of type 2 cytokine receptors; 3) identify the growth factors in type 2 inflammatory niches that propel the proliferation and transformation of epithelial lineages in the stomach. The study will reveal the origin and fate of pre-malignant cells, and help a long-term goal to identify potential biomarkers and targets to break the link between inflammation and tumorigenesis.