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

胃的慢性炎症损伤可导致上皮细胞系的化生分化 并最终发展为胃癌（GC）。胃腺癌（GA）占大多数 GC病例。GA的病因学被描述为萎缩性胃炎的组织病理学进展， 化生、异型增生至腺癌。胃上皮化生包括痉挛性多肽表达 化生（SPEM），其与作为瘤前病变的人GA相关。广泛的研究表明， H.幽门螺杆菌是GC的主要环境危险因素，约1%的感染病例与GC有关。的作用 积累的证据也表明了GC的宿主因素。与其他疾病一样， 突变可以提供可能广泛相关的新见解。事实上，胃炎和GC的发展， 最近发现的人类CTLA 4单倍体不足的罕见病例突出了慢性炎症的可能性 在GC。最近对133例年龄约2-50岁的CTLA 4单倍体功能不全患者的调查发现， 胃炎9%，胃癌3%。这些罕见病例的发现也与 人类GA与遗传易感性CTLA 4不足相关的证据， 多态性我们最近报道了一个转基因CTLA 4 RNAi“敲低”（CTLA 4KD）模型，用于GC启动 CTLA 4不足。在易感遗传背景下，CTLA 4KD小鼠表现出自发性 即使在无菌条件下，也能以100%的无菌率开发SPEM。为了证实基因证据， 用单克隆抗体（mAb）阻断CTLA 4也诱导小鼠中的SPEM。随着年龄的增长，SPEM进展 在所有CTLA 4KD小鼠中，因此，CTLA 4KD小鼠不仅模拟了由CTLA 4不足引发的人GC， 而且还捕获了SPEM和GA进展的共同特征，以及从胃炎、化生到整个级联反应 转移到浸润性腺癌此外，CTLA 4KD模型说明了自身免疫在GC中的关键作用。 自身免疫被认为是最近发现的美国人非贲门癌增加的原因 尤其是非西班牙裔白色女性。总的来说，我们的初步数据表明， GC中CTLA 4不足的因果关系是由于免疫和炎症之间的一种炎性“串扰”， 上皮细胞我们假设2型炎症启动胃上皮化生分化 并促使肿瘤前谱系恶性转化为侵袭性腺癌。我们特别 将：1）确定引起粘膜中异常上皮-免疫相互作用的免疫细胞亚型， 导致化生分化和恶性转化; 2）检查前 由2型细胞因子受体的上皮内在信号传导介导的肿瘤细胞分化; 3）鉴定 2型炎症小生境中的生长因子，其促进上皮谱系的增殖和转化 在胃里。这项研究将揭示癌前细胞的起源和命运，并有助于实现长期目标， 确定潜在的生物标志物和靶点，以打破炎症和肿瘤发生之间的联系。

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.