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

胃慢性炎症损伤可导致上皮样细胞的化生分化 并最终发展为胃(胃)癌(GC)。胃腺癌(GA)占大多数 GC病例。萎缩性胃炎的病因被描述为萎缩性胃炎的组织病理学进展， 化生、异型增生到腺癌。胃化生包括痉挛多肽表达 化生(SPEM)，它与人类GA作为一种癌前病变有关。广泛的研究已经建立了 幽门螺杆菌是胃癌的主要环境危险因素，约1%的感染病例与胃癌有关。的作用 GC的宿主因素也是通过积累证据来指示的。与其他疾病一样，罕见的遗传性疾病 突变可以提供可能广泛相关的新见解。的确，胃炎与胃癌的发生发展 最近发现的罕见的人类CTLA4半缺失病例突出了慢性炎症的可能性 在GC中。最近对133例~2-50岁CTLA4单倍体功能不全患者的调查发现萎缩 胃炎占9%，胃癌占3%。这些罕见病例的发现也与 人类遗传性遗传性CTLA4缺乏症与遗传相关的证据 多态现象。我们最近报道了一种用于启动GC的转基因CTLA4 RNAi“敲除”(CTLA4KD)模型 由CTLA4不足所致。在易感遗传背景下，CTLA4KD小鼠表现出自发 即使在无菌条件下，也能开发出100%外显率的SPEM。证实了遗传证据， 用抗CTLA4的单抗(MAb)阻断CTLA4也可诱发小鼠SPEM。随着年龄的增长，SPEM不断进步 对所有CTLA4KD小鼠均为GA。因此，CTLA4KD小鼠不仅建立了由CTLA4不足引发的人类GC模型， 但也捕捉到了SPEM和GA进展的共同特征，从胃炎、化生 到浸润性腺癌。此外，CTLA4KD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在美国人中发现的非心脏性GC增加的原因 不到50岁的女性，尤其是非西班牙裔白人女性。总体而言，我们的初步数据表明 在GC中CTLA4不足的原因是由于免疫和免疫之间的一种炎症性“串扰” 上皮细胞。我们假设2型炎症启动了胃上皮细胞的化生分化。 并促使癌前谱系恶性转化为侵袭性腺癌。具体来说，我们 将：1)确定引起粘膜异常上皮-免疫相互作用的免疫细胞亚型 导致化生分化和恶变；2)探讨前胃癌的起源和命运 2型细胞因子受体上皮固有信号介导的肿瘤细胞分化；3)鉴定 推动上皮细胞增殖和转化的2型炎症壁龛中的生长因子 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 确定潜在的生物标记物和靶点，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.