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

2型炎症在胃上皮化生分化和肿瘤转化的起始和进展中的作用

• 批准号: 10633096
• 负责人: Zhibin Chen
• 金额: $ 34.69万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633096
• 关键词: 3-Dimensional; Ablation; Adenocarcinoma; Adoptive Transfer; Affect; Age; Age Years; American; Animal Model; Antibody Therapy; Atrophic Gastritis; Autoimmunity; Bone Marrow; CD4 Positive T Lymphocytes; CTLA4 blockade; CTLA4 gene; Cell Differentiation process; Cells; Chief Cell; Chimera organism; Chronic; Cytokine Receptors; DNA Sequence Alteration; Data; Development; Disease; Dysplasia; Environmental Risk Factor; Epithelial Cells; Epithelium; Etiology; Exhibits; Gastric Adenocarcinoma; Gastric Metaplasia; Gastritis; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic study; Goals; Growth Factor; Helicobacter pylori; Human; IL13 gene; IL4 gene; Immune; Immunophenotyping; Inflammation; Inflammatory; Integration Host Factors; Interleukin 4 Receptor; Interleukin-13; Knock-out; Knowledge; LGR5 gene; Link; Lymphoid Cell; Malignant - descriptor; Malignant Neoplasms; Mediating; Metaplasia; Modeling; Monoclonal Antibodies; Mucous Membrane; Mus; Neoplasms; Neoplastic Cell Transformation; Not Hispanic or Latino; Pathway interactions; Patients; Penetrance; Play; Population; Premalignant Cell; Proliferating; RNA Interference; Reporting; Role; Signal Transduction; Stomach; Surveys; T-Lymphocyte; Testing; Th2 Cells; Tissues; Transgenes; Transgenic Organisms; Tumor Immunity; Woman; anti-CTLA4; cancer cell; cancer initiation; cancer prevention; cancer therapy; connective tissue growth factor; cytokine; design; gastric organoids; germ free condition; heparin-binding EGF-like growth factor; human model; insight; interleukin-13 receptor; knock-down; malignant stomach neoplasm; neoplastic; novel; overexpression; potential biomarker; preneoplastic cell; preservation; small hairpin RNA; spasmolytic polypeptide; stem cells; transdifferentiation; trefoil factor; tumor; tumorigenesis

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.

摊位中的慢性炎症损伤会导致上皮谱系的化生分化 以及最终的胃癌（GC）的发展。胃腺癌（GA）占多数 GC病例。 GA的病因已被描述为萎缩性胃炎的组织病理学进展， 化生，腺癌的发育不良。胃化生包括表达痉挛性多肽 Metaplasia（SPEM），它与人类GA作为北京前的GA有关。广泛的研究已经建立 幽门螺杆菌是GC的主要环境风险因素，约1％的感染病例与GC有关。的作用 GC的宿主因素也通过积累证据来表明。与其他疾病一样，罕见的仿制药病例 突变可以提供可能广泛相关的新颖见解。确实，胃炎和GC发展 最近被识别的人类CTLA4单plo不高兴的罕见病例凸显了慢性炎症的潜力 在GC。最近对约2-50岁的CTLA4单倍不高兴患者进行了一项调查，发现萎缩 3％的患者中9％的患者和GC的胃炎。这些极少数情况的发现也包括 人GA与基因引起的遗传易感CTLA4不足的证据 多态性。我们最近报道了GC启动的转基因CTLA4 RNAi“敲低”（CTLA4KD）模型 由CTLA4不足。在敏感的遗传背景上，CTLA4KD小鼠暴露了赞 即使在无菌条件下，SPEM具有100％渗透率的开发。证实遗传证据， CTLA4用单克隆抗体（MAB）也诱导小鼠的SPEM。随着年龄的增长，SPEM进步了 在所有CTLA4KD小鼠中进行GA。那是CTLA4KD小鼠不仅建模由CTLA4不足引发的人类GC， 但还可以捕获SPEM和GA进展的共同特征，并通过胃炎，化生的整个级联 浸润性腺癌。此外，CTLA4KD模型说明了自身免疫性在GC中的关键作用。 已经建议自身免疫性是美国人最近确定的非心脏GC兴起的原因 年龄不到50岁的人，尤其是非西班牙裔白人妇女。总体而言，我们的初步数据表明 GC中CTLA4不足的因果关系是由于免疫和 上皮细胞。我们假设该类型2炎症会引发胃上皮的化学分化 并驱动前塑性谱系向侵入性腺癌的恶性转化。具体来说，我们 意志：1）确定引起粘膜异常上皮相互作用的免疫细胞的亚型 导致转移分化和恶性转化； 2）检查前的起源和命运 由2型细胞因子受体的上皮内部信号传导介导的肿瘤细胞分化； 3）确定 2型炎症壁ni的生长因子，这些炎症壁ches推动上皮谱系的增殖和转化 在看台。该研究将揭示出恶性细胞的起源和命运，并有助于长期目标 确定潜在的生物标志物和靶标，以打破炎症与肿瘤发生之间的联系。