Gastrointestinal microbiota interactions modulating gastric cancer progression

胃肠道微生物群相互作用调节胃癌进展

基本信息

批准号：
10430828
负责人：
Nina Salama
金额：
$ 24.43万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10430828
关键词：
Acids Address Affect Agar Appearance Atrophic Gastritis Bacteria Bacterial Genes Behavior Behavioral Cancer Etiology Cause of Death Cell Death Cell Proliferation Cell model Cells Chronic Colorectal Cancer Data Development Diet Disease Progression Dysplasia Environment Experimental Models Exposure to Flow Cytometry Fusobacterium Infections Fusobacterium nucleatum Gastric Chief Cells Gastric Metaplasia Gastric Parietal Cells Gastric Tissue Gastritis Gene Expression Growth Helicobacter Infections Helicobacter pylori Histologic Human Immune Immune response Immunohistochemistry Infection Inflammation Intervention Intestines KRAS2 gene Lamina Propria Lead Lesion Measurement Metaplasia Metaplastic Cell Microbe Mucins Mus Mutation Organism Organoids Pacific Northwest Patients Persons Phenotype Preparation Risk Factors Series Smoking Spleen Stomach TP53 gene Testing Time Tissue Microarray Tissues Toxin Transplantation Xenograft procedure cancer diagnosis cancer risk carcinogenesis cofactor cohort differential expression gastric organoids glycosylation gut microbiota insight lymph nodes malignant stomach neoplasm member microbial mouse model oral bacteria oral microbial community pathogen exposure systemic inflammatory response tumor tumor progression tumorigenic

项目摘要

PROJECT SUMMARY Gastric cancer is the fourth-leading cause of death worldwide and 80% of cases are attributed Helicobacter pylori (Hp) infection. The precise mechanism for how Hp promotes gastric cancer remains unclear. Intestinal type gastric cancer, the most common histologic type, is thought to arise from a series of tissues changes triggered by chronic inflammation caused by Hp, starting with loss of acid-producing parietal cells (gastric atrophy) and the appearance of metaplastic cells that may lead to dysplasia and gastric cancer. Bacterial factors such as the secreted toxin CagA, as well as host behavioral factors like smoking and diet, contribute to gastric cancer risk. However, only 1-2% of people infected with Hp will ultimately develop gastric cancer and among gastric cancer cases more than half have lost Hp colonization by the time of cancer diagnosis. The tissue changes associated with metaplasia and dysplasia (less acid, altered mucin expression and glycosylation) can favor outgrowth of oral bacteria in the stomach. Thus, additional factors, including other microbes, may contribute to gastric cancer etiology. Fusobacterium nucleatum (Fn) is a member of the oral microbiota but has also been implicated in colorectal cancer through microbial sequencing of human tumors and experimental manipulation in both xenograft and genetically modified mouse models. More recently Fn has been found in advanced gastric lesions and gastric cancer, in an apparent mutually exclusive relationship with Hp. We found that 19% of patients in a Pacific Northwest (PNW) gastric cancer cohort had gastric infection by (Fn). In mice, our preliminary data show Fn is a poor colonizer of the healthy stomach but robustly colonized the stomach during the context of KRAS-driven metaplasia, though not in the presence of Hp. We hypothesize that in humans, Fn gastric colonization may promote the continuation of gastric cancer development when Hp has been cleared. To test this hypothesis we will examine how Fn colonization impacts gastric preneoplastic progression using a mouse model where we can rapidly induce gastric metaplasia through conditional expression of KRAS in chief cells of the stomach (Aim 1). We hypothesize that Hp vs. Fn infection may elicit different host immune responses that could differentially contribute to disease progression. Thus, we will profile gastric and systemic inflammation driven by Fn vs. Hp in mice with metaplasia (Aim2). In Aim 3 we will utilize organoids derived from our mouse models to test phenotypic diversity upon different pathogen exposures. These aims will establish whether Fn can alter the preneoplastic trajectory of metaplasia in the stomach and develop tractable experimental models to mechanistically explore host and bacterial genes required. As well this overall strategy can be used to explore additional candidate cofactors for gastric cancer development.

项目概要胃癌是全球第四大死亡原因，80%的病例归因于螺杆菌幽门螺杆菌 (Hp) 感染。 Hp促进胃癌的确切机制仍不清楚。肠型胃癌是最常见的组织学类型，被认为是由一系列组织变化引起的由幽门螺杆菌引起的慢性炎症引发，首先是产酸壁细胞（胃萎缩）以及可能导致发育异常和胃癌的化生细胞的出现。细菌分泌毒素 CagA 等因素以及吸烟和饮食等宿主行为因素都会导致胃癌风险。然而，只有 1-2% 的 Hp 感染者最终会发展为胃癌，在胃癌病例中，一半以上在癌症诊断时已失去 Hp 定植。这与化生和不典型增生相关的组织变化（酸减少、粘蛋白表达改变和糖基化）有利于口腔细菌在胃中的生长。因此，其他因素，包括其他微生物，可能有助于胃癌的病因。具核梭杆菌 (Fn) 是口腔微生物群的一员，但也与结直肠癌有关通过人类肿瘤的微生物测序和异种移植和实验操作来研究癌症转基因小鼠模型。最近，在晚期胃病变和胃病中发现了 Fn。癌症，与 Hp 存在明显的相互排斥关系。我们发现太平洋地区 19% 的患者西北 (PNW) 胃癌队列 (Fn) 出现胃部感染。在小鼠中，我们的初步数据显示 Fn 是健康胃的殖民者较差，但在 KRAS 驱动的背景下却在胃中强有力地殖民化生，尽管 Hp 不存在。我们假设在人类中，Fn 胃定植当 Hp 被清除后，可能会促进胃癌的继续发展。为了测试这个假设我们将使用小鼠研究 Fn 定植如何影响胃肿瘤前期进展我们可以通过在主细胞中条件性表达 KRAS 来快速诱导胃化生的模型胃（目标 1）。我们假设 Hp 与 Fn 感染可能引发不同的宿主免疫反应可能对疾病进展有不同的贡献。因此，我们将分析胃和全身炎症由化生小鼠中的 Fn 与 Hp 驱动（Aim2）。在目标 3 中，我们将利用来自小鼠的类器官测试不同病原体暴露下的表型多样性的模型。这些目标将确定 Fn 是否可以改变胃化生的癌前轨迹并开发易于处理的实验模型机械地探索所需的宿主和细菌基因。这个总体策略也可用于探索胃癌发展的其他候选辅助因子。