Gastrointestinal microbiota interactions modulating gastric cancer progression

胃肠道微生物群相互作用调节胃癌进展

• 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
• 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

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.

项目摘要 胃癌是全球第四大死亡原因，80%的病例归因于螺杆菌 幽门螺杆菌感染。Hp如何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改变引起的 由幽门螺杆菌引起的慢性炎症引发，始于产酸壁细胞（胃）的丧失 萎缩）和化生细胞的出现，可能导致发育不良和胃癌。细菌 诸如分泌的毒素CagA等因素，以及诸如吸烟和饮食等宿主行为因素， 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，超过一半的病例在癌症诊断时已经丧失了Hp定植。的 与化生和异型增生相关的组织变化（酸减少，粘蛋白表达改变， 糖基化）可以促进口腔细菌在胃中的生长。因此，其他因素，包括 微生物，可能有助于胃癌的病因。 具核梭杆菌（Fn）是口腔微生物群的成员，但也涉及结肠直肠癌。 通过人类肿瘤的微生物测序和异种移植和 转基因小鼠模型最近，在晚期胃病变和胃粘膜中发现Fn。 癌症，与Hp存在明显的互斥关系。我们发现太平洋地区19%的病人 西北（PNW）胃癌队列的胃感染（Fn）。在小鼠中，我们的初步数据显示Fn是一个 健康胃的不良定植者，但在KRAS驱动的背景下， 化生，虽然不是在存在Hp。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。为了验证这一 假设我们将使用小鼠研究Fn定植如何影响胃肿瘤前进展 在这个模型中，我们可以通过KRAS在胃粘膜主细胞中的条件性表达来快速诱导胃化生。 胃（目标1）。我们假设Hp与Fn感染可能引起不同的宿主免疫应答， 可能对疾病进展有不同的影响。因此，我们将描述胃和全身炎症 在化生小鼠中由Fn与Hp驱动（Aim 2）。在目标3中，我们将利用来自小鼠的类器官 模型来测试不同病原体暴露后的表型多样性。这些目标将确定Fn是否 可以改变胃上皮化生的癌前轨迹， 来机械地探索所需的宿主和细菌基因。这一整体战略也可用于 探索胃癌发展的其他候选辅因子。