Immune Regulation of Gastric Cancer

胃癌的免疫调节

• 批准号: 10709271
• 负责人: Jonathan Busada
• 金额: $ 23.78万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709271
• 关键词: Acceleration; Adrenal Glands; Adrenalectomy; Affect; Anti-Inflammatory Agents; Atrophic Gastritis; Autoimmune; Automobile Driving; CD4 Positive T Lymphocytes; Cancer Etiology; Cancer Model; Cancer Patient; Cells; Cessation of life; Chronic; Crohn' s disease; Data; Development; Diagnosis; Disease; Dysplasia; Environment; Epithelium; Future; Gastric Adenocarcinoma; Gastric Metaplasia; Gastric mucosa; Gastritis; Glucocorticoid Receptor; Glucocorticoids; Goals; Helicobacter; Helicobacter Infections; Helicobacter pylori; Hormones; Human; Hyperactivity; Immune; Infection; Inflammation; Inflammatory; Inflammatory Response; Insulin; Knowledge; Laboratories; Link; Malignant Neoplasms; Metaplasia; Mus; Pathogenicity; Pathway interactions; Phenotype; Population; Preneoplastic Conditions; Production; Publishing; Regulation; Resistance; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Steroid-resistant asthma; Stomach; Stomach Neoplasms; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; cancer risk; carcinogenesis; chronic inflammatory disease; cytokine; diagnostic tool; efficacy evaluation; gastric cancer prevention; gastric carcinogenesis; high throughput screening; immunoregulation; malignant stomach neoplasm; mortality; mouse model; novel diagnostics; novel therapeutic intervention; polarized cell; prevent; recruit; response; spasmolytic polypeptide; steroid hormone; transcriptome; tumor; tumor microenvironment

ABSTRACT - Immune Regulation of Gastric Cancer Gastric cancer is the 4th leading cause of cancer deaths worldwide. Over 90% of gastric cancers are associated with long-term Helicobacter pylori infection. However, the infection alone has limited pathogenic effects on the gastric mucosa. Rather, the infection triggers massive gastric inflammation, which becomes increasingly hyper- active, damaging the stomach and creating the requisite environment for carcinogenesis. However, the mecha- nisms and pathways that regulate the onset of hyperactive inflammation are unknown. Glucocorticoids are potent anti-inflammatory steroid hormones produced by the adrenal glands. We have shown that glucocorticoids are critical for suppressing pathogenic gastric inflammation. Adrenalectomized mice spontaneously develop massive gastric inflammation driving a potentially pre-neoplastic condition called Spasmolytic polypeptide-expressing metaplasia (SPEM). Glucocorticoid signaling is also disrupted in gastric cancers, but the role of these hormones in gastric cancer development and progression has not been studied. The overall goal of this proposal is to establish the role of glucocorticoids in preventing Helicobacter-induced gastric cancer development. Our prelim- inary data suggest that endogenous glucocorticoids are critical regulators of the gastric inflammatory response to Helicobacter infection. Loss of glucocorticoid signaling accelerates gastric epithelial damage, metaplasia, and dysplasia. Thus, the loss of glucocorticoid signaling likely accelerates Helicobacter-induced gastric cancer de- velopment. However, glucocorticoid protection from gastric cancer development has never been studied. Spe- cific Aim 1 will examine how glucocorticoid signaling regulates gastric T cell activation and polarization. Specific Aim 2 will examine how long-term Helicobacter infection disrupts endogenous glucocorticoid signaling within the stomach, promoting hyperactive inflammation even upon Helicobacter eradication. Specific Aim 3 will utilize the INS-GAS mouse model of gastric carcinogenesis to study whether glucocorticoid signaling protects from gastric cancer development. Moreover, we will use fresh tumor samples to examine how glucocorticoid signaling mod- ulates the tumor microenvironment in humans. These studies will be the first to investigate how glucocorticoid signaling regulates gastric cancer development. Ultimately, the knowledge generated here will facilitate the launch of human studies and the development of novel diagnostic and therapeutic strategies to prevent gastric cancer.

摘要 - 胃癌的免疫调节 胃癌是全球癌症死亡的第四个主要原因。超过90％的胃癌是相关的 长期幽门螺杆菌感染。但是，仅感染对病原体影响有限 胃粘膜。相反，感染会触发严重的胃炎，这变得越来越多 主动，破坏胃并为致癌作用创造必要的环境。但是，机甲 - 调节多动炎症发作的Nism和途径尚不清楚。糖皮质激素有效 肾上腺产生的抗炎类固醇激素。我们已经表明糖皮质激素是 对于抑制致病性胃炎至关重要。肾上腺切除小鼠自发发展 胃炎症驱动一种可能表达痉挛性多肽的潜在前塑性疾病 Metaplasia（SPEM）。糖皮质激素信号在胃癌中也被破坏，但是这些激素的作用 在胃癌的发展和进展中尚未研究。该提议的总体目标是 确定糖皮质激素在防止螺旋杆菌诱导的胃癌发展中的作用。我们的预赛 Inary数据表明，内源性糖皮质激素是胃炎症反应的关键调节剂 感染螺旋杆菌。糖皮质激素信号传导的损失会加速胃上皮损伤，化生和 发育不良。因此，糖皮质激素信号传导的丧失可能会加速螺旋细菌诱导的胃癌 速度。但是，从未研究过糖皮质激素免受胃癌发展的保护。 sp CIFIC AIM 1将检查糖皮质激素信号如何调节胃T细胞激活和极化。具体的 AIM 2将检查长期的旋转杆菌感染如何破坏内源性糖皮质激素信号传导 胃，即使根除旋转螺旋杆菌，也会促进过度活跃的炎症。特定目标3将利用 胃癌发生的INS-GAS小鼠模型，以研究糖皮质激素信号是否可以保护胃 癌症发展。此外，我们将使用新鲜肿瘤样品来检查糖皮质激素信号传导如何模仿 唤起人类肿瘤微环境。这些研究将是第一个研究糖皮质激素的研究 信号传导调节胃癌的发展。最终，这里产生的知识将有助于 人类研究的启动以及开发新颖的诊断和治疗策略以防止胃 癌症。