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.

胃癌的免疫调节 胃癌是全球第四大癌症死亡原因。超过90%的胃癌与 长期幽门螺杆菌感染然而，感染本身对患者的致病作用有限。 胃粘膜相反，感染会引发大规模的胃部炎症，变得越来越高， 活跃，破坏胃，创造必要的环境致癌。不过，机甲-- 调节过度活跃炎症发作的机制和途径是未知的。糖皮质激素是有效的 肾上腺产生的抗炎类固醇激素。我们已经证明糖皮质激素是 对抑制致病性胃炎至关重要。肾上腺切除的小鼠自发地产生大量的 胃炎症驱动一种称为痉挛性多肽表达的潜在肿瘤前状态， 化生（SPEM）。糖皮质激素信号在胃癌中也被破坏，但这些激素的作用 在胃癌的发展和进展中的作用尚未研究。本提案的总体目标是 确定糖皮质激素在预防螺杆菌诱导的胃癌发展中的作用。我们的初步调查- 泌尿系资料提示内源性糖皮质激素是胃炎症反应的重要调节因子 幽门螺杆菌感染糖皮质激素信号传导的丧失加速胃上皮损伤、化生和胃粘膜损伤。 发育不良因此，糖皮质激素信号传导的丧失可能加速螺杆菌诱导的胃癌的发生。 - 谢谢然而，糖皮质激素对胃癌发展的保护作用从未被研究过。特殊 cific Aim 1将研究糖皮质激素信号如何调节胃T细胞活化和极化。具体 目的2将研究长期螺杆菌感染如何破坏内源性糖皮质激素信号转导， 胃，促进过度活跃的炎症，即使在根除螺杆菌。具体目标3将利用 INS-GAS胃癌发生小鼠模型，研究糖皮质激素信号是否保护胃癌 癌症发展此外，我们将使用新鲜的肿瘤样本来研究糖皮质激素信号转导模式， 改变人类肿瘤的微环境。这些研究将首次探讨糖皮质激素如何 信号传导调节胃癌的发展。最终，这里产生的知识将促进 启动人体研究，开发新的诊断和治疗策略，以预防胃溃疡 癌