Epithelial-stromal cross-talk in esophageal inflammation and carcinogenesis.

食管炎症和癌变中的上皮-基质相互作用。

• 批准号: 8959570
• 负责人: Anisa Shaker
• 金额: $ 8.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959570
• 关键词: Acids; Address; Apoptosis; Applications Grants; Bile fluid; Biochemical Genetics; Bone Morphogenetic Proteins; CCL2 gene; Cell Survival; Chronic; Disease; Epithelial; Epithelial Cell Proliferation; Epithelial-Stromal Communication; Epithelium; Equilibrium; Erinaceidae; Esophageal; Esophageal Adenocarcinoma; Esophagitis; Event; Exposure to; Gastric Acid; Gastroesophageal reflux disease; Gene Expression; Growth; Homeostasis; Human; IL8 gene; Inflammation; Inflammatory; Injury; Interleukin-6; Interruption; Investigation; Knowledge; Laboratories; Lead; Letters; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Modeling; Myofibroblast; Paracrine Communication; Protein Family; Protein Secretion; Publishing; Reflux; Research; Risk; Risk Factors; Role; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Stimulus; Stratified Squamous Epithelium; Stromal Cells; TLR4 gene; TRPV1 gene; Ulcer; United States; Work; cancer risk; carcinogenesis; cytokine; gastrointestinal; gastrointestinal disorder diagnosis; genetic approach; inflammatory marker; inhibitor/antagonist; insight; member; novel; paracrine; pathogen; public health relevance; repaired; response; response to injury; therapeutic target; toll-like receptor 4

 DESCRIPTION (provided by applicant): Esophageal adenocarcinoma (EAC) is the fastest growing malignancy in the West and the 6th most lethal cancer in the world. Gastro-esophageal reflux disease (GERD) is a chronic-inflammatory disorder associated with an 8 fold increased risk of EAC. Exposure to gastric acid, duodenal bile, and luminal pathogens leads to inflammation and ulceration, exposing stromal cells to noxious signals and ongoing injury. An aberrant epithelial response to injury and inflammation ultimately culminates in EAC. Disruptions in epithelial-stromal interactions likely further contribute to inflammation and malignancy. GERD therapy primarily relies on acid suppression therapy which has not changed cancer risk. Investigation of intercellular cross-talk in GERD is therefore critical to elucidating early biologcal drivers of malignancy. This grant application addresses this knowledge deficit by the novel use of human esophageal myofibroblasts adapted into a 3D organotypic model that recapitulates esophageal stratified squamous epithelium. Myofibroblasts are stromal cells that regulate epithelial homeostasis, inflammation and proliferation via paracrine mechanisms. Preliminary work suggests that in response to GERD stimuli human esophageal myofibroblasts (MFs) are potent sources of pro- carcinogenic cytokines and members of the bone morphogenetic protein (BMP) family. The overarching hypothesis of this project is that human esophageal myofibroblasts (MFs) regulate epithelial inflammation and repair in GERD via paracrine mediated signaling pathways that when disrupted lead to esophageal malignancy. To address this hypothesis, we will use biochemical and genetic approaches in the 3D organotypic model to mimic human esophageal MF exposure to luminal and epithelial derived noxious signals to delineate the epithelial-stromal cross talk that governs inflammatory and proliferative responses in GERD. We will determine the mechanism by which human esophageal MF cytokine secretion in GERD activates signaling pathways that regulate epithelial inflammation and epithelial growth. This aim is significant because it will delineate biologically relevant cytokine driven stromal-epithelial interactions and sheds insight into the mechanism linking inflammation and carcinogenesis. We will also determine the mechanism by which human esophageal secretion of BMPs regulates epithelial proliferation, differentiation and apoptosis in GERD. This aim is significant because it delineates novel BMP driven stromal-epithelial interactions in the GERD and provides the rationale for therapeutic targeting of potentially modifiable signaling pathways.

 描述（由申请人提供）：食管腺癌（EAC）是西方发展最快的恶性肿瘤，也是世界上第6大致死性癌症。胃食管反流病（GERD）是一种慢性炎症性疾病，与EAC风险增加8倍相关。暴露于胃酸、十二指肠胆汁和管腔病原体导致炎症和溃疡，使基质细胞暴露于有害信号和持续损伤。对损伤和炎症的异常上皮反应最终在EAC中达到高潮。上皮-基质相互作用的破坏可能进一步导致炎症和恶性肿瘤。GERD治疗主要依赖于抑酸治疗，这并没有改变癌症风险。因此，研究GERD中的细胞间串扰对于阐明恶性肿瘤的早期生物学驱动因素至关重要。这项资助申请通过新的使用人食管肌成纤维细胞适应于3D器官型模型，重现食管复层鳞状上皮，解决了这一知识缺陷。肌成纤维细胞是通过旁分泌机制调节上皮稳态、炎症和增殖的基质细胞。初步工作表明，在响应GERD刺激时，人食管肌成纤维细胞（MF）是促致癌细胞因子和骨形态发生蛋白（BMP）家族成员的有效来源。该项目的首要假设是，人食管肌成纤维细胞（MFs）通过旁分泌介导的信号通路调节GERD中的上皮炎症和修复，当中断时导致食管恶性肿瘤。为了解决这一假设，我们将在3D器官型模型中使用生物化学和遗传学方法来模拟人食管MF暴露于管腔和上皮来源的有害信号，以描述控制GERD中炎症和增殖反应的上皮-基质串扰。我们将确定GERD中人食管MF细胞因子分泌激活调节上皮炎症和上皮生长的信号通路的机制。这一目标是重要的，因为它将描绘生物学相关的细胞因子驱动的基质-上皮相互作用，并揭示了炎症和癌变的机制。我们还将确定人食管分泌BMP调节GERD中上皮细胞增殖、分化和凋亡的机制。这一目标是重要的，因为它描绘了新的BMP驱动的基质-上皮相互作用的GERD，并提供了治疗靶向潜在的可修改的信号传导途径的基本原理。