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

 描述(申请人提供)：食管腺癌(EAC)是西方增长最快的恶性肿瘤，在世界上排名第六。胃食道反流病(GERD)是一种慢性炎症性疾病，与EAC的风险增加8倍相关。暴露于胃酸、十二指肠胆汁和腔内病原体会导致炎症和溃疡，使基质细胞暴露于有害信号和持续的损伤中。上皮对损伤和炎症的异常反应最终导致EAC。上皮-间质相互作用的中断可能进一步导致炎症和恶性肿瘤。GERD治疗主要依赖于酸抑制疗法，这并没有改变癌症的风险。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。这项拨款申请解决了这一知识缺陷，通过将人食管肌成纤维细胞改编成3D器官模型，重现食管层状鳞状上皮。肌成纤维细胞是一种基质细胞，通过旁分泌机制调节上皮细胞的动态平衡、炎症和增殖。初步研究表明，在GERD刺激下，人食管肌成纤维细胞(MFS)是致癌细胞因子的有效来源，是骨形态发生蛋白(BMP)家族的成员。该项目的主要假设是，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的上皮炎症和修复，当信号通路中断时，会导致食道恶性肿瘤。为了解决这一假设，我们将在3D器官模型中使用生化和遗传学方法来模拟人类食道MF暴露于管腔和上皮来源的有害信号中，以描绘GERD中控制炎症和增殖反应的上皮-间质串扰。我们将确定GERD中人食道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。这一目标具有重要意义，因为它将描绘生物相关的细胞因子驱动的间质-上皮相互作用，并深入了解炎症和癌症发生的机制。我们还将确定人食道BMPs分泌调节GERD上皮细胞增殖、分化和凋亡的机制。这一目标具有重要意义，因为它描绘了GERD中新的BMP驱动的间质-上皮相互作用，并为潜在可修改的信号通路的治疗靶向提供了理论基础。

 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.