A cellular key to the gastric inflammation-metaplasia-carcinoma sequence?

胃炎症-化生-癌序列的细胞关键？

• 批准号: 7177229
• 负责人: DEBORAH L. GUMUCIO
• 金额: $ 11.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7177229
• 关键词: cellular; key; gastric; inflammation; metaplasia

DESCRIPTION (provided by applicant): Gastric cancer is one of the most frequent causes of cancer-related death world wide. Chronic inflammation as a result of Helicobacter pylori infection is an important initiating factor in a sequence that develops over years and progresses from atrophic gastritis, intestinal metaplasia, dysplasia and finally, adenocarcinoma. It has been speculated that the mutational changes that finally result in gastric cancer originate in the stem cell compartment; thus, characterization of gastric stem cells is an important clinical goal. However, the prospective recognition and isolation of gastric stem cells has been heretofore impossible because of the lack of specific markers for these cells. Moreover, the tools necessary to trace the progeny of single gastric progenitor cells (to establish definitively whether these cells give rise to gastric tumors) have not been available. Data presented here show that the mouse villin promoter is active in a subpopulation of gastric cells that exhibit characteristics of progenitor or stem cells; the cells are called pGPC (putative gastric progenitor cells). pGPC arise early in development and are found throughout life in epithelial compartments known to contain stem cells. Lineage tracing experiments in situ suggest that pGPC have multi-lineage potential. Interestingly, interferon gamma (IFNgamma), a potent pro-inflammatory stimulus known to be tightly associated with the development of gastric cancer, causes a robust increase in the number of pGPC. The hypothesis underlying this work is that pGPC are gastric progenitor or stem-like cells and that they play a key role in the "chronic gastritis-intestinal metaplasia-carcinoma" sequence. Thus, the goal of this project is to further characterize pGPC in vivo in murine stomachs and to investigate whether these cells give rise to metaplastic lesions and to gastric tumors. This work can provide major insights into gastrointestinal stem cell biology, an area that has been notoriously difficult to investigate at the single cell level. Moreover, if it is demonstrated that tumors indeed arise from pGPC, this will have enormous implications for the further study and future clinical management of gastric cancer.

描述（由申请人提供）：胃癌是世界范围内癌症相关死亡的最常见原因之一。幽门螺杆菌感染引起的慢性炎症是一个重要的起始因素，其发展过程持续多年，并从萎缩性胃炎、肠上皮化生、异型增生发展到腺癌。据推测，最终导致胃癌的突变变化起源于干细胞室;因此，胃干细胞的表征是一个重要的临床目标。然而，由于缺乏特异性标记物，胃干细胞的前瞻性识别和分离迄今为止是不可能的。此外，还没有必要的工具来追踪单个胃祖细胞的后代（以明确确定这些细胞是否会引起胃肿瘤）。本文提供的数据显示，小鼠绒毛蛋白启动子在表现出祖细胞或干细胞特征的胃细胞亚群中是活跃的;这些细胞被称为pGPC（推定的胃祖细胞）。pGPC在发育早期出现，并且在整个生命过程中在已知含有干细胞的上皮隔室中发现。原位谱系示踪实验表明pGPC具有多谱系潜能。有趣的是，干扰素γ（IFN γ），一种已知与胃癌发展密切相关的强效促炎刺激物，导致pGPC数量的强劲增加。这项工作的假设是，pGPC是胃祖细胞或干细胞样细胞，他们在“慢性胃炎-肠化生-癌”序列中发挥关键作用。因此，本项目的目标是进一步表征pGPC在小鼠胃中的体内特性，并研究这些细胞是否引起化生性病变和胃肿瘤。这项工作可以为胃肠道干细胞生物学提供重要的见解，这是一个众所周知的难以在单细胞水平上研究的领域。此外，如果证明肿瘤确实是由pGPC引起的，这将对胃癌的进一步研究和未来的临床管理产生巨大的影响。