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

描述(申请人提供)：胃癌是全球最常见的癌症相关死亡原因之一。幽门螺杆菌感染导致的慢性炎症是一个重要的启动因素，经过多年的发展，从萎缩性胃炎、肠化生、不典型增生到腺癌。有人推测，最终导致胃癌的突变起源于干细胞，因此，胃干细胞的特征是一个重要的临床目标。然而，到目前为止，由于缺乏胃干细胞的特异性标志物，对胃干细胞的预期识别和分离一直是不可能的。此外，还没有必要的工具来追踪单个胃祖细胞的后代(以确定这些细胞是否会导致胃肿瘤)。这里提供的数据显示，小鼠绒毛膜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具有活性；这些细胞被称为pGPC(推定的胃祖细胞)。PGPC出现在发育早期，并在整个生命中发现于已知含有干细胞的上皮室中。原位谱系示踪实验表明，pGPC具有多谱系潜能。有趣的是，干扰素伽马(IFNGamma)，一种已知与胃癌发生密切相关的强有力的促炎刺激因素，会导致pGPC数量的强劲增加。支持这项工作的假设是，pGPC是胃祖细胞或干细胞样细胞，它们在“慢性胃炎-肠化生-癌”序列中发挥关键作用。因此，该项目的目标是进一步确定小鼠胃中pGPC的活体特征，并研究这些细胞是否会引起化生病变和胃肿瘤。这项工作可以为胃肠道干细胞生物学提供重要的见解，这一领域一直是出了名的难以在单细胞水平上进行研究。此外，如果证实肿瘤确实起源于pGPC，这将对胃癌的进一步研究和未来的临床治疗具有巨大的意义。

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.