Common Stem Cell of Origin for Junctional and Gastric Adenocarcinoma

总结 尽管它们分别出现在远端食管和远端胃， (EAC)和肠胃癌（iGC）共享单一疾病的自然史和分子遗传学。 从历史上看，EAC和iGC是第一批与先前存在的离散的、前肿瘤相关的癌症。 癌性病变可发展为发育异常，然后在二十年的时间间隔内发展为侵袭性疾病。在 这两种情况下，最早的癌前病变是一个奇怪的“肠化生，IM”被称为“巴雷特的” EAC的“食管（BE）”和iGC的“胃肠化生（GIM）”。这些共同的进化 癌症遗传学的突破使EAC和iGC成为一个簇， 与其他胃癌和食道癌不同。虽然人们普遍预计， 内镜和消融技术应用于前驱病变将意味着EAC和iGC的结束， EAC和iGC的水平没有明显下降，大多数患者仍然存在晚期疾病， 五年生存率低。这一可怕的临床现实预示着一个广泛的努力，以了解细胞的起源， 这些疾病，它们最早出现的病理学，以及它们的检测和药物治疗， 淘汰一个高度合作的团队，由上消化道肿瘤学家，干细胞和 分子生物学家，小鼠癌症模型专家和蛋白质组学专家已经采用了先进的 干细胞克隆技术，在每个连续的病变中捕获患者匹配的干细胞， EAC和iGC患者。除了这些干细胞所提供的高分辨率遗传学外， 分析显示BE和GIM干细胞在全基因组水平上是不可区分的 表达谱分析下降到定义细胞身份的同源异型转录因子的水平。共同 BE和GIM干细胞的细胞表面标记物在两个细胞表面都识别出离散的细胞群。 胃食管（GE）交界处和正常小鼠的远端胃，我们假设是 EAC和iGC的IM的内在来源。这些标记也使克隆 相应的位点特异性干细胞，我们发现它们的基因表达谱难以区分，并且是 在体外分化时致力于IM。在三个目标中，我们将1）使用类似的方法克隆内在 来自人胎儿和成人GE连接和胃粘膜的IM干细胞; 2）工程小鼠模型， 内源性IM细胞中致癌因子的条件性表达;和3）鉴定选择性地 靶向内在IM干细胞作为治疗剂的先导，以预防EAC和iGC。我们预计这些研究 本文提出的将提供新的见解，这些非常相似的生物学和起源， 广泛分布的癌症，提供了前瞻性早期检测筛查所必需的数据集， 选择性治疗，消除这些癌症演变所必需的新生病变。

SUMMARY Despite their emergence from distal esophagus and distal stomach, respectively, esophageal adenocarcinoma (EAC) and intestinal gastric cancer (iGC) share the natural histories and molecule genetics of a single disease. Historically, EAC and iGC were among the first cancers to be linked to the prior presence of discrete, pre- cancerous lesions that can progress to dysplasia and then invasive disease over a two-decade interval. In both cases the earliest precancerous lesion was an odd "intestinal metaplasia; IM" known as "Barrett's esophagus (BE)" for EAC and "gastric intestinal metaplasia (GIM)" for iGC. These common evolutionary features have been extended by cancer genetics breakthroughs that place EAC and iGC into single cluster distinct from other gastric and esophageal cancers. While it was widely anticipated that advances in endoscopic and ablative technologies applied to precursor lesions would spell the end of EAC and iGC, rates of EAC and iGC have not appreciably decreased and most patients still present with advanced disease and poor five-year survival. This dire clinical reality has predicated a broad effort to understand the cell-of-origin of these diseases, their earliest emergence towards pathology, as well as their detection and pharmaceutical elimination. A highly collaborative team consisting of upper gastrointestinal oncologists, stem cell and molecular biologists, experts in murine cancer modeling, and proteomics specialists has employed advanced stem cell cloning technologies to capture patient-matched stem cells in each of the successive lesions in patients with EAC and iGC. In addition to the high-resolution phylogenetics afforded by these stem cells, this analysis has revealed the BE and GIM stem cells are indistinguishable at the level of whole genome expression profiling down to the level of homeotic transcription factors that define cellular identity. Common cell surface markers of BE and GIM stem cells identify a discrete population of cells at both the gastroesophageal (GE) junction and in the distal stomach of normal mice which we hypothesize are the intrinsic source of the IM for EAC and iGC respectively. These markers have also enabled the cloning of the corresponding site-specific stem cells, which we find to be indistinguishable gene expression profiles and to be committed to IM upon in vitro differentiation. In three aims, we will 1) use similar methods to clone the intrinsic IM stem cells from human fetal and adult GE junctions and gastric mucosa; 2) engineer mouse models for conditional expression of oncogenic factors in intrinsic IM cells; and 3) identify small molecules that selectively target intrinsic IM stem cells as leads for therapeutics to prevent EAC and iGC. We anticipate that the studies proposed herein will provide new insights into the biology and origin of these remarkably similar and widespread cancers, provide datasets essential for prospective early detection screens, and yield highly selective therapeutics that eliminate the nascent lesions essential for the evolution of these cancers.