Common Stem Cell of Origin for Junctional and Gastric Adenocarcinoma

摘要 尽管食管腺癌分别出现在食道远端和胃远端，但食管腺癌 肠型胃癌(IGC)和肠型胃癌(EAC)具有相同的自然病史和分子遗传学。 从历史上看，EAC和IGC是最早被认为与先前存在离散的、前期的和 癌性病变可发展为不典型增生，然后在20年内发展为侵袭性疾病。在……里面 这两个病例最早的癌前病变都是一种奇怪的“肠化生”，称为“Barrett‘s” 食道(BE)代表EAC，胃肠上皮化生(GIM)代表IGC。这些共同的进化 癌症遗传学的突破将EAC和IGC归入单一簇，从而扩展了这些特征 与其他胃癌和食道癌不同。虽然人们普遍预计， 应用于前驱病变的内窥镜和消融技术将意味着EAC和IGC、RATES的终结 EAC和IGC的发病率并没有明显下降，大多数患者仍然患有晚期疾病和 可怜的五年存活率。这一可怕的临床现实预示着需要做出广泛的努力来理解细胞起源。 这些疾病，它们最早出现在病理学上，以及它们的检测和药物 淘汰赛。由上消化道肿瘤学家、干细胞和 分子生物学家、小鼠癌症建模专家和蛋白质组学专家使用了先进的 干细胞克隆技术在每一个连续的皮损中捕获与患者匹配的干细胞 EAC和IGC患者。除了这些干细胞提供的高分辨率系统发育，这一点 分析表明，BE和GIM干细胞在全基因组水平上是无法区分的 表达谱下至定义细胞特性的同源异型转录因子的水平。普普通通 BE和GIM干细胞的细胞表面标记识别两个 胃食道(GE)连接和正常小鼠的远端胃中，我们假设是 分别为EAC和IGC的IM的内在来源。这些标记还使克隆 相应的特定部位干细胞，我们发现它们是无法区分的基因表达谱，并且是 致力于体外分化的IM。在三个目标中，我们将1)使用类似的方法来克隆内在的 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 致癌因子在固有IM细胞中的条件表达；以及3)识别选择性地 靶向固有IM干细胞，作为预防EAC和IGC的治疗先导。我们预计这些研究 在此提出的建议将提供对这些惊人相似和 广泛传播的癌症，为未来的早期检测筛查提供必要的数据集，并产生高收益 选择性疗法消除对这些癌症的演变至关重要的新生病变。

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.