Identification and characterization of cancer cells of origin in the epidermis

摘要 癌症现在是这个国家的头号死因。最近开发的许多治疗方法 专注于控制现有肿瘤的生长，其中一些治疗方法已经转变为 将以前致命的癌症转化为可控的疾病。对肿瘤的研究已经导致了一个深入的 现有疾病的表征和许多与癌症相关的基因的鉴定。的 我们对癌症的大部分了解都是基于现有的肿瘤，但对癌症的认识却很少。 肿瘤发生的机制。虽然我们知道很多关于“基因命中”， 环境的损害导致肿瘤的形成，目前还不清楚哪些细胞作为癌细胞 混元任何细胞都能产生肿瘤吗？大多数成人组织含有多种细胞类型，包括 干细胞、过渡扩增细胞和分化细胞。许多人认为成体干细胞 是最有可能起源的癌细胞，因为它们在组织中的寿命长， 自我更新或无限增长。此外，许多被认为参与 肿瘤发生也已显示在成体干细胞的干细胞自我更新中起作用。 然而，肿瘤发生中靶向的特定细胞类型的身份被以下事实所掩盖： 大多数肿瘤发生的研究利用预先存在的肿瘤组织，这是一种回顾性方法。直到最近 目前还没有工具可以将基因击中组织中的特定细胞类型， 作为癌细胞的起源。此外，很少有模型系统允许隔离 来自经历转化的组织的细胞，其忠实地模仿天然肿瘤发生。简而言之， 积累的关于肿瘤发生的文献大量依赖于从转化的肿瘤细胞积累的数据。 在未知细胞类型中由未知机制靶向的组织。我们设计了一个模型 该系统采用前瞻性方法来识别癌细胞的起源。我们正在利用 最新的工具和遗传技巧，以靶向遗传击中特定细胞类型的表皮， 最常见的癌症靶组织。有了这些工具，我们可以将基因命中 细胞或它们的传递扩增后代以探测更好地能够作为癌细胞起源的细胞。 此外，该模型系统允许在肿瘤治疗期间的任何时间点纯化靶细胞。 开始或进展。这将使我们能够确定哪些基因受到肿瘤起始的影响， 其在良性肿瘤与恶性肿瘤的起始中特异性改变。这些发现应该能证明 不仅对癌症的治疗至关重要，甚至可能对癌症的预防也至关重要。另外这款 这项工作将发掘出大量关于干细胞及其后代的信息， 被癌症利用。

Abstract Cancer is now the number one cause of death in this country. Many recently developed treatments have focused on managing the growth of existing tumors, and some of these treatments have turned previously lethal cancers into manageable conditions. The study of tumors has led to an in depth characterization of existing disease and the identification of many genes that are linked to cancer. The majority of what we know about cancer is based on existing tumors, but there is little knowledge on the mechanisms behind tumor initiation. While we know a great deal about the "genetic hits" and environmental insults that lead to tumor formation, it remains unclear which cells serve as cancer cells of origin. Can any cell make a tumor? Most adult tissues contain a wide variety of cell types including stem cells, transit-amplifying cells and differentiated cells. Many have proposed that adult stem cells are the most likely cancer cell of origin because of their longevity in the tissue and their capacity for self-renewal, or unlimited growth. Furthermore, many of the pathways thought to participate in tumorigenesis have also been shown to play a role in stem cell self-renewal in adult stem cells. However, the identity of the particular cell types targeted in tumorigenesis is obscured by the fact that most studies of tumorigenesis utilize pre-existing tumor tissue, a retrospective approach. Until recently there were no tools available to deliver genetic hits to specific cell types in a tissue to ask which could serve as cancer cells of origin. In addition, there are few model systems that allow for the isolation of cells from tissue undergoing transformation that faithfully mimic natural tumorigenesis. In short, the accumulated literature on tumorigenesis relies a great deal on data accumulated from transformed tissue targeted by an unknown mechanism in an unknown cell type. We have designed a model system that takes a prospective approach to identifying cancer cells of origin. We are taking advantage of the latest tools and genetic tricks to target genetic hits to particular cell types in the epidermis, the most common target tissue of cancer. With these tools, we are applying genetic hits to either stem cells or their transit-amplifying progeny to probe which is better able to serve as a cancer cell of origin. In addition, this model system allows for the purification of the targeted cells at any point during tumor initiation or progression. This will enable us to identify which genes are affected by tumor initiation, and which are specifically altered in benign versus malignant tumor initiation. These findings should prove critical to not only the treatment of cancer but potentially even the prevention of cancer. In addition, this work will unearth a wealth of information about stem cells and their progeny, and whether pathways that regulate stem cells are exploited by cancer.