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。许多最近开发的治疗方法 专注于管理现有肿瘤的生长，其中一些治疗方法已经转向 以前致命的癌症转变为可控制的条件。对肿瘤的研究导致了对 现有疾病的特征和许多与癌症有关的基因的鉴定。这个 我们对癌症的大多数了解都是基于现有的肿瘤，但对癌症的了解很少 肿瘤启动背后的机制。虽然我们知道很多关于“基因冲击”和 导致肿瘤形成的环境侮辱，目前尚不清楚哪些细胞是癌细胞 原产地。任何细胞都能形成肿瘤吗？大多数成人组织含有各种各样的细胞类型，包括 干细胞、转导扩增细胞和分化细胞。许多人提出成人干细胞 是最有可能起源的癌细胞，因为它们在组织中的寿命和它们对 自我更新，或无限增长。此外，许多被认为参与其中的途径 肿瘤的发生也被证明在成体干细胞的干细胞自我更新中起作用。 然而，肿瘤发生过程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都是利用已有的肿瘤组织，这是一种回溯性的方法。直到最近 没有可用的工具来向组织中的特定细胞类型传递基因命中，以问哪种工具可以 作为起源的癌细胞。此外，很少有模型系统允许隔离 来自正在经历转化的组织的细胞，忠实地模仿自然的肿瘤发生。简而言之， 积累的关于肿瘤发生的文献在很大程度上依赖于从转化而来的数据 以未知细胞类型中的未知机制为靶标的组织。我们设计了一个模型 该系统采取前瞻性的方法来识别起源的癌细胞。我们正在利用 在最新的工具和遗传技巧中，针对表皮中特定细胞类型的基因命中， 最常见的癌症靶组织。有了这些工具，我们正在将基因命中应用于这两个茎 细胞或其运输放大后代的探针，更能作为起源的癌细胞。 此外，该模型系统允许在肿瘤过程中的任何时间点对靶细胞进行纯化 开始或进展。这将使我们能够确定哪些基因受到肿瘤启动的影响，以及 它们在良性肿瘤和恶性肿瘤的启动过程中发生了特异性的改变。这些发现应该证明 不仅对癌症的治疗至关重要，甚至对癌症的预防也至关重要。此外，这一点 这项工作将挖掘出大量关于干细胞及其后代的信息，以及 调节干细胞的物质被癌症所利用。

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.