Identification and characterization of cancer cells of origin in the epidermis

表皮起源癌细胞的鉴定和表征

• 批准号: 8401501
• 负责人: William E Lowry
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401501
• 关键词: Adult; Affect; Alleles; Applied Genetics; Benign; Biological Models; Cancer Biology; Carcinoma; Cause of Death; Cell Separation; Cells; Country; Data; Development; Disease; Epidermis; Epithelial; Gene Expression Profile; Gene Mutation; Genes; Genetic; Goals; Growth; Human; Knowledge; Lead; Link; Literature; Longevity; Malignant Neoplasms; Methods; Molecular; Molecular Profiling; Mouse Strains; Oncogenes; Pathway interactions; Play; Relative (related person); Role; Specificity; Stem cells; Stimulus; System; Time; Tissues; Transgenic Organisms; Tumor Promoters; Tumor Suppressor Genes; Tumor Tissue; Variant; Work; abstracting; adult stem cell; base; cancer cell; cancer initiation; cancer prevention; cancer therapy; cell type; design; epidermis cell; genetic strain; in vivo; promoter; prospective; recombinase; research study; self-renewal; stem; stem cell biology; tool; tumor; tumor initiation; tumor progression; tumorigenesis

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.

抽象的 癌症现在是这个国家的第一大死因。许多最近开发的治疗方法 专注于控制现有肿瘤的生长，其中一些治疗方法已经转变 将以前致命的癌症转变为可控制的状况。对肿瘤的研究已经深入 现有疾病的特征以及与癌症相关的许多基因的鉴定。这 我们对癌症的了解大部分都是基于现有的肿瘤，但对癌症的了解却很少。 肿瘤发生背后的机制。虽然我们对“基因打击”了解很多， 环境损害导致肿瘤形成，但目前尚不清楚哪些细胞可作为癌细胞 原产地。任何细胞都可以产生肿瘤吗？大多数成人组织含有多种细胞类型，包括 干细胞、转运扩增细胞和分化细胞。许多人提出成体干细胞 是最有可能的癌细胞来源，因为它们在组织中的寿命很长并且具有 自我更新，或无限成长。此外，许多被认为参与的途径 肿瘤发生也被证明在成体干细胞的干细胞自我更新中发挥作用。 然而，肿瘤发生中针对的特定细胞类型的身份被以下事实所掩盖： 大多数肿瘤发生研究都利用预先存在的肿瘤组织，这是一种回顾性方法。直到最近 没有可用的工具可以将基因击中到组织中的特定细胞类型，以询问哪些可以 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忠实地模仿自然肿瘤发生。简而言之， 积累的关于肿瘤发生的文献很大程度上依赖于从转化中积累的数据 未知细胞类型中未知机制所针对的组织。我们设计了一个模型 系统采用前瞻性方法来识别癌细胞的起源。我们正在利用优势 最新的工具和遗传技巧可将基因命中目标表皮中的特定细胞类型， 最常见的癌症靶组织。借助这些工具，我们可以对任一干进行基因打击 细胞或其转运扩增子代来探测哪个能够更好地作为癌细胞起源。 此外，该模型系统允许在肿瘤发生过程中的任何时刻纯化靶细胞 启动或进展。这将使我们能够确定哪些基因受到肿瘤发生的影响，并且 它们在良性肿瘤与恶性肿瘤的发生过程中发生了特别的改变。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 这项工作将发掘有关干细胞及其后代的大量信息，以及通路是否 调节干细胞的功能被癌症利用。