Polyclonal Intestinal Tumors: Formation, Progression, and Significance

多克隆肠肿瘤：形成、进展和意义

• 批准号: 8033178
• 负责人: Richard Brott Halberg
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033178
• 关键词: Address; Adenocarcinoma; Adenomatous Polyposis Coli; Alleles; Azoxymethane; Benign; Caliber; Cancer Biology; Cancer Etiology; Cell Lineage; Cells; Cellular Structures; Cessation of life; Chemoprevention; Clonal Expansion; Colonic Neoplasms; Colorectal Cancer; Consensus; Data; Databases; Development; Disease; Drug Delivery Systems; Ethylnitrosourea; Growth; Health; Human; Image; Image Analysis; Imaging Techniques; Individual; Intervention; Intestinal Cancer; Intestinal Neoplasms; Intestines; Karyotype; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Monitor; Mus; Mutation; Nature; Pathway interactions; Pharmaceutical Preparations; Population; Research Personnel; Science; Signal Pathway; Signaling Molecule; Stem cells; Structure; Techniques; Technology; Testing; Time; Tissue Banking; Tissue Banks; Tumor-Derived; United States; Work; adenoma; anticancer research; chemotherapy; design; experience; genetic manipulation; interest; malignant state; mouse model; neoplastic cell; progenitor; research study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer is a leading cause of cancer death in the United States. Many investigators believe that a tumor is derived from a single abnormal progenitor and its descendents. The data supporting this long-held view are neither extensive nor definitive. Moreover, the experimental techniques used were heavily biased. We believe that a tumor is derived from multiple abnormal progenitors because clonal interactions among these cells provide a selective advantage during formation, growth, and progression. This hypothesis will be tested using a unique combination of newly developed mouse models, statistical analyses, and imaging techniques. We will analyze tumors from mice treated with either ethylnitrosourea (ENU) or azoxymethane (AOM), mice in which Apc is inactivated somatically by silencing, and mice in which tumorigenesis is initiated because of a mutation in the TGF2 signaling pathway (Aim 1). If polyclonality provides a selective advantage, heterotypic tumors should be common among these distinct mouse models. The tumors will be maintained in a tissue bank that will be well documented using an Access database. We will explore how heterotypic tumors emerge (Aim 2). Our initial study indicates that the most likely explanation involves clonal interactions occurring over very short distances. We will test whether polyclonality persists as tumors grow and progress from benign to malignant states (Aim 3). The results from our proposed experiments could fundamentally change the understanding of tumorigenesis in the mammalian intestine. The acceptance of this new view will undoubtedly impact the design of approaches for chemoprevention and chemotherapy. Signaling molecules mediating clonal interactions would likely be ideal targets for drug intervention. Potential mediators can be first examined utilizing our tissue bank of highly characterized tumors from a variety of mouse models. Each candidate that is still deemed interesting can then be fully tested using our experimental platform, i.e., one could determine whether elimination of the candidate through either drug intervention or genetic manipulation completely impairs the formation, growth, or progression of polyclonal tumors. PUBLIC HEALTH RELEVANCE: Initial studies from us and others indicate early adenomas are often derived from multiple progenitors, i.e., these tumors are polyclonal, not monoclonal as long believed by many investigators. Polyclonal tumors appear to emerge because of interactions occurring over very short distances. We extend our initial study by answering several fundamental questions regarding polyclonality using a unique combination of newly developed mouse models, statistical analyses, and imaging platforms. A deep understanding of this issue will likely impact the development of management strategies for intestinal cancer.

描述（由申请人提供）：大肠癌是美国癌症死亡的主要原因。许多研究人员认为，肿瘤来自一个异常祖细胞及其后代。支持这种长期观点的数据既不广泛也不确定。此外，使用的实验技术严重偏见。我们认为，肿瘤来自多个异常祖细胞，因为这些细胞之间的克隆相互作用在形成，生长和进展过程中提供了选择性的优势。该假设将通过新开发的小鼠模型，统计分析和成像技术的独特组合进行检验。我们将分析用乙硝基乙酸（ENU）或甲氧基甲烷（AOM）治疗的小鼠的肿瘤，其中APC通过沉默使APC灭活的小鼠，并且由于TGF2信号通路中的突变而启动了肿瘤发生的小鼠（AIM 1）。如果多克隆性提供了选择性的优势，则异型肿瘤在这些不同的小鼠模型中应该是常见的。肿瘤将在组织库中维持，该组织将使用访问数据库进行充分记录。我们将探讨异性肿瘤如何出现（AIM 2）。我们的最初研究表明，最可能的解释涉及在很短的距离内发生克隆相互作用。随着肿瘤的增长和从良性到恶性状态的发展，多克隆性是否存在（AIM 3）。我们提出的实验的结果可以从根本上改变对哺乳动物肠道肿瘤发生的理解。接受这种新观点无疑会影响化学预防和化学疗法的方法的设计。介导克隆相互作用的信号分子可能是药物干预的理想目标。可以首先使用来自各种小鼠模型的高度表征肿瘤的组织库对潜在的介体进行检查。然后，可以使用我们的实验平台对每个仍被认为有趣的候选人进行全面测试，即，可以通过药物干预或遗传操作来确定消除候选者是否完全损害多克隆肿瘤的形成，生长或进展。公共卫生相关性：我们和其他人的初步研究表明，早期的腺瘤通​​常来自多个祖细胞，即这些肿瘤是多克隆的，而不是单克隆的，因为许多研究者长期认为。由于相互作用在非常短的距离内发生，多克隆肿瘤似乎出现了。我们通过回答新开发的鼠标模型，统计分析和成像平台的独特组合来回答有关多克隆性的几个基本问​​题，扩展了我们的初步研究。对这个问题的深入了解可能会影响肠癌管理策略的发展。