Polyclonal Intestinal Tumors: Formation, Progression, and Significance

描述（由申请人提供）：结直肠癌是美国癌症死亡的主要原因。许多研究人员认为，肿瘤是由一个异常的祖先和它的后代。支持这一长期观点的数据既不广泛也不明确。此外，所使用的实验技术存在严重偏差。我们认为肿瘤是由多种异常祖细胞产生的，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优势。将使用新开发的小鼠模型、统计分析和成像技术的独特组合来检验这一假设。我们将分析来自用乙基亚硝基脲（ENU）或氧化偶氮甲烷（AOM）治疗的小鼠的肿瘤，其中Apc通过沉默体细胞失活的小鼠，以及由于TGF 2信号通路突变而引发肿瘤发生的小鼠（Aim 1）。如果多克隆性提供了选择性优势，那么异型肿瘤在这些不同的小鼠模型中应该是常见的。将肿瘤保存在组织库中，并使用Access数据库进行充分记录。我们将探讨异型肿瘤是如何出现的（目的2）。我们的初步研究表明，最可能的解释涉及克隆相互作用发生在非常短的距离。我们将测试多克隆性是否随着肿瘤的生长和从良性到恶性状态的进展而持续（目标3）。我们提出的实验结果可能从根本上改变对哺乳动物肠道肿瘤发生的理解。这一新观点的接受无疑将影响化学预防和化学治疗方法的设计。介导克隆相互作用的信号分子可能是药物干预的理想靶点。潜在的介质可以首先利用我们的组织库的高度表征的肿瘤从各种小鼠模型进行检查。每个仍然被认为有趣的候选人可以使用我们的实验平台进行全面测试，即，可以确定通过药物干预或遗传操作消除候选物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，早期腺瘤通常来源于多个祖细胞，即，这些肿瘤是多克隆的，而不是许多研究者长期认为的单克隆的。多克隆肿瘤的出现似乎是因为在很短的距离内发生的相互作用。我们通过使用新开发的小鼠模型，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，从而扩展了我们的初步研究。对这一问题的深入了解可能会影响肠癌管理策略的制定。

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.