Polyclonal Intestinal Tumors: Formation, Progression, and Significance

描述(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，肿瘤是由单一的异常祖细胞及其后代产生的。支持这一长期观点的数据既不广泛，也不确定。此外，使用的实验技术有很大的偏见。我们认为肿瘤起源于多个异常祖细胞，因为这些细胞之间的克隆性相互作用在形成、生长和发展过程中提供了选择性优势。这一假设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进行验证。我们将分析用乙基亚硝脲(ENU)或偶氮甲烷(AOM)治疗的小鼠的肿瘤，通过沉默使APC躯体失活的小鼠，以及由于TGF2信号通路突变而启动肿瘤形成的小鼠(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很常见。肿瘤将保存在一个组织库中，该组织库将使用Access数据库进行良好的记录。我们将探索异型肿瘤是如何出现的(目标2)。我们最初的研究表明，最可能的解释是发生在很短距离内的克隆相互作用。我们将测试随着肿瘤的生长和从良性状态向恶性状态的进展，多克隆是否持续存在(目标3)。我们提议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。接受这一新观点无疑将影响化学预防和化疗方法的设计。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。潜在的介体可以首先利用我们的高度特征化的肿瘤组织库从各种小鼠模型中进行检查。然后，可以使用我们的实验平台对每个仍然被认为有兴趣的候选对象进行全面测试，即可以确定通过药物干预或基因操作消除候选对象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，早期腺瘤通常来自多个祖细胞，即这些肿瘤是多克隆的，而不是许多研究人员长期以来认为的单克隆。多克隆肿瘤的出现似乎是因为发生在非常短的距离内的相互作用。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关于多克隆的几个基本问题，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治疗策略的制定。

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.