The Role of Aryl Hydrocarbon Receptor in Colon Tumorigenesis

描述(申请人提供)：鉴于环境因素在结直肠癌(CRC)中的重要性，人们普遍认为，通过改变饮食、补充或治疗性地给予化学保护剂，或通过防止暴露于引发或促进肿瘤的化学暴露，可以显著降低这种疾病的发病率。目前流行的化学保护剂清单包括天然存在的饮食化合物，如吲哚-3-甲醇、白杨素和姜黄素，以及舒林酸和其他非甾体抗炎药等治疗剂。有趣的是，许多已提出的化学预防药物是已知的芳香烃受体(AHR)激动剂。我们假设AHR在环境因素如何影响人类人群中的结直肠癌方面扮演着重要而复杂的角色。在信心十足地提出增加AHR激动剂暴露的建议之前，必须解决一些数据差距。首先，我们必须了解实验动物的AHR激活和AHR缺失如何导致不同部位癌症的增加和减少。其次，我们必须了解AHR激活是否是已知化学预防药物作用模式中的一个重要步骤。如果受体激动性与化学预防从机制上联系在一起，我们如何调节剂量使我们不会模仿二恶英的致癌作用？如果它不是机械地与 化学预防，我们能否改变化学预防药物的结构以使这种偏离靶点的AHR效应降到最低？我们认为AHR在结直肠癌中的双功能作用可以用重组小鼠模型来解释。我们假设AHR的促癌和抗癌活性取决于受体被表达和激活的细胞类型，以及受体在该细胞类型中被激活的程度。此外，我们认为，结肠粘膜上皮细胞中AHR的激活导致结肠内淋巴细胞反应的改变，正是通过这种AHR依赖的淋巴细胞生物学，我们产生了抗癌活性。为了验证这些想法，我们提供了以下具体目标：目的1.使用细胞特异性缺失来定义AHR信号的细胞独立性和对CRC的易感性。目的2.使用AHR条件激活模型来确定组织自主性，并测试AHR信号的变阻器模型和对结直肠癌的易感性。目的3.阐明AHR在结直肠癌模型中抑制肿瘤的可能机制。通过这些目标，我们建议开发新的动物模型，几乎肯定会在我们理解环境和饮食化学物质如何影响屏障器官中的结直肠癌等疾病方面向前迈进一大步。在这项工作之前，对AHR在抗癌发生中的作用的彻底表征从未被仔细地进行过，这使得这些实验变得必要、及时和新颖。

DESCRIPTION (provided by applicant): Given the importance of environmental factors in colorectal cancer (CRC), it is widely held that the incidence of this disease can be significantly reduced through dietary alterations, supplementation or therapeutic administration of chemoprotective agents, or by preventing exposure to initiating or tumor promoting chemical exposures. The list of currently popular chemoprotective agents includes naturally occurring dietary compounds such as indole-3- carbinol, chrysin and curcumin, as well as therapeutic agents like Sulindac and other NSAIDs. Interestingly, many proposed chemopreventative agents are known agonists of the aryl hydrocarbon receptor (AHR). We hypothesize that the AHR plays an important, yet complex, role in how environmental factors influence CRC in human populations. There are a number of data gaps that must be addressed before recommendations for increasing exposure to AHR agonists can be made with confidence. First, we must understand how AHR activation and AHR deletion in experimental animals lead to both increases and decreases in cancers at various sites. Second, we must understand whether AHR activation is an important step in the mode of action of known chemopreventative agents. If receptor agonism is mechanistically linked to chemoprevention, how do we modulate doses so we do not mimic the pro-carcinogenic effects of dioxins? If it is not mechanistically related to chemoprevention, can we modify structures of the chemopreventative agents to minimize this off-target AHR effect? We propose that the bifunctional role of the AHR in CRC can be explained using recombinant mouse models. We hypothesize that the pro- and anti-carcinogenic activity of the AHR depends upon the cell type in which the receptor is expressed and activated, as well as the degree to which the receptor is activated in that cell type. In addition, we propose that activation of the AHR in colonic mucosal epithelial cells leads to an altered lymphocyte response within the colon and that it us through this AHR-dependent lymphocyte biology that anti-carcinogenic activity is produced. To test these ideas, we offer the following specific aims: Aim 1. Use cell specific deletion to define cell autonomy of AHR signaling and susceptibility to CRC. Aim 2. Use models of conditional activation of AHR to determine tissue autonomy and test the rheostat model of AHR signaling and susceptibility to CRC. Aim 3. Clarify the underlying mechanism of AHR-mediated tumor suppression in the CRC model. Through these aims, we propose the development of novel animal models that will almost certainly provide a significant step forward in our understanding of how environmental and dietary chemicals influence diseases such as CRC at barrier organs. Prior to this work, a thorough characterization of AHR's role in anti- carcinogenesis has never been carefully performed, making these experiments essential, timely and novel.