The Role of Aryl Hydrocarbon Receptor in Colon Tumorigenesis

描述（由申请人提供）：考虑到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、补充或治疗性施用化学保护剂，或通过防止暴露于引发或促进肿瘤的化学物质，可以显著降低结直肠癌的发病率。目前流行的化学保护剂包括天然存在的膳食化合物，如吲哚-3-甲醇、菊花素和姜黄素，以及治疗药物，如舒林达克和其他非甾体抗炎药。有趣的是，许多提出的化学预防剂是已知的芳烃受体（AHR）的激动剂。我们假设AHR在环境因素如何影响人群结直肠癌中起着重要但复杂的作用。在有信心地提出增加AHR激动剂暴露的建议之前，必须解决许多数据空白。首先，我们必须了解实验动物中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剂作用模式中的重要步骤。如果受体激动作用与化学预防有机制联系，我们如何调节剂量，使我们不模仿二恶英的致癌性作用？如果没有机械上的联系

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.