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Suppression of Cancer Inflammation with AHR Modulators

用 AHR 调节剂抑制癌症炎症

基本信息

批准号：
8529529
负责人：
ADAM b GLICK
金额：
$ 21.13万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-13 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8529529
关键词：
Agonist Applications Grants Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Autoimmunity B-Lymphocytes Bone Marrow CD8B1 gene Cancer Model Cell Line Cell physiology Cells Chronic Cutaneous Data Dendritic Cells Development Dioxins Disease Epithelial Gene Expression Generations Genes Goals Human Hyperplasia Immune Immunocompetent Immunocompromised Host Immunosuppressive Agents Infection Inflammation Inflammatory Lead Leukocytes Lewis Lung Carcinoma Ligands Link Malignant Neoplasms Mediating Melanoma Cell Modeling Mus Myelogenous Nuclear Oncogenes Oncogenic Outcome Pathogenesis Pathology Pharmaceutical Preparations Physiological Physiological Processes Physiology Play Prevention therapy Prostate carcinoma Radiation Chimera Relative (related person)Response Elements Retroviridae Risk Role Signal Transduction Skin Neoplasms Structure Suppressor-Effector T-Lymphocytes T-Lymphocyte T-Lymphocyte Subsets Testing Tetrachlorodibenzodioxin Tissues Toxic Environmental Substances Transcriptional Activation Transitional Cell Carcinoma activating transcription factor anti-cancer therapeutic aryl hydrocarbon receptor ligand cancer prevention cancer therapy immune function in vivo innate immune function keratinocyte macrophage malignant breast neoplasm malignant phenotype mouse Ahr protein neoplastic cell prevent receptor response small molecule tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Environmental agonists of the Aryl Hydrocarbon Receptor (AHR) such as TCDD (dioxin) and polycyclic aromatic hydrocarbons generate a chronic inflammatory and immunosuppressive tissue microenvironment that can promote cancer development. While a direct role of the AHR in cancer pathogenesis has not been demonstrated, recent studies show that increased levels of nuclear AHR correlate with tumor grade in urothelial carcinoma and breast cancer, and that many genes involved in the malignant phenotype of tumor cells are directly regulated by the AHR. More recently, it has become evident that the AHR plays a role in normal physiology and disease pathology through the action of endogenous agonists. The AHR is also critical for differentiation of proinflammatory Th17 cells and plays an important role in function these and of innate immune cells such as dendritic cells and macrophages in responses to infection, autoimmunity and inflammatory diseases. These physiological functions are likely to be mediated by recently identified endogenous AHR ligands. While AHR modulated proinflammatory signaling has been described in tumor cells, and critical relevance of the AHR in normal and pathological immune function has been documented, there is no information on the contribution of tumor cell or immune cell AHR to cancer driven inflammation. Newly developed AHR ligands that can prevent DRE and non-DRE AHR activities have the potential to suppress inflammatory signaling either in response to environmental or endogenous agonists, and thus be important drugs for the prevention and therapy of cancer, but more detailed information on the mechanism of action and critical target cells is required. The overall goal of this exploratory grant proposal is to determine the relative contribution to cancer inflammation and tumor development of the AHR in epithelial and immune cell compartments, and to determine if AHR selective modulators suppress inflammation through actions on tumor cell or immune cell AHR. If successful these initial studies will provide the first demonstration for a role leukocyte AHR in cancer inflammation and the impetus for more detailed structure/function analysis of AHR antagonists in other cancer models that could provide important new information for use of these compounds as anti-cancer therapeutics.

描述(申请人提供)：芳香烃受体(AHR)的环境激动剂，如TCDD(二恶英)和多环芳烃，会产生慢性炎症和免疫抑制组织微环境，可促进癌症的发展。虽然AHR在肿瘤发病机制中的直接作用尚未得到证实，但最近的研究表明，在尿路上皮癌和乳腺癌中，核AHR水平的增加与肿瘤的分级有关，许多参与肿瘤细胞恶性表型的基因都直接受AHR的调控。最近，AHR通过内源性激动剂的作用在正常生理和疾病病理中发挥作用已变得明显。AHR在Th17细胞的分化以及树突状细胞和巨噬细胞等天然免疫细胞对感染、自身免疫和炎症性疾病的反应中发挥重要作用。这些生理功能可能是由新近发现的内源性AHR配体介导的。虽然AHR在肿瘤细胞中调节促炎信号已经被描述，并且AHR在正常和病理免疫功能中的重要相关性已经被证明，但关于肿瘤细胞或免疫细胞AHR在癌症引起的炎症中的作用的信息还没有。新开发的能够阻止DRE和非DRE AHR活性的AHR配体具有抑制环境或内源性激动剂响应的炎症信号的潜力，因此是预防和治疗癌症的重要药物，但需要更详细的作用机制和关键靶细胞的信息。这项探索性拨款提案的总体目标是确定研究上皮细胞和免疫细胞间的AHR在癌症炎症和肿瘤发展中的作用，并确定AHR选择性调节剂是否通过作用于肿瘤细胞或免疫细胞AHR来抑制炎症。如果成功，这些初步研究将首次证明白细胞AHR在癌症炎症中的作用，并推动在其他癌症模型中对AHR拮抗剂进行更详细的结构/功能分析，从而为将这些化合物用作抗癌治疗药物提供重要的新信息。