Suppression of Cancer Inflammation with AHR Modulators

用 AHR 调节剂抑制癌症炎症

• 批准号: 8384652
• 负责人: ADAM b GLICK
• 金额: $ 17.87万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-13 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384652
• 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

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. PUBLIC HEALTH RELEVANCE: Environmental agonists of the Aryl Hydrocarbon Receptor (AHR) such as TCDD (dioxin) and polycyclic aromatic hydrocarbons generate both chronic inflammatory and immunosuppressive responses through activation of proinflammatory gene expression that can lead to a cancer promoting tissue microenvironment. The AHR also plays a role in normal physiological process through the action of recently identified endogenous ligands, and increased levels and nuclear localization of the AHR has been linked to more aggressive cancer grade. This proposal will examine whether AHR in immune cells or tumor cells is critical for generation of cancer inflammation and whether small molecule modulators of the AHR have potential as anti-cancer therapeutics through a blockade of cancer promoting proinflammatory gene expression.

描述（由申请人提供）：芳烃受体（AHR）的环境激动剂，如TCDD（二恶英）和多环芳烃，产生慢性炎症和免疫抑制组织微环境，可促进癌症发展。虽然AHR在癌症发病机制中的直接作用尚未得到证实，但最近的研究表明，细胞核AHR水平的增加与尿路上皮癌和乳腺癌的肿瘤分级相关，并且参与肿瘤细胞恶性表型的许多基因直接受AHR调节。最近，已经证明AHR通过内源性激动剂的作用在正常生理学和疾病病理学中起作用。AHR对于促炎性Th 17细胞的分化也是至关重要的，并且在这些细胞和先天免疫细胞如树突细胞和巨噬细胞响应感染、自身免疫和炎性疾病的功能中起重要作用。这些生理功能可能是由最近鉴定的内源性AHR配体介导的。虽然已经在肿瘤细胞中描述了AHR调节的促炎信号传导，并且已经记录了AHR在正常和病理免疫功能中的关键相关性，但是没有关于肿瘤细胞或免疫细胞AHR对癌症驱动的炎症的贡献的信息。新开发的能够阻止DRE和非DRE AHR活性的AHR配体具有抑制响应于环境或内源性激动剂的炎症信号传导的潜力，因此是用于预防和治疗癌症的重要药物，但是需要关于作用机制和关键靶细胞的更详细的信息。这一探索性赠款提案的总体目标是确定相对 本发明的目的在于确定AHR选择性调节剂是否通过对肿瘤细胞或免疫细胞AHR的作用来抑制炎症。如果成功的话，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，从而为这些化合物作为抗癌治疗剂的用途提供重要的新信息。 公共卫生相关性：芳烃受体（AHR）的环境激动剂如TCDD（二恶英）和多环芳烃通过激活促炎基因表达产生慢性炎症和免疫抑制反应，这可导致促癌组织微环境。AHR还通过最近鉴定的内源性配体的作用在正常生理过程中发挥作用，并且AHR的水平和核定位的增加与更具侵袭性的癌症等级有关。该提案将研究免疫细胞或肿瘤细胞中的AHR是否对癌症炎症的产生至关重要，以及AHR的小分子调节剂是否具有通过阻断癌症促进促炎基因表达作为抗癌治疗剂的潜力。