Role of Receptor for Advanced Glycation End Product (RAGE) Pathway in Brain Tumor

高级糖基化终产物 (RAGE) 通路受体在脑肿瘤中的作用

• 批准号: 8890797
• 负责人: Behnam Badie
• 金额: $ 34.86万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890797
• 关键词: Acute; Advanced Glycosylation End Products; Astrocytoma; Binding; Binding Proteins; Brain; Brain Neoplasms; Brain Pathology; Carbon Nanotubes; Cells; Cerebrum; Combined Modality Therapy; Development; Diffuse; Disease; Environment; Gene Expression; Glioma; Goals; Growth; HMGB1 gene; Human; Hypoxia; Immune; Immune response; Immune system; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knowledge; Lead; Ligands; MAP Kinase Gene; MAPK3 gene; Macrophage Activation; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Mediator of activation protein; Membrane; Microdialysis; Microglia; Modeling; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Oxidative Stress; Pathway interactions; Patients; Play; Process; Proteins; Receptor Activation; Receptor Inhibition; Regulation; Research; Rodent; Role; S100A8 gene; S100A9 gene; STAT3 gene; Small Interfering RNA; Stroke; Surface; TYK2; Techniques; Testing; Therapeutic; Trauma; Vascular blood supply; angiogenesis; conventional therapy; cytokine; glycation; immune activation; immune function; immunoregulation; improved; inhibitor/antagonist; innate immune function; innovation; innovative technologies; macrophage; monocyte; nanoparticle; neoplastic cell; novel; pathogen; receptor; receptor for advanced glycation endproducts; response; response to injury; targeted treatment; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): With a two-year survival of less than 20%, malignant gliomas are among the most fatal cancers in humans. Although immunotherapy is being studied as a possible treatment for malignant brain tumors, the immunosuppressive glioma environment has limited the efficacy of this approach. As active mediators of the innate immune response, microglia (MG) and macrophages (MPs) constitute the first line of cellular defense against brain pathogens. Our group and others have shown that the effector function of MG/MPs appears to be suppressed in gliomas through activation of STAT3, yet the exact mechanism by which gliomas induce STAT3 in MG/MPs is unknown. We recently demonstrated that exposure of MG to glioma factors and to low (nM) levels of S100B, a Ca2+binding protein that is highly expressed in astrocytomas, upregulated receptor for advanced glycation end products (RAGE, a S100B receptor), induced STAT3, and inhibited MG proinflammatory function in vitro. Furthermore, blockage of RAGE inhibited STAT3 activity in cultured MG and in MG/MPs in murine gliomas. These findings suggest that the RAGE pathway may play an important role in TAM inactivation and STAT3 induction, and that this process may be mediated through secretion of S100B by glioma cells. Thus, we hypothesize that MG/MP immune function in gliomas is modulated by S100B through engagement of RAGE and inhibition of this pathway may further enhance MG/MP pro-inflammatory function in gliomas. To further study this novel glioma-MG/MP interaction, we will first measure levels of RAGE ligands in i.c. gliomas. Cerebral microdialysis technique will be used to measure intratumoral concentrations of RAGE- activating factors (S100B, S100A8, S100A9, HMGB1, and AGEs) in human gliomas propagated in rodents. These studies will provide important information on S100B and other known RAGE ligands that are secreted in the tumor microenvironment and potentially involved in MG/MP STAT3 activation. In the second aim, we will evaluate the effect of S100B/RAGE inhibition on tumor MP function. RAGE/RAGE ligand interactions will be selectively inhibited and MG/MP immune activation will be studied in murine glioma models. Finally, in the last aim, we will study the molecular mechanisms by which S100B activates STAT3 through the RAGE pathway in tumor MG/MPs. Results from these studies will have significant impact on current treatment of brain tumors as blockage of S100B-RAGE pathway may lead to MG/MP activation and enhancement of immunotherapeutic approaches against diffuse gliomas.

描述（由申请人提供）：恶性神经胶质瘤是人类最致命的癌症之一，为期两年的生存率不到20％。尽管正在研究免疫疗法是对恶性脑肿瘤的可能治疗方法，但免疫抑制神经胶质瘤环境限制了这种方法的疗效。作为先天免疫反应的主动介体，小胶质细胞（MG）和巨噬细胞（MPS）构成了针对脑病原体的细胞防御的第一线。我们的小组和其他人表明，Mg/MPS的效应子功能似乎通过激活STAT3抑制了胶质瘤，但是胶质瘤诱导Mg/MPS中STAT3的确切机制尚不清楚。我们最近证明，MG暴露于神经胶质瘤因子和低（NM）水平S100B，S100B，S100B，一种Ca2+结合蛋白，在星形胶质细胞瘤中高度表达，晚期糖化终终产物（RAGE，S100B受体）的受体上调受体，STAT3，诱导的STAT3，诱导的STAT3，并抑制MG MG Proinmy proinmanfammanmation Floflammant foldromplammation Floflammation。此外，在鼠神经胶质瘤中的培养的MG和Mg/MPS中的愤怒阻塞抑制了STAT3活性。这些发现表明，愤怒途径可能在TAM失活和STAT3诱导中起重要作用，并且该过程可以通过神经胶质瘤细胞的S100B分泌来介导。因此，我们假设胶质瘤中的Mg/MP免疫功能是通过S100B通过愤怒的参与而调节的，并且抑制该途径可能会进一步增强胶质瘤中的MG/MP促炎功能。为了进一步研究这种新型神经胶质瘤/MP的相互作用，我们将首先测量I.C.的愤怒配体水平。神经胶质瘤。脑微透析技术将用于测量在啮齿动物中传播的人神经膜瘤中的愤怒激活因子（S100B，S100A8，S100A9，HMGB1和AGES）的肿瘤内浓度。这些研究将提供有关肿瘤微环境中分泌的S100B和其他已知愤怒配体的重要信息，并可能参与MG/MP STAT3激活。在第二个目标中，我们将评估S100B/RAGE抑制对肿瘤MP功能的影响。愤怒/愤怒的配体相互作用将被选择性抑制，并将在鼠神经胶质瘤模型中研究Mg/MP免疫激活。最后，在最后一个目标中，我们将研究S100B通过肿瘤MG/MPS的愤怒途径激活STAT3的分子机制。这些研究的结果将对当前对脑肿瘤的治疗产生重大影响，因为S100B-RAGE途径的阻塞可能导致MG/MP激活并增强针对弥漫性胶质瘤的免疫治疗方法。