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）：恶性胶质瘤是人类最致命的癌症之一，两年生存率低于20%。虽然免疫疗法正在研究作为一种可能的治疗恶性脑肿瘤，免疫抑制胶质瘤的环境限制了这种方法的疗效。小胶质细胞（MG）和巨噬细胞（MP）作为先天性免疫反应的主动介质，构成了抵抗脑病原体的第一道细胞防御。我们的小组和其他人已经表明，MG/MPs的效应器功能似乎是通过激活STAT 3在胶质瘤中被抑制，但胶质瘤诱导STAT 3在MG/MPs中的确切机制尚不清楚。我们最近证明，MG暴露于胶质瘤因子和低（nM）水平的S100 B（一种在星形细胞瘤中高度表达的Ca 2+结合蛋白），上调晚期糖基化终产物受体（S100 B受体），诱导STAT 3，并抑制MG体外促炎功能。此外，阻断STAT 3抑制STAT 3活性在培养的MG和MG/MPs在小鼠胶质瘤。这些发现表明，TAM的失活和STAT 3的诱导，这一过程可能是通过分泌S100 B胶质瘤细胞介导的，可能发挥了重要作用。因此，我们假设MG/MP免疫功能在胶质瘤中是由S100 B通过参与的炎症和抑制这一途径可能进一步增强MG/MP促炎功能的胶质瘤。为了进一步研究这种新的胶质瘤-MG/MP相互作用，我们将首先测量i.c.神经胶质瘤脑微透析技术将用于测量啮齿动物中增殖的人神经胶质瘤中肿瘤内的TNF-α激活因子（S100 B、S100 A8、S100 A9、HMGB 1和AGEs）浓度。这些研究将提供关于S100 B和其他已知的在肿瘤微环境中分泌并可能参与MG/MP STAT 3激活的STAT 3配体的重要信息。在第二个目标中，我们将评估S100 B/P450抑制对肿瘤MP功能的影响。将选择性抑制MG/MP配体相互作用，并在鼠胶质瘤模型中研究MG/MP免疫活化。最后，在最后一个目标中，我们将研究S100 B通过肿瘤MG/MPs中的STAT 3信号通路激活STAT 3的分子机制。这些研究的结果将对目前脑肿瘤的治疗产生重大影响，因为阻断S100 B-MMP通路可能导致MG/MP激活和增强针对弥漫性胶质瘤的免疫方法。