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

高级糖基化终产物 (RAGE) 通路受体在脑肿瘤中的作用

• 批准号: 9899943
• 负责人: Behnam Badie
• 金额: $ 40.76万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899943
• 关键词: Ablation; Affect; Aftercare; Alternative Splicing; Animal Model; Animals; Attenuated; Autophagocytosis; Biometry; Brain Neoplasms; Cell Adhesion Molecules; Cell Proliferation; Cells; Combined Modality Therapy; Data; Development; Diagnosis; Engineering; Environmental Risk Factor; Excision; Funding; Genetic; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; HMGB1 gene; Heterogeneity; Human; Immune; Immune Evasion; Inflammation; Inflammatory; Inflammatory Response; Intervention; Kinetics; Lead; Leukocyte Trafficking; Ligands; Malignant Glioma; Mass Spectrum Analysis; Measures; Microglia; Modeling; Monitor; Mus; Myelogenous; Neoplasm Metastasis; Observational Study; Operative Surgical Procedures; Pathway interactions; Patients; Pattern recognition receptor; Phagocytosis; Pharmacology; Phenotype; Physiological; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Inhibition; Recurrence; Regulation; Resected; Role; S100A8 gene; S100A9 gene; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Toll-like receptors; Trauma; Tumor Cell Invasion; Tumor-associated macrophages; Up-Regulation; Variant; Viral Vector; activation product; angiogenesis; chemokine; conventional therapy; cytokine; experimental study; glycation; improved; insight; macrophage; migration; multidisciplinary; neoplastic cell; neuro-oncology; neuroimmunology; neurosurgery; neutrophil; novel strategies; p38 Mitogen Activated Protein Kinase; receptor expression; receptor for advanced glycation endproducts; recruit; soluble RAGE; success; targeted treatment; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY Malignant gliomas are aggressive tumors that often recur within the resection margin after treatment. In addition to the development of targeted therapies against neoplastic cells, treatments aimed at tumor stroma are being considered to enhance conventional therapies. Tumor-associated inflammatory cells, such as macrophages and neutrophils, comprise a significant component of the glioma stroma and actively participate in angiogenesis, invasion and metastasis. These myeloid-derived cells express pattern recognition receptors such as the receptor for advanced glycation endproducts (RAGE) that constantly monitor the tumor micro- environment (TME). Engagement of RAGE by its ligands results in activation of multiple downstream pathways that regulate cell proliferation, survival, differentiation, migration, phagocytosis and autophagy. During the previous funding cycle, we demonstrated that upregulation of a common glioma RAGE ligand, S100B, promoted macrophage recruitment and altered their conversion into tumor-promoting cells. Furthermore, we showed that genetic ablation of RAGE in TME prolonged survival of glioma-bearing mice by attenuating tumor- associated inflammation and angiogenesis. These studies also revealed significant variability in the expression of other RAGE ligands in animal glioma models. The objective of this competing renewal is to evaluate the role of the RAGE pathway on TME remodeling and tumor progression in gliomas. Our central hypothesis is that gliomas release RAGE ligands that contribute to the polarization of inflammatory cells, and promote tumor growth and invasion. To test this, we propose the following experiments. In Aim 1 we will measure RAGE ligands in human glioma tumor samples in order to determine their physiological concentrations in the TME. Aim 2 will characterize changes in tumor inflammation after inhibition of RAGE ligands. Finally in Aim 3, we will determine the effect of RAGE activation on glioma progression and optimize the antitumor activity of targeting the RAGE axis. These studies will provide the first insights into the effect of the RAGE pathway and surgical trauma on glioma recurrence. This critically needed understanding of the mechanism of immune evasion in gliomas will be valuable in optimizing antiglioma therapies.

项目摘要 恶性胶质瘤是一种侵袭性肿瘤，治疗后常在切除边缘复发。在 除了针对肿瘤细胞的靶向治疗的发展外，针对肿瘤间质的治疗 正在考虑加强传统疗法。肿瘤相关炎性细胞，如 巨噬细胞和嗜中性粒细胞构成神经胶质瘤基质的重要组成部分，并积极参与 血管生成、侵袭和转移。这些髓源性细胞表达模式识别受体 如晚期糖基化终末产物受体（AGEs），它持续监测肿瘤微- 环境（TME）。通过其配体的结合导致多个下游途径的激活 其调节细胞增殖、存活、分化、迁移、吞噬作用和自噬。期间 上一个资金周期，我们证明了一种常见的胶质瘤配体S100 B， 促进巨噬细胞募集并改变它们转化为促肿瘤细胞。而且我们 表明，基因切除TME中的TME可以通过减少肿瘤的生长， 相关的炎症和血管生成。这些研究还揭示了表达的显着变异性 在动物神经胶质瘤模型中的其他配体。这种竞争性更新的目的是评估 神经胶质瘤中TME重塑和肿瘤进展中的TME通路的作用。我们的核心假设是 神经胶质瘤会释放导致炎症细胞极化的配体， 生长和入侵。为了验证这一点，我们提出了以下实验。在目标1中，我们将测量 在一些实施方案中，本发明提供了人神经胶质瘤肿瘤样品中的配体以确定它们在TME中的生理浓度。 目的2将描述抑制TNF配体后肿瘤炎症的变化。在目标3中，我们 将确定CD 45活化对胶质瘤进展的影响，并优化CD 45的抗肿瘤活性。 瞄准了横轴这些研究将首次深入了解β-淀粉样蛋白途径的作用， 手术创伤对胶质瘤复发影响。这迫切需要了解免疫的机制， 在胶质瘤中的逃避将在优化抗胶质瘤疗法中是有价值的。