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: 9312100
• 负责人: Behnam Badie
• 金额: $ 41.09万
• 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/9312100
• 关键词: Ablation; Advanced Glycosylation End Products; 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; MAPK14 gene; 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; Recruitment Activity; 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; 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; receptor; receptor expression; receptor for advanced glycation endproducts; 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 恶性神经胶质瘤是侵袭性肿瘤，在治疗后通常会在切除边缘复发。在 除了开发针对肿瘤细胞的靶向疗法，针对肿瘤基质的治疗 被认为可以增强常规疗法。肿瘤相关的炎性细胞，例如 巨噬细胞和嗜中性粒细胞是胶质瘤基质的重要组成部分，并积极参与 在血管生成，侵袭和转移中。这些髓样细胞表达模式识别受体 例如，不断监测肿瘤微型糖基化糖化终产物（RAGE）的受体 环境（TME）。通过其配体对愤怒的参与导致多个下游途径的激活 调节细胞增殖，生存，分化，迁移，吞噬作用和自噬。在 以前的融资周期，我们证明了普通神经胶质瘤rage配体S100B的上调 促进了巨噬细胞的募集，并改变了其转化为促肿瘤细胞。此外，我们 表明，通过减弱肿瘤 - 相关的炎症和血管生成。这些研究还揭示了表达的显着差异 动物神经胶质瘤模型中的其他愤怒配体这种竞争更新的目的是评估 愤怒途径在神经胶质瘤中TME重塑和肿瘤进展中的作用。我们的中心假设是 神经胶质瘤释放有助于炎症细胞极化的愤怒配体，并促进肿瘤 生长和入侵。为了测试这一点，我们提出以下实验。在目标1中，我们将衡量愤怒 为了确定其在TME中的生理浓度，人神经胶质瘤肿瘤样品中的配体。 AIM 2将表征抑制愤怒配体后肿瘤炎症的变化。终于在AIM 3中，我们 将确定愤怒激活对神经胶质瘤进展的影响并优化 针对愤怒轴。这些研究将为愤怒途径的影响提供首次见解和 神经胶质瘤复发的手术创伤。这种迫切需要理解免疫机制 弹性瘤中的逃避对于优化抗激瘤疗法将是有价值的。