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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要恶性神经胶质瘤是一种侵袭性肿瘤，通常在治疗后在切除边缘内复发。在除了开发针对肿瘤细胞的靶向疗法外，还针对肿瘤基质进行治疗正在考虑加强传统疗法。肿瘤相关炎症细胞，例如巨噬细胞和中性粒细胞是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。这些骨髓来源的细胞表达模式识别受体例如持续监测肿瘤微量的晚期糖基化终末产物受体（RAGE）环境（TME）。 RAGE 与其配体的结合导致多个下游途径的激活调节细胞增殖、存活、分化、迁移、吞噬作用和自噬。期间在之前的资助周期中，我们证明了常见神经胶质瘤 RAGE 配体 S100B 的上调，促进巨噬细胞募集并改变其转化为促肿瘤细胞。此外，我们研究表明，TME 中 RAGE 的基因消除通过减弱肿瘤抑制作用，延长了患有神经胶质瘤的小鼠的生存期。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动物神经胶质瘤模型中其他 RAGE 配体的研究。此次竞争性更新的目的是评估 RAGE 通路在胶质瘤 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 RAGE 配体，有助于炎症细胞的极化，并促进肿瘤生长生长和侵袭。为了测试这一点，我们提出以下实验。在目标 1 中，我们将测量 RAGE 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。目标 2 将表征抑制 RAGE 配体后肿瘤炎症的变化。最后在目标 3 中，我们将确定 RAGE 激活对神经胶质瘤进展的影响并优化其抗肿瘤活性针对 RAGE 轴。这些研究将首次深入了解 RAGE 通路的影响以及手术创伤对神经胶质瘤复发的影响。这迫切需要了解免疫机制神经胶质瘤的逃避对于优化抗神经胶质瘤治疗非常有价值。