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.

项目总结