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

项目总结 恶性胶质瘤是一种侵袭性肿瘤，治疗后常在切除切缘内复发。在……里面 除了开发针对肿瘤细胞的靶向治疗外，针对肿瘤间质的治疗 正在考虑加强传统疗法。肿瘤相关炎症细胞，如 巨噬细胞和中性粒细胞是胶质瘤间质的重要组成部分，并积极参与。 在血管生成、侵袭和转移中起重要作用。这些髓系细胞表达模式识别受体。 如晚期糖基化终产物受体(RAGE)，它持续监测肿瘤的微观- 环境(TME)。RAGE与其配体的结合可激活多条下游通路 调节细胞的增殖、存活、分化、迁移、吞噬和自噬。在.期间 在上一个资金周期，我们证明了常见的胶质瘤RAGE配体S100B， 促进巨噬细胞募集，并将其转化为促进肿瘤的细胞。此外，我们 研究表明，TME中RAGE的基因消融通过抑制肿瘤生长，延长了荷瘤小鼠的存活时间。 相关的炎症和血管生成。这些研究还显示，在表达上存在显著的差异 动物胶质瘤模型中的其他RAGE配体。这一竞争性更新的目标是评估 RAGE通路在脑胶质瘤TME重塑和肿瘤进展中的作用。我们的中心假设是 胶质瘤释放的RAGE配体有助于炎症细胞的极化，并促进肿瘤 增长和入侵。为了测试这一点，我们提出了以下实验。在目标1中，我们将测量愤怒 以确定其在TME中的生理浓度。 目的2研究RAGE配体抑制后肿瘤炎症的变化。最后，在目标3中，我们 将确定RAGE激活对胶质瘤进展的影响并优化其抗肿瘤活性 瞄准愤怒轴心。这些研究将为RAGE途径的影响提供第一个洞察力 手术创伤治疗脑胶质瘤复发。这就迫切需要了解免疫的机制。 胶质瘤中的逃避在优化抗胶质瘤治疗方面将是有价值的。

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.