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

高级糖基化终产物 (RAGE) 通路受体在脑肿瘤中的作用

• 批准号: 8707217
• 负责人: Behnam Badie
• 金额: $ 33.81万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707217
• 关键词: Acute; Advanced Glycosylation End Products; Astrocytoma; Binding; Binding Proteins; Brain; Brain Neoplasms; Brain Pathology; Carbon Nanotubes; Cells; Cerebrum; Combined Modality Therapy; Development; Diffuse; Disease; Environment; Gene Expression; Glioma; Goals; Growth; HMGB1 gene; Human; Hypoxia; Immune; Immune response; Immune system; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knowledge; Lead; Ligands; MAP Kinase Gene; MAPK3 gene; Macrophage Activation; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Mediator of activation protein; Membrane; Microdialysis; Microglia; Modeling; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Oxidative Stress; Pathway interactions; Patients; Play; Process; Proteins; Receptor Activation; Receptor Inhibition; Regulation; Research; Rodent; Role; S100A8 gene; S100A9 gene; STAT3 gene; Small Interfering RNA; Stroke; Surface; TYK2; Techniques; Testing; Therapeutic; Trauma; Vascular blood supply; angiogenesis; conventional therapy; cytokine; glycation; immune activation; immune function; immunoregulation; improved; inhibitor/antagonist; innate immune function; innovation; innovative technologies; macrophage; monocyte; nanoparticle; neoplastic cell; novel; pathogen; receptor; receptor for advanced glycation endproducts; response; response to injury; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): With a two-year survival of less than 20%, malignant gliomas are among the most fatal cancers in humans. Although immunotherapy is being studied as a possible treatment for malignant brain tumors, the immunosuppressive glioma environment has limited the efficacy of this approach. As active mediators of the innate immune response, microglia (MG) and macrophages (MPs) constitute the first line of cellular defense against brain pathogens. Our group and others have shown that the effector function of MG/MPs appears to be suppressed in gliomas through activation of STAT3, yet the exact mechanism by which gliomas induce STAT3 in MG/MPs is unknown. We recently demonstrated that exposure of MG to glioma factors and to low (nM) levels of S100B, a Ca2+binding protein that is highly expressed in astrocytomas, upregulated receptor for advanced glycation end products (RAGE, a S100B receptor), induced STAT3, and inhibited MG proinflammatory function in vitro. Furthermore, blockage of RAGE inhibited STAT3 activity in cultured MG and in MG/MPs in murine gliomas. These findings suggest that the RAGE pathway may play an important role in TAM inactivation and STAT3 induction, and that this process may be mediated through secretion of S100B by glioma cells. Thus, we hypothesize that MG/MP immune function in gliomas is modulated by S100B through engagement of RAGE and inhibition of this pathway may further enhance MG/MP pro-inflammatory function in gliomas. To further study this novel glioma-MG/MP interaction, we will first measure levels of RAGE ligands in i.c. gliomas. Cerebral microdialysis technique will be used to measure intratumoral concentrations of RAGE- activating factors (S100B, S100A8, S100A9, HMGB1, and AGEs) in human gliomas propagated in rodents. These studies will provide important information on S100B and other known RAGE ligands that are secreted in the tumor microenvironment and potentially involved in MG/MP STAT3 activation. In the second aim, we will evaluate the effect of S100B/RAGE inhibition on tumor MP function. RAGE/RAGE ligand interactions will be selectively inhibited and MG/MP immune activation will be studied in murine glioma models. Finally, in the last aim, we will study the molecular mechanisms by which S100B activates STAT3 through the RAGE pathway in tumor MG/MPs. Results from these studies will have significant impact on current treatment of brain tumors as blockage of S100B-RAGE pathway may lead to MG/MP activation and enhancement of immunotherapeutic approaches against diffuse gliomas.

描述(申请人提供)：恶性胶质瘤是人类最致命的癌症之一，两年存活率不到20%。虽然免疫疗法正在被研究作为一种可能的治疗恶性脑瘤的方法，但免疫抑制的胶质瘤环境限制了这种方法的有效性。小胶质细胞(MG)和巨噬细胞(MPS)作为天然免疫反应的活性介质，构成了抵御脑内病原体的第一道细胞防线。我们和其他人已经证明，在胶质瘤中，MG/MPS的效应功能似乎是通过激活STAT3而受到抑制，但胶质瘤在MG/MPS中诱导STAT3的确切机制尚不清楚。我们最近证实，MG暴露在胶质瘤因子和低水平(NM)的S100B(一种在星形细胞瘤中高表达的钙结合蛋白)中，上调了晚期糖基化终产物受体(RAGE，一种S100B受体)，在体外诱导STAT3，并抑制MG的促炎功能。此外，阻断RAGE可抑制培养的MG和小鼠脑胶质瘤MG/MPS中STAT3的活性。这些结果提示RAGE通路可能在失活和STAT3诱导中起重要作用，这一过程可能是通过胶质瘤细胞分泌S100B而介导的。因此，我们推测S100B通过RAGE参与调节胶质瘤的MG/MP免疫功能，抑制这一途径可能进一步增强胶质瘤的MG/MP促炎功能。为了进一步研究这种新的胶质瘤-MG/MP相互作用，我们将首先测量I.C.中RAGE配体的水平。神经胶质瘤。脑微透析技术将被用来检测在啮齿动物体内传播的人脑胶质瘤中RAGE激活因子(S100B、S100A8、S100A9、HMGB1和AGEs)的浓度。这些研究将为S100B和其他已知的RAGE配体提供重要的信息，这些配体分泌在肿瘤微环境中，可能参与MG/MP STAT3的激活。在第二个目的中，我们将评估S100B/RAGE抑制对肿瘤MP功能的影响。RAGE/RAGE配体的相互作用将被选择性地抑制，MG/MP免疫激活将在小鼠脑胶质瘤模型中进行研究。最后，我们将研究S100B通过RAGE途径激活肿瘤MG/MPS中STAT3的分子机制。这些研究结果将对目前脑肿瘤的治疗产生重大影响，因为阻断S100B-RAGE通路可能导致MG/MP激活，并加强对弥漫性胶质瘤的免疫治疗。