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

描述（由申请人提供）：恶性胶质瘤是人类最致命的癌症之一，两年生存率低于20%。尽管免疫疗法正在被研究作为恶性脑肿瘤的一种可能的治疗方法，但免疫抑制胶质瘤环境限制了这种方法的疗效。作为先天免疫反应的活性介质，小胶质细胞（MG）和巨噬细胞（MPs）构成了抵御脑病原体的第一道细胞防线。我们的研究小组和其他研究人员已经表明，MG/MPs的效应功能似乎通过激活STAT3在胶质瘤中被抑制，但胶质瘤在MG/MPs中诱导STAT3的确切机制尚不清楚。我们最近证明，MG暴露于胶质瘤因子和低（nM）水平的S100B（一种在星形细胞瘤中高表达的Ca2+结合蛋白），上调晚期糖基化终产物受体（RAGE，一种S100B受体），诱导STAT3，并在体外抑制MG的促炎功能。此外，RAGE阻断抑制了培养MG和小鼠胶质瘤中MG/MPs的STAT3活性。这些发现提示RAGE通路可能在TAM失活和STAT3诱导中发挥重要作用，这一过程可能通过胶质瘤细胞分泌S100B介导。因此，我们假设S100B通过参与RAGE调节胶质瘤中MG/MP的免疫功能，抑制这一途径可能进一步增强胶质瘤中MG/MP的促炎功能。为了进一步研究这种新的胶质瘤- mg /MP相互作用，我们将首先测量脑胶质瘤中RAGE配体的水平。脑微透析技术将用于测量在啮齿动物中增殖的人胶质瘤中RAGE-激活因子（S100B、S100A8、S100A9、HMGB1和AGEs）的瘤内浓度。这些研究将为S100B和其他已知的RAGE配体提供重要信息，这些配体在肿瘤微环境中分泌，可能参与MG/MP STAT3激活。在第二个目标中，我们将评估S100B/RAGE抑制对肿瘤MP功能的影响。RAGE/RAGE配体相互作用将被选择性抑制，MG/MP免疫激活将在小鼠胶质瘤模型中进行研究。最后，在最后一个目标中，我们将研究S100B在肿瘤MG/MPs中通过RAGE通路激活STAT3的分子机制。这些研究的结果将对当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，并增强对弥漫性胶质瘤的免疫治疗方法。

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.