胶质瘤中PAFR通过募集骨髓源性巨噬细胞并诱导其M2型极化促进肿瘤恶性进展的机制研究

Tumor associated microenviroment plays a pivotal role in tumor progression. Recent study showed that the infiltration and M2 polarization of bone marrow-derived macrophages (BMDMs) has a close relationship with glioma progression. However, the underlying machinery through which glioma cells regulate and educate BMDMs is still illusive. Previously we have reveled that PAFR promoted tumor progression in multitudes of cancers, which has been published in Oncogene and Cancer research. In the recent work, we discovered that PAFR was upregulated in gliomas. The overexpression of PAFR positively correlated with tumor grades and inversely correlated with outcome. Further study showed that PAFR could potentially induce infiltration and M2 polarization of the BMDMs via activated G protein and Src/AKT signal, thus mediating glioma malignant progression. As we known, this is the first time that study reveal the critical role of PAFR in the regulation of crosstalk between tumor and microenviroment. Such a finding will break through the restrain of traditional views which merely focused on tumor cells alone. More importantly, our findings will also provide a novel therapeutic target for glioma patients, as well as solid theoretical and experimental proofs.

微环境是介导肿瘤恶性进展的重要因素之一。最新研究显示，骨髓源性巨噬细胞（BMDMs）的浸润及M2型极化与胶质瘤恶性进展密切相关，然而胶质瘤通过何种机制调控并驯化BMDMs至今未明。申请者以往发表在cancer research及oncogene期刊上的成果表明PAFR促进多种肿瘤恶性进展。近期我们发现PAFR在胶质瘤中也存在高表达，且与其病理级别、患者不良预后密切相关。深入研究发现，PAFR可通过G蛋白激活肿瘤细胞中Src/AKT信号，并可调控BMDMs的迁移与M2型极化。综上，我们提出如下假设：PAFR通过小G蛋白/Src/AKT信号轴，上调多种因子表达、分泌，介导BMDMs的募集和M2型极化，从而促进胶质瘤恶性进展。本研究将突破以往仅局限于关注肿瘤细胞本身的认识，有望首次揭示PAFR调控胶质瘤细胞与微环境互作的机制，为临床制定抗胶质瘤恶性进展的靶向治疗策略提供实验依据。

胶质瘤作为原发中枢神经系统肿瘤中发病率最高的恶性肿瘤，如何改善其预后是神经外科界亟待解决的难题。尽管以显微外科为主导的多模态治疗在近年来取得了长足进步，然而胶质瘤患者的中位生存期仍仅有12-15个月。探索介导胶质瘤恶性进展的重要分子，深入研究其作用机制，是寻找胶质瘤靶向治疗方案、提高患者总体疗效的关键。申请者一直专注于胶质瘤发生、发展的相关研究，前期工作发现PAFR在胶质瘤中发挥着重要的癌基因作用，其可能参与肿瘤微环境的重塑，然而分子机制不甚明确。本项目围绕PAFR调控肿瘤细胞/骨髓源性巨噬细胞（BMDMs）互作，进而促进胶质瘤恶性进展这一科学问题，系统性、创新性地开展科研工作，产出了较为理想的实验结果。..本项目主要研究内容为：验证PAFR参与调控胶质瘤恶性表型，阐明其调控BMDMs介导肿瘤微环境重塑的分子机制，发现肿瘤细胞/微环境互作协同促进胶质瘤恶性进展。..本项目的重要结果、关键数据：.1.PAFR可调控胶质瘤细胞生长、侵袭、能量代谢等多种恶性表型，并参与影响炎症因子的表达与分泌；.2. PAFR-AKT信号轴可通过分泌炎症因子，进而介导BMDMs发生M2型极化；.3.M2型极化后的BMDMs可反馈性增强胶质瘤细胞的侵袭能力。..本项目的科学意义：本研究从多层面证实了PAFR在胶质瘤中的重要癌基因作用，阐明了其通过介导胶质瘤细胞/BMDMs互作，协同促进胶质瘤恶性进展的分子机制，为研究关键癌分子调控胶质瘤恶性进展的机制提供了实验依据，并对PAFR在胶质瘤诊疗中的临床转化提供了理论基础。