基于EndoMT与TAMs极化crosstalk研究西黄丸抗胶质母细胞瘤侵袭转移的分子机制

Glioblastoma is the most lethal of intra-calvariu m malignant tumorand a global burden of disease and death. Its hight proliferating and infiltrative are can’t be avoided yet. We found that tumor-associated endothelial cells (TEC) settled in Vascular niche which undergo endothelial mesenchymal transition (EndoMT) could secrete inflammatory factor, induce polarization of tumor-associated macrophage to M2 macrophage and promote the invasion and metastasis of GBM. According to traditional Chinese medical theory, “Stasis toxicity communicates residence” is the major pathogenesis of invasion and metastasis of solid tumor, we found Xihuang Pill, the representative traditional Chinese medicine formula for clearing heat and relieving toxin, showed the remarkable effect of reverse EndoMT. Based on comprehensive literatures and our previous research, we supposed that “Xihuang Pill can ameliorate stasis toxicity by regulating the crosstalk between endothelial mesenchymal transition of tumor-associated endothelial cells and macrophages polarization though Notch/IL-6/Stat3/TGF-β Axis to against invasion and metastasis of GBM”. In this study, clinical samples, cell co-culture system and animal models will be used to explore the underlying molecular mechanisms of Xihuang pill’s regulation on this crosstalk. This study will provide a new idea for studying tumor microenvironment and new experimental evidences for the application of Xihuang pill in clinical glioma therapy.

胶质母细胞瘤(GBM)是颅内常见恶性肿瘤，迄今仍无法避免其快速进展与复发转移。我们前期发现GBM血管龛中的肿瘤相关内皮细胞（TEC）经历了内皮细胞间质转化（EndoMT）并分泌大量炎性因子，诱使肿瘤相关巨噬细胞（TAM）向M2型极化，促进GBM的恶性进展。根据中医学之瘀毒传舍是实体瘤侵袭转移关键病机的理论，我们发现清热解毒名方西黄丸能逆转临床GBM患者标本中分离纯化的TEC的EndoMT过程。综合文献与本组资料，我们提出假设：西黄丸可通过Notch/IL-6/Stat3/TGF-β轴干预EndoMT和TAMs极化之间的Crosstalk，改善瘀毒传舍微环境，防治GBM侵袭转移。围绕此假设，本课题将利用临床标本、细胞共培养体系及动物模型，从分子、细胞和整体水平解析西黄丸调控该交叉对话的分子机制。本课题可为肿瘤微环境研究提供一种新的思路，同时为西黄丸在临床GBM治疗中的应用提供新的实验依据。

胶质母细胞瘤(GBM)是颅内常见恶性肿瘤，迄今仍无法避免其快速进展与复发转移。本项目对”清热解毒、活血化瘀”法（西黄丸）改善“瘀毒传舍”微环境和防治GBM侵袭转移的作用和机制进行了研究。采用体内外实验发现XHP可通过TNFR /PI3K/Akt/NF-κB通路降低肿瘤相关内皮细胞（TECs）表达TGF-β的水平，逆转EndoMT，抑制胶质瘤肿瘤组织中新生血管生成；进一步研究表明XHP 还可抑制TEC表达IL-6，干预TEC和肿瘤相关巨噬细胞（TAMs）间crosstalk，间接调控TAMs极化方向。另外，项目还检测了XHP对于肿瘤相关巨噬细胞极化的直接作用和调控机制，体内外研究表明XHP可能通过干预JAK/STATs通路下调IL-6及IL-4，进而降低M2 型TAMs的比例。综上，本研究可为肿瘤微环境研究提供一种新的研究策略，同时为西黄丸在临床GBM辅助治疗中应用提供新的实验数据和理论依据。