基于SDF-1/CXCR4生物轴介导CAFs调控肺癌转移作用机制探讨臭牡丹黄酮类化合物干预作用

Tumor microenvironment plays an important role in lung cancer metastasis.Tumor associated fibroblasts (CAFs) which is the main stromal cells in lung cancer microenvironment can restore the tumor microenvironment and act on the adjacent tumor cells to promote transfer. The SDF-1 / CXCR4 biological axis is the messenger of CAFs and tumor cell interactions, can be mediated CAFs promote lung migration, adhesion and invasion.With the Clerodendrum bungei flavonoids has an effective intervention in lung cancer metastasis, We speculate its effect of Detoxification and scattered stasis is to improve the tumor microenvironment. With pharmacological effects in anti-inflammatory and anti-tumor of Clerodendrum bungei flavonoids, the study take SDF-1 as a breakthrough point, establish CAFs and A549 co-culture system in vitro, and the A549 -GFP mix CAFs injected into nude mice to establish nude mouse lung transplantation tumor model in vivo, with the Clerodendrum bungei flavonoids intervention, to observe the the influence on invasion and metastasis of tumor cells and the regulatory mechanism of SDF-1/CXCR4 axis, to clarify intervention mechanism of Clerodendrum bungei flavonoids in lung cancer metastasis.

肿瘤微环境在肺癌转移中发挥着重要作用，肿瘤相关成纤维细胞(CAFs)是肺癌微环境中最主要的基质细胞，能重塑肿瘤微环境，作用于邻近的肿瘤细胞促进转移。趋化因子SDF-1及其受体CXCR4组成的SDF-1/CXCR4生物轴是CAFs与肿瘤细胞发生交互作用的信使，能介导CAFs促进肺癌迁移、黏附、侵袭。我们发现臭牡丹黄酮类化合物能有效干预肺癌转移，推猜其解毒散瘀之功效在于改善肿瘤微环境，基于其具有抗炎抗肿瘤药理作用，本研究以趋化因子SDF-1作为切入点，体外建立CAFs和A549共培养体系，体内采用A549-GFP混合CAFs注入裸鼠体内的方法建立裸鼠肺癌移植瘤模型，观察臭牡丹黄酮类化合物对肿瘤细胞的侵袭转移力的影响和SDF-1/CXCR4轴的调控机制，以阐明臭牡丹黄酮类化合物干预肺癌转移的作用机理。

肺癌微环境在肺癌转移中发挥重要作用，基于臭牡丹黄酮类化合物具有抗炎拮抗肺癌转移的作用，本项目以基质衍生因子SDF-1入手从肿瘤微环境中SDF-1/CXCR4生物轴介导CAFs调控肺癌转移的角度探讨臭牡丹黄酮类化合物干预作用。本项目体外实验建立CAFs和A549共培养体系，揭示SDF-1/CXCR4信号轴介导CAFs诱导A549迁移、黏附、侵袭的作用机制以及臭牡丹黄酮类化合物的干预作用。体内实验采用A549+HFL1细胞注入裸鼠腋下的方法建立裸鼠肺癌移植瘤模型，观察臭牡丹黄酮类化合物对肺癌转移的影响以及SDF-1/CXCR4信号轴的调控机理。实验结果显示肿瘤微环境中肺癌细胞对成纤维细胞具有活化作用，活化的成纤维细胞分泌SDF-1结合肺癌细胞上的CXCR4受体激活SDF-1/CXCR4生物轴调控PI3K/AKT-VEGF，MEK/ERK-MMP9通路，促进肿瘤细胞EMT，促进血管生成和细胞外基质溶解提高肺癌细胞转移力，臭牡丹黄酮类化合物能抑制CAF分泌SDF-1，抑制SDF-1/CXCR4生物轴关键因子pAKT，CXCR4，ERK，MEK，PI3K，进而影响VEGF，MMP9的生成，改善肿瘤微环境，抑制肺癌细胞侵袭转移，本研究为中医药拮抗肺癌转移提供了实验依据。